04 August 2009

Mechanism of Bone Metastases



Mechanism of Bone Metastases
by: Dr.Priya Gopalan

Outline
* Background
* Predictors of metastasis to bone
* Tumor cell homing to bone
* Tumor cell interaction with bone
* Therapeutic interventions

Bone Metastases
Types of bone metastases
Diagnosis
* Bone scan - best for osteoblastic lesions
* MRI
* CT scan with bone windows
* PET-CT
* Plain films
* Markers of bone turnover

Prognosis
Relative risk ratios during zoledronic acid therapy
(skeletal-related events)
NSCLC and solid tumors
High vs. low NTX levels
Reasons for preferential metastasis to bone
* Highly vascular organ (sluggish blood flow)
* Paget’s “seed-and-soil” hypothesis
o Bone marrow niche provides:
+ Chemotactic signal to home (e.g. SDF-1)
+ Adhesion receptors to extravasate
+ Growth factors to proliferate (e.g. TGF-b, IGF-1)
Predictors of metastasis to bone (Breast Cancer)
Tumor cell homing
* Organs that are primary sites of breast cancer metastasis produce high levels of SDF-1
* Blocking CXCR4 in vitro inhibited prostate cancer migration through bone marrow endothelial cells
* Blocking CXCR4 in vivo reduces bone metastases in breast and prostate cancers
* CXCR4/ SDF-1 axis also important in
o NSCLC:
o RCC:
* Integrins may also direct organ-specific mets
o When avb3 is overexpressed on breast cancer cells, bone metastases are enhanced
o CXCR4 binding to SDF-1 activates avb3 and mediates its binding to endothelial cells
o avb3 antagonist inhibits bone colonization by avb3-expressing tumor cells
o a2b1 on prostate cancer cells supports bone colonization
* Other chemokines produced by OBs
o Osteopontin
o Bone sialoprotein

Normal bone remodeling
Osteoprotegerin
Osteoblasts/osteoclasts interaction with tumor cells
Osteomimicry by tumor cells
Therapeutic targets
* Osteoblastic lesions
o Endothelin-1 (anti-receptor antibody)
* Osteolytic lesions
o Bisphosphonates
o RANKL (anti-RANKL antibody)
o PTHrP
o Osteoprotegerin (Fc-OPG)
* Endothelin A receptor inhibitor, Atrasentan
o M00-211 trial - Double-blinded, randomized, multi-institutional placebo-controlled Phase III trial with 809 patients with hormone-resistant metastatic prostate cancer

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Cutaneous Toxicities of Cancer Therapy



Cutaneous Toxicities of Cancer Therapy
By:Dr.Saiama Waqar

Outline
* Alopecia
* Hyperpigmentation
* Hand-foot syndrome
* Radiation sensitivity and recall
* Hypersensitivity
* Nail dystrophies
* Extravasation injuries
* Skin toxicity from targeted therapies
* Conclusion

Alopecia
* Drugs that target rapidly dividing cells often affect the proliferating cells in the hair follicle
* Terminal hair follicles with rapid matrix formation more affected (scalp more than body hair, eyebrows, eyelashes)
o completely lost in a short time: transplant
o gradually lost over several weeks: cyclic chemotherapy
* Methotrexate: affects the follicle melanocytes, resulting in depigmented band of hair, “flag sign”
* Visible regrowth within 3-6 months
* Often regrows with a change in color or texture (switching from straight to curly), mechanism of change unclear
* Psychologically, one of the most stressful side effects

Grading of alopecia
Grade
Minimal loss, grade 1
< 25%; obvious to the patient but not necessarily to others

Moderate loss, grade 2
25 to 50 %; obvious thinning of scalp hair but not enough to lead to the use of a wig or alternate head covering

Severe loss, grade 3

> 50% of hair lost; generally indicates the need for a wig or alternate head covering in those for whom alopecia is a major concern

