04 August 2009

Mechanism of Bone Metastases

Mechanism of Bone Metastases
by: Dr.Priya Gopalan

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

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

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 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
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 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

+ Endpoint - TTP
+ Results
# TTP HR 0.89 (CI 0.76,1.04, p=0.136)
# Median time to bone alk phos progression 505 vs 254 days (p<0.01)

* Long-term treatment of osteolytic metastases
* Preferentially bind areas of high bone turnover
* Aminobisphosphonates
o e.g. zoledronate, aledronate, risedronate
o Block prenylation of osteoclast proteins (small GTP-binding proteins, e.g. ras and rho), leading to apoptosis
* Non-aminobisphosphonates
o e.g. clodronate, etidronate
o Inhibit ATP-dependent enzymes, leading to apoptosis
* Also may inhibit tumor adherence to bone, inhibit angiogenesis, reduce IL-6 production

* Clodronate approved in Europe but not US
* Double-blind, placebo-controlled, multicenter trial with 1,069 patients with operable breast cancer randomized to clodronate or placebo
o 1° endpoint - relapse in bone
o 2° endpoints - relapse in other sites, mortality, toxicity
o Significant reduction in bone metastases during medication period (HR 0.44, CI 0.22-0.86, p=0.016), but not in total follow-up period
o Reduced mortality (98 in clodronate arm, 129 in placebo arm, p=0.047)

* 754 pts with metastatic breast cancer (with osteolytic bone metastases) randomized to pamidronate or placebo
o 1° objective - skeletal events per year and time to 1st skeletal-related event (SRE)
o Only 115 of 367 (31.3%) on pamindronate arm and 100 of 384 (26.0%) on placebo arm completed the study
o Pamidronate arm - 2.4 skeletal events/yr; placebo arm - 3.7 events/yr (p<0.001); also observed longer time to 1st SRE in pamidronate arm (12.7 vs 7 months, p<0.001)
o Limited by significant number of pts who did not complete study
Bisphosphonate - zoledronate

* 1803 premenopausal women with Stage I and II breast cancer randomized to tamoxifen/anastrozole ± zoledronic acid
* 1° endpoint DFS; 2° RFS, OS; explor: bone met-free survival
* DFS (HR 0.643 [CI 0.46-0.91], p=0.011)
* RFS (HR 0.653 [CI 0.46-0.92], p=0.014)
* No change in OS
* See effects outside bone

Bisphosphonates - zoledronate (prostate cancer)
* Zometa 039 trial: 643 men with hormone-refractory metastatic prostate cancer received zoledronate 4 mg, 8mg then 4mg, or placebo for 18 months
o Zometa decreased SREs and pain, but no difference in disease progression or performance status
* Trials with pamidronate and clodronate in metastatic prostate cancer showed no significant benefits
* Randomized, placebo-controlled Phase III trial, with 773 pts with lung, RCC, etc. metastatic to bone randomized to zoledronate vs placebo q3 months for 21 months
* 1° endpoint - % patients with ≥1 SRE
* Zolendronate delayed the onset and reduced risk of skeletal-related events compared to placebo in pts with bone metastases due to lung cancer or other solid tumors.
o Reduced time to 1st SRE with treatment (236 vx 155 days, p=0.009), decreased number of events/year (1.74 vs. 2.71, p=0.012), HR developing skeletal event reduced in zoledronate arm (HR 0.693, p=0.003)

* Osteonecrosis of the jaw

Other therapies

Mechanism of Bone Metastases.ppt


Cutaneous Toxicities of Cancer Therapy

Cutaneous Toxicities of Cancer Therapy
By:Dr.Saiama Waqar

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

* 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
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)

* 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

* 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

* 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
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

* 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

Radiation sensitization and recall
* Some chemotherapeutic agents can sensitize the skin to radiation
* recall phenomenon in previously irradiated tissue (wks to yrs after RT)
o when chemotherapy is administered
* Exact mechanism not clearly understood,
o radiation effects on the microvasculature
o altered cutaneous immunologic responses
* maculopapular eruptions with erythema, vesicles, desquamation
o mild rash to severe skin necrosis

Radiation sensitization and recall
* No specific therapy recommended
o topical corticosteroids
o Ultraviolet radiation
* caution about sun exposure
o wear protective clothing
o sunscreen products
+ 5-FU increases photosensitivity to sunlight
+ MTX may reactivate a sunburnes of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6

Hypersensitivity reactions
* Can occur either from drug itself or from solubility vehicle (eg. Cremophor for paclitaxel)
* Prevention: premedicate
o Steroids (dexamethasone), H1 blockers (benadryl), H2 blockers (pepcid)
* Management of hypersensitivity reactions:
o epinephrine, hydrocortisone, and histamine blockers, along with monitoring of BP