Chemotherapy drugs causing alopecia

* Often
o Bleomycin
o Etoposide
o Methotrexate
o Mitoxantrone
o Paclitaxel
* Common
o Cyclophosphamide
o Daunorubicin
o Doxorubicin
o Docetaxel
o Idarubicin
o Ifosphamide
o Paclitaxel
* Infrequent
o 5-FU
o Hydroxyurea
o Thiotepa
o Vinblastine
o Vincristine
o Vinorelbine
* Rare
o procarbazine

Prevention of alopecia
* scalp tourniquets:
o pneumatic device placed around the hairline during chemo infusion
o inflated to a pressure >SBP
o Several studies: effective for preventing hair loss
+ utilized different techniques, variation in chemotherapy regimens, tourniquet pressure, sample size, and criteria to assess alopecia (data difficult to interpret)
o Side effects: headache, varying degrees of nerve compression

Prevention of alopecia
* Hypothermia with scalp icing devices:
o Vasoconstriction of scalp blood vessels, less absorption of chemo as hair follicles less metabolically active at 24C
o ice turban, gel packs, cool caps, thermocirculator, room air conditioner
o 50-80% response, though variable chemotherapy regimens and definitions of alopecia, small sample size
* Not effective in liver disease
o Delayed drug metabolism, persistent levels beyond protective period
* Scalp metastases:
o mycosis fungoides, limited to scalp. CR after chemo without scalp cooling
o 61 pts with met breast cancer and liver dysfunction, 1 pt scalp met

Preventive devices
* 1990- FDA stopped sale of these devices citing absence of safety or efficacy data
* Cranial prostheses (wigs) and scarves use encouraged

Pharmacologic interventions for alopecia
* Topical minoxidil (shorten time to maximum regrowth, did not prevent alopecia)
* AS101(NSCLC pts: garlic-like halitosis and post-infusion fevers)
* Alpha tocopherol (cardioprotection for doxorubicin, noted less alopecia)
* Topical calcitriol (cell lines- protects cancer cells)
* IL-1(rats, cytarabine, cell cycle specific, protected)
* Inhibitors of p53 (mice deficient p53, no alopecia)

Hyperpigmentation
* usually resolves with drug discontinuation
o gingival margin pigmentation seen with cyclophosphamide is usually permanent
* Patterns of pigmentation:
o Diffuse
o Local at site of infusion
* Sites of pressure /trauma
o Hydrea and cisplatin
* Busulfan
o “busulfan tan” can mimic Addison's disease.
o Although busulfan can also cause adrenal insufficiency, the skin change is 2/2 toxic effect on melanocytes
o Distinguish busulfan toxicity from true Addison's disease by normal levels of MSH & ACTH
* Liposomal doxorubicin
o macular hyperpigmentation over the trunk and extremities, including the palms and soles
o not been described with unencapsulated doxorubicin

Drugs causing hyperpigmentation

HAND-FOOT SYNDROME
* also known as palmar–plantar erythrodysesthesia (PPE)
* originally described in patients receiving high-dose cytarabine
* skin lesions begin as erythema and edema of the palms or soles and is associated with sensitivity to touch or paresthesia
* can progress to desquamation of the affected areas and significant pain

Hand foot syndrome
Acral erythema from docetaxel

Pathogenesis
* Unclear: small capillaries in the palms and soles rupture with increased pressure from walking or use, creating an inflammatory reaction
* formulation of drugs and duration of exposure can impact the incidence
o liposome-encapsulated doxorubicin more than standard formulation
o 5-FU bolus lower than CIVI and capecitabine (converted into 5-FU in vivo)

Hand foot syndrome Grading
Grade
Signs and symptoms

1 Minimal skin changes or dermatitis (eg, erythema) without pain
2 Skin changes (eg, peeling, blisters, bleeding, edema) or pain, not interfering with function
3 Skin changes with pain, interfering with function

Treatment
* No proven preventive therapy
o Pyridoxine (vitamin B6) may help reduce the incidence and severity
o Celecoxib reported to reduce incidence
* Management largely symptomatic with reduction of drug doses where appropriate
* emollients and protective gloves can be helpful

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Acute Intermittent Porphyria



Acute Intermittent Porphyria
Heme/Onc Grand Rounds
By:Jane Chawla, M.D.

History of Present Illness
Physical Exam & Laboratory Data

* VS: T 36.2 P 142 R 20 BP 178/112
* Gen: Sleepy but arousable, AxO x3
* HEENT: PERRL, EOMI, OP Clear
* Neck: Supple, no LAD
* CV: tachy, regular rhythm, no m/g/r
* Lungs: CTAB
* GI: soft, ND, mild periumbilical discomfort to palpation
* Extr: no c/c/e
* Skin: No rashes or skin lesion
* Neuro: CN II-XII intact, strength 4/5 throughout, paresthesia in bilat lower extremities, 2+ reflexes, upgoing toes



Labs:
Random Problem List?
* Hyponatremia
* Tachycardia
* Hypertension
* Elevated Creatinine
* Abdominal Pain
* Transaminitis
* Weakness
* Cortisol – wnl
Cosyntropin Stim Test – wnl
Urine lytes → SIADH
* EKG – sinus tachycardia
CT Angio (-)
Urine VMA/metanephrine (-)
* Renal Ultrasound – wnl
responded to fluids
* LFTs – Mild transaminitis
CT Abdomen/Pelvis (-)
Hepatitis panel (-)

PORPHYRIA
Heme central to understanding Porphria
* Heme is part of hemoglobin, myoglobin, catalases, peroxidases, and cytochromes
* Heme is made in every human cell (85% in erythroid cells & much of the rest in the liver)
* First enzyme in heme synthesis pathway is ALA synthetase (ALAS)
* Increase demand induces ALAS
* Heme downregulates ALAS by feedback inhibition
* Partial block in this pathway induces ALAS and causes accumulation of heme precursors upstream from block

Porphyria is a disruption in the heme pathway
* Group of metabolic diseases resulting from a partial deficiency of an enzyme in the heme biosynthetic pathway
* Seven enzymes in the pathway
* Four of the porphyrias cause acute attacks
* Increased demand for heme can precipitate attacks secondary to overproduction of toxic heme precursors (porphyrins, ALA)
* The porphyrins have no useful function and act as highly reactive oxidants damaging tissues

Overview of the Seven Porphyrias
Overview of the Four Acute Porphyrias
* Four acute porphyrias cause acute, self-limiting attacks that lead to chronic and progressive deficits
* Symptoms of acute attacks mimic other diseases and increase the potential for misdiagnosis.
* Acute porphyrias are clinically indistinguishable during acute attacks, except the neurocutaneous porphyrias (variegate porphyria and hereditary coproporphyria) can cause dermatologic changes
* Acute attacks lead to an increase in porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) which can be detected in the urine
* Things that make diagnosis difficult: variable clinic course, lack of understanding about diagnostic process, and lack of a universal standard for test result interpretation

Patient Focus: Acute Intermittent Porphyria
* Most common porphyria
* Deficiency of hepatic PBG deaminase
* Autosomal dominant pattern with incomplete penetrance
* Affected individuals have a 50% reduction in erythrocyte PBG deaminase activity
* Latent prior to puberty
* Symptoms more common in females than males
* Increased urinary ALA & PBG

Prevalence in the General Population
Key Clinical Features
* Gastrointestinal symptoms - Abdominal pain (most common presenting complaint), nausea/vomiting, constipation, and diarrhea.
* Dehydration
* Hyponatremia
* Cardiovascular symptoms - tachycardia, hypertension, arrhythmias
* Neurologic manifestations - motor neuropathy, sensory neuropathy, mental symptoms, seizures.