Drugs causing hypersensitivity
* Color changes
o Mee’s lines - transverse white
o hyperpigmentation
* Beau’s lines - transverse grooves/lines
o related to the effect of chemotherapy causing decreased nail growth
* Paronychia -inflammation of the nail fold
o Seen with cetuximab

Beau’s lines
* Onycholysis (separation of the nail plate from the nail bed)
o can be painful
o anthracyclines, taxanes (especially weekly paclitaxel), and topical 5-fluorouracil
* frozen-glove study to prevent docetaxel-induced onycholysis & cutaneous toxicity
o 45 patients, frozen glove for 90 minutes on the right hand, using the left hand as control
o Frozen glove reduced the nail and skin toxicity

Grading of nail changes
Nail changes/toxicity

1 Discoloration, ridging (koilonychias), pitting
2 Partial or complete loss of nail(s), pain in nailbed(s)
3 Interfering with ADL
Nail changes with docetaxel

Drugs causing nail changes
* Pigmentary changes
o Bleomycin
o Busulfan
o Cisplatin
o Cyclophosphamide
o Docetaxel
o Doxorubicin
o Etoposide
o Fluorouracil
o Hydroxyurea
o Idarubicin
o Ifosfamide
o Melphalan
o Methotrexate
o Mitomycin
o Mitoxantrone

* Onycholysis
o Paclitaxel
o Docetaxel
o Gemcitabine
o Capecitabine
o Cyclophosphamide
o Doxorubicin
o Etoposide
o Fluorouracil
o Hydroxyruea
* Inflammatory changes
o Gefitinib
o Cetuximab
o Capecitabine
o Docetaxel
o Paclitaxel

Extravasation injury
* The accidental extravasation of intravenous drugs occurs in approximately 0.1% to 6% of patients receiving chemotherapy
* Depending on the agent and amount, the sequelae of extravasation can range from erythema and pain to necrosis and sloughing of the skin
* The most toxic drugs are the vesicants, such as the anthracyclines, vinca alkaloids, nitrogen mustards, as well as paclitaxel and cisplatin

Vesicants and irritants
Treatment of extravasation
* immediate discontinuation of the infusion
* cooling with ice packs
o warm soaks for vinca alkaloids
* for persistent/progressive local symptoms - surgical consult
* early local debridement of can reduce extent of later injury

Extravasation of vinblastine in a 57-year-old male receiving chemotherapy for bladder cancer

Antidotes for extravasation
o topical DMSO (dimethyl sulfoxide) to enhance absorption of the extravasated drug, routine use still controversial
o Thiosulfate -nitrogen mustard extravasation (injection of a 1/6 molar solution into the area of extravasation)
o Dexrazoxane - anthracycline extravasation
* Regardless of antidote, local therapy, and prompt surgical intervention is paramount

Skin Toxicity from targeted therapy
* Because the EGFR is also expressed by basal keratinocytes, sebocytes, the outer root sheath, and some endothelial cells, agents that inhibit EGFR are associated with dermatologic side effects
Erlotinib eruption on the arms

Cutaneous reactions associated with molecularly targeted agents
Monoclonal antibodies to EGFR
Infusion reactions; acneiform eruption; paronychial inflammation; photosensitivity
* Cetuximab, panitumumab

EGFR pathway inhibitors
Acneiform eruption; paronychial inflammation; photosensitivity
* Erlotinib
* Gefitinib
* Lapatinib

Multitargeted tyrosine kinase inhibitors
Skin exanthem; SJS; acute generalized exanthematous pustulosis; Sweets syndrome; hand-foot syndrome; photosensitivity; pigmentary changes, hair depigmentation; alopecia

* Imatinib
* Dasatinib
* Sorafenib
* Sunitinib

EGFR-inhibitor induced skin changes
* (a-c) stratum corneum thickness, (d) apoptosis (apoptotic cells by 10,000).
* On-therapy (gefitinib) biopsy specimen showing (e) keratin plugs and micro-organisms in dilated infundibula and (f) acute folliculitis.