Pathophysiology of the Acute Attack
Autonomic Nervous System
Peripheral Nervous System
Hypothalamus
Limbic area

Porphyrins excreted from liver
ALA crosses BBB
Causes oxidative damage
Accumulates in brain with neuronal and glial cell damage
Symptoms due to porphyrin
Precursor accumulation
Rather than deficiency of Heme
Porphyrins don’t Cross BBB
ALA induces liver
Damage via oxidative effects
Exacerbating Factors of Acute Attack
* Drugs that increase demand for hepatic heme (especially cytochrome P450 enzymes)
* Crash diets (decrease carbohydrate intake)
* Endogenous hormones (progesterone)
* Cigarette smoking (induces cytochrome P450)
* Metabolic stresses (infections, surgery, psychological stress)

Diagnosis of Acute Porphyria
Algorithm for Acute Porphyria Diagnosis
Treatment of the Acute Attack
* Hospitalization to control/treat acute symptoms:
o Seizures – Seizure precautions, medications?
o Electrolyte abnormalities
o Dehydration / hyponatremia
o Abdominal Pain – narcotic analgesics
o Nausea/vomiting – phenothiazines
o Tachycardia/hypertension – Beta blockers
o Urinary retention / ileus
* Withdraw all unsafe medications
* Monitor respiratory function, muscle strength, neurological status
* Mild attacks (no paresis or hyponatremia) – Intravenous 10% glucose at least 300 g per day
* Severe attacks – Intravenous hemin (3-4 mg/kg qdaily for 4 days) ASAP (can give IV glucose while waiting for IV hemin)
* Cimetidine for treatment of crisis and prevention of attacks

Hematin (Panhematin)

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03 August 2009

Eating and Sleeping Disorders



Eating and Sleeping Disorders

Eating Disorders
* 13.4% of girls and 7.1% of boys engage in disordered eating patterns.
* Paradox: As emphasis on thinness is increasing, so is the problem of obesity.
* 7 million women and 1 million men in the U.S. suffer from eating disorders.
* 15% of young women have “substantially disordered” eating attitudes and behaviors.

Factors Associated with Disordered Eating Patterns
* Being overweight
* Low self-esteem
* Depression
* Substance use
* Suicidal ideation
* More prevalent among females
* Least likely among African American females

Eating Disorders
Prevalence of Weight Concerns of Youth in Grades 5-12

Eating Disorders Anorexia Nervosa
* Anorexia Nervosa: Eating disorder characterized by:
o Refusal to maintain a body weight above the minimum normal weight for a person’s age and height.
o Intense fear of becoming obese that does not diminish with weight loss.
o Body image distortion
o In females, absence of at least 3 consecutive menstrual cycles otherwise expected to occur.
Anorexia Nervosa
* Subtypes:
o Restricting: Lose weight through dieting or exercising.
o Binge-Eating/Purging: Lose weight through use of self-induced vomiting, laxatives, or diuretics.
* Physical complications:
o Cardiac arrhythmia, low blood pressure, slow heart rate, weakened heart muscle
o Lethargy, dry skin, brittle hair, swollen parotid glands, hypothermia
o Males: Osteoporosis, substance use disorder, antisocial personality disorder
* Associated characteristics:
o Obsessive-compulsive behaviors and thoughts about food
* Associated characteristics:
o Personality disorders/characteristics:
+ Restricting: introversion, conformity, perfectionism, rigidity
+ Binge eating/purging: Extroverted, histrionic, emotionally volatile, impulse control problems, substance abuse

* Course and outcome: Highly variable
o Usually begins in adolescence
o Better outcome for binge-eating/purging
o More severe is associated with constricted/ overcontrolled profile
o ~ 44% recover completely, ~28% show some weight gain but remain underweight, poor outcome for ~ 24%
o Death: 5-20%, primarily from cardiac arrest or suicide


Eating Disorders Bulimia Nervosa
* Bulimia Nervosa: Eating disorder characterized by:
o Recurrent episodes of binge eating (rapid consumption of large quantities of food) at least twice a week for 3 months, during which the person loses control over eating and uses vomiting, laxatives, and excess exercise to control weight.
o More psychopathology than non-bulimics: Greater external locus of control, lower self-esteem and sense of personal effectiveness, negative self-image, although most are within normal weight range.

* More prevalent than anorexia
o Up to 3% of women suffer from bulimia, another 10% report some symptoms
o ~10% of bulimics are male
* Physical complications:
o Effects of vomiting: Erosion of tooth enamel, dehydration, swollen parotid glands, low potassium (can weaken heart and cause arrhythmia and cardiac arrest)
o Binge eating may cause stomach ruptures
o Gastrointestinal disturbances

* Related to:
o Coping responses to stress
o Mood disorders, especially seasonal affective disorder
o Also shares characteristics of borderline personality

* Course and outcome:
o Generally begins late adolescence/early adulthood
o Mixed, but better course than for anorexia
o Some bulimics continue to show disturbed eating patterns, low self-esteem, depressive disorder, but most recover either fully or partially.
o Poorer prognosis with associated history of substance use and longer duration before treatment.

Eating Disorders Binge-Eating Disorder (BED)
* Diagnostic category “provided for further study” in DSM-IV-TR:
o Binge Eating Disorder: Involves a large consumption of food over a short period of time at least twice weekly for 6 months
o Unlike bulimia, does not involve use of extreme behavioral attempts of vomiting, fasting, or excessive exercise as compensation for binge eating.
o Diagnosis: History of binge-eating episodes at least 2 days/week for 6 months
* Prevalence:
o Prevalence: 0.7-4% of population
o Females are 1.5 times as likely as males to have the disorder.
o Prevalent among white, African American, and American Indian women (possibly 10%), although white women are more likely to be seen for the disorder.

* Associated characteristics/risk factors:
o Overweight with history of weight fluctuation
o Prevalence: 2-5%
o Adverse childhood experiences, parental depression, vulnerability to obesity, repeated negative comments re weight and body
o Binges preceded by poor mood, low alertness, feelings of poor eating control, cravings for sweets.
o Complications: High blood pressure, high cholesterol, diabetes, and depression
* Comorbid features:
o Major depressive disorder
o Obsessive-compulsive personality disorder
o Avoidant personality disorder
* Course and outcome:
o Begins in late adolescence/early adulthood
o Positive course compared with other eating disorders: Most recover within 5 years
o Weight remains high (over time, ~1/3 meet criteria for obesity)

Eating Disorders Eating Disorder Not Otherwise Specified
* Eating Disorder Not Otherwise Specified: Eating disorders not meeting criteria for anorexia or bulimia nervosa:
o Individuals with binge-eating disorder
o Female who meets criteria for anorexia but has regular menses
o Individual who has lost significant weight but is in normal weight range

Eating Disorders Hyperphagia
* Hyperphagia: Excessive hunger and overly large amounts of food ingestion.
Eating Disorders Rumination
* Rumination: An eating disorder characterized by having the contents of the stomach drawn back up into the mouth, chewed for a second time, and swallowed again. This regurgitation appears effortless, may be preceded by a belching sensation, and typically does not involve retching or nausea. In rumination, the regurgitant does not taste sour or bitter. The behavior must exist for at least 1 month, with evidence of normal functioning prior to onset.

Eating Disorders Pica
* Pica: An appetite for non-foods (e.g., coal, soil, chalk, paper etc.) or an abnormal appetite for some things that may be considered foods, such as food ingredients (e.g., flour, raw potato, starch). In order for these actions to be considered pica, they must persist for more than one month, at an age where eating dirt, clay, etc., is considered developmentally inappropriate.
* Geophagia: Eating of dirt or clay.

Do You Have an Eating Disorder?