Cetuximab skin toxicity
Moderate rosacea-like eruption from cetuximab
80 year old patient receiving cetuximab and radiation for nasopharyngeal cancer

Erlotinib rash treatment
Severity of Rash
Treatment Protocol
Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily.
Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily AND oral minocycline 100mg twice-daily for a minimum of 4 weeks and continuing thereafter as required, until resolution of the rash by one severity grade. Scalp lesions will be treated with a topical lotion clindamycin 2%, triamcinolone acetonide 0.1% in equal parts of propylene glycol and water.
Stop erlotinib therapy for 1 week and restart at 100mg once-daily. Treatment of rash with topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily AND oral minocycline 100mg twice-daily for a minimum of 4 weeks and continuing thereafter as required. Scalp lesions will be treated with a topical lotion clindamycin 2%, triamcinolone acetonide 0.1% in equal parts of propylene glycol and water until resolution.
Dose modification guidelines for cetuximab (Erbitux) based upon dermatologic toxicity

Cutaneous Toxicities of Cancer Therapy.ppt


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
* 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

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 (-)

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
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)
* Used in the treatment of the acute porphyrias since the 1970s
* Mechanism of Action: Reduces production of ALA / porphyrins by negative feedback inhibition on ALA synthetase
* Derived from outdated PRBCs from community blood banks
* Reconstitution of lyophilized hematin with 25% albumin recommended
o Reconstituted in sterile water originally –> less stable / degraded easily
o Degradation products cause an ↑ in adverse reactions
* Adverse reactions: Due to degradation products binding to endothelial cells, platelets, & coagulation factors
o Thrombophlebitis
o Anticoagulation (transient ↑ PT, bleeding may occur)
o Thrombocytopenia

* thrombophlebitis if given through large vein or central line
* Dosing:
o Acute attacks: 3-4 mg/kg/day x 4 or more days
o Max daily dose 6 mg/kg or 313 mg (1 vial) – even in obese patients
o Prevention of attacks: not well established; once or twice weekly infusions

A Study of Hemin Use in Clinical Practice

* Hemin approved under Orphan Drug Act of 1983
* Hemin removed from market in 2000 by FDA: 8/00-6/01
o Abbott Laboratories required to conduct open-label study of the safety of hemin manufactured at a new facility
o Largest trial / case series to date on hemin therapy
* Study design: “Real world” data about acute porphyria diagnosis, treatment & perceived efficacy of treatment
* Methods:
o Hemin only available through study participation – compassionate basis
o All pts judged to need hemin by their physicians were enrolled
o Confirmation of diagnosis not required
o Pts received hemin as normally prescribed by their physicians
o No specific outcome measures, exclusion criteria, or follow-up

Results of Hemin Used in Clinical Practice

* Study Population: 130 pts; 92% Caucasian; 72% female
* Precipitating factors: (40/130 pts): drugs (22%); hormonal (24%)
* Results:
o 111 pts treated for 305 acute attacks & 40 pts for prophylaxis
o Diagnostic lab findings reported in 53% (half with +results)
o Hemin regarded as effective for 73% of patients
+ Despite doses less than recommended in 20% of pts (< 3-4 mg/kg/day)
o Propylaxis with hemin in 1/3 of patients
+ Wide variability in prophylaxis regimens  lack of published guidelines
+ Among 31 receiving hemin prophylaxis for >1 month, 68% did not require subsequent tx for acute attacks
o 44% of pts experienced adverse events – most attributed to underlying disease and not hemin
+ Phlebitis was most common adverse event attributed to hematin

Long-Term Complications from Symptomatic Disease

* Neurological Sequelae
* Hypertension
* Renal failure
* Cirrhosis
* Hepatocellular carcinoma

Renal failure: Is hypertension the cause or the effect

* Debate about cause: Hypertension or another etiology?
* Increased risk of renal failure in those with more acute attacks
* Andersson et al  Population-based study (Sweden)
o Renal biopsies (n=16)  ischemic lesions, ? related to protracted vasospasm
o Theory of injury  Vasospasm from:
+ Porphyrin metabolites &
+ an upregulated SNS  ↑ urinary excretion of catecholamines during an acute attack
o By this theory, hypertension is not the sole cause of renal insufficiency

Hepatocellular Carcinoma (HCC)

* Estimated 60 to 70-fold ↑ risk of HCC in AIP patients
* Andersson  Retrospective population-based mortality study
o HCC  27% with AIP vs 0.2% deceased without AIP
o HCC more common in women (2:1)
o HCC more common in those with symptomatic disease
o Cirrhosis more common in AIP pts (12%) vs non-AIP (0.5%)
o Cirrhosis in AIP pts higher in W>M 3:1
* Retrospective analysis for genetic mutations in 17 pts with AIP & HCC (L Bjersing)
o Is PBGD a tumor suppressor gene? (No, 1 allele present in tumor)
o No mutations seen in p53 or ras (these mutations have been implicated in HCC caused by HBV or aflatoxin)
* De Siervi et al ALA is toxic to two hepatocellular cancer cell lines (HEP G2 & HEP 3B)
o Degree of cytotoxicity was directly related to concentration of ALA
o Adding hemin or D-glucose to ALA + cells decreased toxicity with HEP G2 cells
* Proposed Mechanism of cirrhosis / carcinogenesis:
o Reduced free heme pool  ↓ cytochrome P450 & antioxidant enzymes reactive oxygen species DNA damage
o ALA that accumulates can oxidize proteins & cause DNA damage