Overview of Major Risk Factors for Eating Disorders

Hunger and Satiety
* Ig Nobel awards celebrate the sillier side of science
* The Ig Nobel for nutrition went to a concept that sounds like a restaurant marketing ploy: a bottomless bowl of soup.
* Cornell University professor Brian Wansink used bowls rigged with tubes that slowly and imperceptibly refilled them with creamy tomato soup to see if test subjects ate more than they would with a regular bowl.
* "We found that people eating from the refillable soup bowls ended up eating 73 percent more soup, but they never rated themselves as any more full," said Wansink, a professor of consumer behavior and applied economics. "They thought 'How can I be full when the bowl has so much left in it?' "
* His conclusion: "We as Americans judge satiety with our eyes, not with our stomachs.“
* CNN.Com 10-7-07
* Societal influences:
o Mass media portray ideal female body as 5’7” 110 lbs; actual average is 5’4” 162 lbs
o Sociocultural demand for thinness
o Peer influences
o Criticisms by family members about weight
o Dating

* Body dissatisfaction:
o Males see their bodies as smaller than what they believe is preferred; females see their bodies as larger than what they believe is preferred
o Most dissatisfaction parallels low self-esteem
* Certain predisposition and characteristics lead some people to interpret images of thinness as evidence of their own inadequacy.
* Exposure to ultra-thin ideal by media can lead to:
o Internalization of that image and eating patterns intended to bring about that ideal
o Negative affect, which triggers dieting
o Social comparison, which leads to disordered eating to meet external standards of comparison.

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Eating Disorders, Obesity & Sleep Disorders



Eating Disorders, Obesity & Sleep Disorders

Eating Disorders
* Characterized by severe disturbances in eating behavior
* Types of eating disorders:
o Anorexia Nervosa (peak onset – 14-18 yrs)
o Bulimia Nervosa (peak onset – late adolescence to early adulthood)
o Binge-eating Disorder (unknown)

Anorexia Nervosa
* Essential features:
o Refusal to maintain a minimally normal body weight (for height and age)
o Intensely afraid of gaining weight
o Exhibit a severe disturbance in perception of shape/size of one’s body
o Absence of at least 3 consecutive menstrual periods
* Self-esteem highly dependent on shape/size
* Refusal to maintain minimal body weight:
o Generally weigh less than 85% of the normal body weight
* Weight loss is usually a result of:
o Reduction of food
o Purging (vomiting, laxatives)
o Excessive exercise regimes
* Intensely afraid of gaining weight:
o Fear of becoming fat is not alleviated by weight loss
o Weight loss is seen as an impressive achievement and a sign of self-discipline
o Weight gain is viewed as failure of self-control
* Distorted view of body weight and shape
o Some feel overweight all over, no matter how thin they become
+ Others feel that a particular part of the body is “too fat”
o Some demonstrate excessive weighing
+ Measure body parts
+ Use mirrors to check body parts for fat
* Resulting physiological problems:
o Constipation, impaired renal functioning
o Cold intolerance  lanugo
o Emaciation, yellowing of the skin, dry skin
o Tend to lose 20-25% of body weight, some lose up to 35%;
o Cardiovascular/heart problems, amenorrhea, osteoporosis & death

Bulimia Nervosa

* Essential features:
o Binge eating
o Inappropriate compensatory methods to prevent weight gain
o Binge eating and compensatory behaviors must occur, on average, at least 2x/wk for 3 months
o Perception of self is excessively influenced by one’s body shape and weight.
* Binge eating:
o Eating an amount of food that is definitely larger than most individuals would eat under similar circumstances
+ Binges can last up to 2 hours
o Could occur in one setting or as a continuation of eating

* Food consumed typically includes sweet, high-caloric foods
* Usually ashamed of the eating problem
o Attempt to hide their symptoms

* Binge eating usually occurs in secrecy, or as inconspicuously as possible:
o Binges may be planned in advance
o Usually characterized by rapid consumption
o Eating continues until person is uncomfortably, even painfully full
o The individual experiences a sense of a lack of control during the binge-eating episode

* Recurrent use of inappropriate compensatory behaviors:
o 80-90% of binge eaters who seek treatment report self-induced vomiting  relief from discomfort/fear of gaining weight  eventually can vomit at will
o Others use laxatives, diuretics and enemas
* Compensatory behaviors (cont.)
o Individuals with bulimia may fast for a day or more to compensate for binges
o They may compensate by exercising excessively

* Similar to Anorexia Nervosa in that the individual:
o Has a fear of gaining weight
o Has a desire to lose weight
o Are dissatisfied with their bodies

* Different from Anorexia Nervosa in that:
o Individuals with Bulimia recognize their behavior is not normal
+ People with Anorexia Nervosa don’t
o Despite behaviors, weight is usually normal
+ People with anorexia become very thin
o Individuals with Bulimia are more likely to seek and respond to treatment.

* Resulting physiological problems:
o Skin irritations (esp. around mouth and fingers due to contact with stomach acid)
o Tooth decay and cavities
o Damaged taste receptors
o Abdominal pain, bowel problems
o Digestive disorders
o Possible cessation of menstruation

Theoretical Perspectives: Anorexia and Bulimia Nervosa

* Sociocultural factors:
o http://www.youtube.com/watch?v=knEIM16NuPg
o http://www.youtube.com/watch?v=I0u0wWOMIsE&feature=related
o Social learning theory:
o Purging is a negative reinforcer; it alleviates the fear of gaining weight
* Cognitive theory:
o Behaviors are a result of irrational thoughts

* Family factors
o Tend to be dysfunctional
+ Critical, less nurturing, overprotective
+ Mother tends to feel daughter is unattractive and needs to lose weight
o Identified patient
* History of childhood physical/sexual abuse
o Especially with bulimia

* Biological factors:
o Low serotonin levels may prompt binge eating in people with bulimia, esp. carbohydrate cravings
o Genetics
+ Eating disorders tend to run in families

Binge Eating Disorder
* Essential features:
o Binge eating without purging or compensatory behaviors
o Must average at least 2 episodes/week for 6 months or longer
o Impaired control over eating
o Experience significant distress due to the eating behavior
* Impaired control over eating:
o Eating rapidly
o Eating until painfully full
o Eating large amounts when not hungry
* Significant distress
o Eating alone out of embarrassment
o Feeling disgust, guilt or depressed after the eating episode
o Concern over how episodes will affect body size/shape

* Associated features:
o Some episodes are triggered by depression or anxiety
+ Others report no specific trigger, though report the behavior initially relieves tension
o Some report a dissociative quality during the episodes
o Most are overweight & were yo-yo dieters.

Obesity: A Chronic Medical Disease
* Weighing 20% above the recommended weight
* Americans eat 815 billion calories daily
o That’s 200 billion more than is necessary to maintain their weight
o Those extra calories would sustain a country of 80 million people
* Potential Causes
o High set-point
o Genetics
o Hypothalamus
o Coping technique
o Clock-watchers
o Addiction
o Eat too much + inactivity

Sleep Disorders
* Dyssomnias:
o Disorders in which a person has difficulty getting to sleep, staying asleep or sleeping too much
* Characterized by a disturbance in the:
o Amount of sleep
o Quality of sleep
o Or the timing of sleep
* Dyssomnia disorders include:
o Primary Insomnia
o Primary Hypersomnia
o Narcolepsy
o Breathing-Related Sleep Disorder
o Circadian Rhythm Sleep Disorder

Primary Insomnia
* Essential features:
o Difficulty falling asleep, staying asleep, or awakening too early that lasts at least one month (some report nonrestorative sleep)
o Causes distress or impairment in social, occupational or other important areas of functioning
* Some facts:
o As much as 30% of the population suffers from this; 9-15% have chronic bouts; nearly everyone has bouts at some point
o Primarily affects middle-age and older pop.; affects more females than males
* Most probable cause of insomnia – stress
o Person goes to bed  thinks about the days events or problems in life  mind races  can’t get to sleep  think about the fact s/he can’t get to sleep causes bodily arousal and more anxiousness  makes it even less likely s/he will get to sleep

* Question
o What should you do if you don’t fall asleep within about 20 minutes of getting in bed?