Prevention & Follow-up: Caring for Patients Between Attacks
* Avoidance of alcohol, smoking, and exacerbating drugs
* Adequate carbohydrate intake
* Medical alert bracelets/wallet cards
* Gonadotropin-releasing hormone analogues
* Iron overload from hemin (100 mg of hemin contains 8 mg of iron)
* Hepatocellular carcinoma screening
* End-Stage renal disease prevention
* Screening for Osteoporosis
o risk from GNRH analogues, immobility, malnutrition, & vitamin D deficiency

* Prior to 1970, fatality rates were 10% to 52%, now 10%
* Since introduction of hematin mortality has decreased
* Overall mortality in patients with acute attacks is 3-fold higher than the general population
* Delayed diagnosis and treatment contribute to higher mortality
Future Treatment Directions
* Liver transplantation
* Animal models used to mimic porphyrias with experiments to correct enzyme deficiency in tissues
* Non-viral mediated gene transfers
If You Were Asleep….Key Points to Remember
* Porphyrias are metabolic diseases resulting from a partial deficiency of an enzyme in the heme biosynthetic pathway
* Cause acute attacks secondary accumulation of heme precursors
* Clinical features: abdominal pain, tachycardia, hypertension, hyponatremia, seizures, motor neuropathy etc.
* Screen for porphyria with qualitative urinary PBG and if elevated measure quantitative urinary PBG and ALA
* Confirm diagnosis with urinary and fecal fractionated porphyrins and DNA testing
* Treat acute attacks with IV hemin
* Prevent acute attacks with smoking cessation, avoidance of inciting agents

Acute Intermittent Porphyria.ppt


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.

* Top figure
o Body image ratings of women who score high on measure of distorted eating behaviors.
* Bottom Figure
o Body image ratings of women who score low on measure of distorted eating behaviors.

Route to Eating Disorders Eating Disorders
* Family and peer influences
o Psychodynamic (for anorexia):
+ Fear of maturation:
# Growing up and separating from family
# Developing own identity
# Fulfills unconscious desire to remain a child
o Family systems: Problematic family communication patterns result in anorexia
o Socialization agents (peers and family)
o Relationship problems and role models

Eating Disorders
* Cultural factors:
o Culture-bound (Western cultures) and other societies influenced by Western culture.
o Many African Americans seem insulated from thinness standard, but equally as likely to have binge-eating disorder.
o Internalization of U.S. societal values regarding attractiveness affects self-esteem and body dissatisfaction.
Differences in Body Image and Weight Concerns Among African American and White Females

Eating Disorders Other Etiological Factors
* Personality characteristics and negative emotional moods
* Sexual abuse
* Low self-esteem and feelings of helplessness
* Passivity, dependence, nonassertivness
* Anorexia: Perfectionism, obedience, academic and athletic success, model children
* Bulimia: Perfectionism, seasonal affective disorder
* Genetic factors: First-degree relatives

Eating Disorders Treatment
* Prevention programs:
o Goals of school-based intervention program:
+ Develop positive attitude toward one’s body
+ Become aware of societal messages re being female
+ Develop healthier eating/exercise habits
+ Increase comfort in expressing feelings
+ Develop healthy strategies to deal with stress
+ Increase assertiveness skills
o Teach females to examine consequences of gender messages
o Institutional awareness of the problem is critical
* Anorexia nervosa:
o Inpatient/outpatient depends on weight and health of individual
o Initial goal: Restore weight with psychological support
+ Nutritional/physical rehabilitation
+ Identify/understand dysfunctional attitudes
+ Improve interpersonal/social functioning
+ Address comorbid psychopathology/psychological conflicts

* Anorexia nervosa:
o Family therapy: Parents involved in meal planning, reduce criticism (understanding seriousness of anorexia), negotiate new relationship patterns, move toward separation and individuation.