Primary Hypersomnia

* Essential feature:
* Excessive sleepiness for at least 1 month
o Prolonged sleep episodes
o Daytime sleep episodes which occur almost daily
o Must be severe enough to cause distress or impairment in social, occupational or other important areas of functioning

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Sleep and Sleep Disorders



Sleep and Sleep Disorders
The Science of Sleep
By:Robert Averbuch, MD
Assistant Professor of Psychiatry

Lecture Outline

* Physiology of Normal Sleep
o Non-REM
o REM
o Normal patterns of sleep
* Sleep Disorders
o Dyssomnias
o Parasomnias

Physiology of Normal Sleep

2 Phases: REM and Non-REM Sleep

Non-REM Sleep

* 4 stages of progressively deeper sleep
* Normal muscle tone
* Associated with increased 5HT (serotonin)
* Decreased autonomic activity:
o Lower BP, Pulse, respirations slow

Stage One
* Brief transition between wakefulness and sleep (accounts for only 5% of sleep time)
Stage Two
* Light sleep
* Accounts for 50% of total sleep time
* ElectroEncephaloGram (EEG) shows some characteristic findings…

EEG in Stage 2
Stages 3,4

* Most restful, restorative stages of sleep
* Aka: Delta wave sleep/ slow wave sleep
* Greatest proportion is in the first 1/3 to 1/2 of night

NREM Sleep: Theories of its purpose…

* The decrease in metabolic demand on the brain during NREM allows glycogen stores to replenish
* Allows for consolidation of memories and learning

REM (dreamland)

* 10-20 min. cycles consisting of:
o Rapid Eye Movements
o ElectroEncepahaloGram shows fast activity very similar to wakeful EEG pattern
o Suppression of peripheral muscle tone
o Penile Tumescence
o Often increased autonomic tone- ie, increased blood pressure, resp, heart rate

REM (dreamland)

* Where dreaming occurs
* REM is marked by increased cholinergic activity
o Thus REM-supression seen with anti-cholinergic drugs (ex. some antidepressants)

Normal Sleep Pattern
* Sleep cycles between NREM and REM approx. 4-5 times/night
* Cycles last approx. 90min
* REM duration and frequency increase thru night
* Proportion of slow wave sleep (stages 3,4) decreases thru night

Normal Sleep Parameters
* Sleep Onset Latency- the time it takes one to fall asleep, averages 10-20min
* REM Latency- time between sleep onset and the first REM period, averages 90-120min

Normal Sleep Distribution
* REM sleep accounts for approximately 25% of total sleep time
* Non-REM sleep accounts for 75% of sleep time, with 25% of that spent in Stages 3,4 (most restful portion)

Sleep Onset
* Mediated by increased Serotonergic activity in the Dorsal Raphe Nuclei of the Pons
o Dampens activity in the ascending reticular activating system (RAS), inducing sleep
* Dopamine has opposite effect- promotes wakefulness

Age-Related Changes

* Decreases in dreaming, total sleep time, REM, and slow-wave (deep sleep)
* Increases in early morning awakening, fragmentation, daytime napping, and phase advancement-
o Ie, earlier to bed, and awaken earlier

“Measuring” Sleep
Polysomnography

The Polysomnogram

* EEG, ECG
* EOG (oculogram)
* Chin EMG (myelogram)
* Ant. Tibialis EMG
* Pulse Oxymeter
* Blood Pressure

Sleep Disorders
Sleep Disorders- 2 Divisions

* Dyssomnias- disorders of quality, timing, or amount of sleep (quantity)
* Parasomnias- abnormal behaviors associated with sleep or sleep-wake transition, that often produce arousals

Dyssomnias

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