* Bulimia nervosa:
o Identify conditions contributing to purging
o Identify physical conditions resulting from purging
o Normalize eating pattern and eliminate binge-purge cycle
* Bulimia nervosa:
o Cognitive-behavioral therapy and use of antidepressants:
+ Encourage eating 3 or more balanced meals a day
+ Reduce rigid food rules and body image concerns
+ Develop cognitive and behavioral strategies

* Binge-Eating Disorder
o Similar to treatments for bulimia with fewer physical complications
o Because most are overweight, therapy programs try to help individual lose weight
o Three phases:
+ Determine underlying cognitive factors
+ Use cognitive strategies to change distorted beliefs about eating
+ Relapse prevention strategies

Primary Sleep Disorders
* Most adults require 8 hours of sleep to function optimally.
* Insufficient sleep results in lapses in attention, vigilance, and deterioration of performance.
* Five stages of sleep:
o Stage 1 (5%): Transition from wakefulness to sleep
o Stage 2 sleep (50%)
o Stages 3-4 (10-20%): Deepest level
o Rapid eye movement (REM-20-25%): Dream sleep

Primary Sleep Disorders Dyssomnias
* Most problems are either inability to initiate or maintain sleep at night or excessive daytime sleepiness.
* Dyssomnias: Difficulties in getting to sleep, maintaining sleep, or complaints of excessive sleepiness during the day.

Primary Sleep Disorders Primary Insomnia
* Primary Insomnia: Characterized by difficulty getting to sleep, maintaining sleep, or having nonrestorative sleep for at least one month, causing clinically significant distress in social, occupational, or other areas of functioning.
o Causative factors: caffeine, alcohol, heavy meals, exercising 2 hours before bedtime, stress, intrusive/ uncontrollable cognitive activity, altered sleep habits
o Highest rate: 52% of older adults
* Many people with primary insomnia have undiagnosed sleep Apnea or Restless Leg Syndrome.
* RLS (which is also sometimes referred to as Jimmy Legs, spare legs or "the kicks") may be described as uncontrollable urges to move the limbs in order to stop uncomfortable, painful or odd sensations in the body, most commonly in the legs. Moving the affected body part eliminates the sensation, providing temporary relief. The sensations and need to move may return immediately after ceasing movement, or at a later time. RLS may start at any age, including early childhood, and is a progressive disease for a certain percentage of sufferers, although it has been known for the symptoms to disappear permanently in some sufferers.

Primary Sleep Disorders Primary Hypersomnia
* Primary Hypersomnia: Characterized by excessive daytime sleepiness or prolonged nighttime sleep for at least one month, causing significant distress or impairment in social, occupational, or other important areas of functioning.
o Compelling need to nap during the day that provides no relief from sleepiness.
o Results in problems with driving, work performance, or social functioning.

Primary Sleep Disorders Narcolepsy
* Narcolepsy: Characterized by overwhelming need for daytime sleep even when adequate sleep occurs at night; daily for at least 3 months, together with at least 2 of the following:
o Irresistible drowsiness/falling asleep without warning
o Cataplexy
o Sleep paralysis during wakefulness
o Hypnogogic hallucinations before falling asleep

Primary Sleep Disorders Breathing-Related Sleep Disorder

* Breathing-Related Sleep Disorder: Excessive sleepiness caused by sleep disruption through abnormalities of breathing during sleep
o Obstructive Sleep Apnea: Upper-airway obstruction during sleep
+ Undiagnosed in ~75% of treatable cases
+ Disruptive snoring, breathing pauses, gasping, excessive daytime sleepiness
+ Obstruction of airway prevents breathing during sleep
o Central sleep apnea syndrome
o Central alveolar hypoventilation syndrome

Primary Sleep Disorders Circadian Rhythm Sleep Disorder
* Circadian Rhythm Sleep Disorder: Pattern of recurrent sleep disruption caused by disruption of the biological sleep-wake cycle or mismatch between internal “clock” for sleeping and waking and environmental demands.
o Jet lag, shift work
o Associated with major disasters (e.g., Exxon Valdez oil spill)

Primary Sleep Disorders Dyssomnias Not Otherwise Specified

* Dyssomnias Not Otherwise Specified: Do not meet criteria for specific dyssomnia, but produce significant impairment:
o Insomnia caused by environmental factors
o Excessive sleepiness caused by sleep deprivation
o Restless leg syndrome
o Periodic limb movement disorder

Primary Sleep Disorders Parasomnias
* Parasomnias: Activation of physiological systems at inappropriate times during the sleep-wake cycle.
* Generally involve activation of the autonomic nervous system, including cognitive processes during sleep or sleep-wake transitions.

Primary Sleep Disorders Parasomnias
* Nightmare disorder: Nightmares several times/week during REM sleep.
o 3% of preschoolers and school-aged children
* Sleep Terror Disorder: Vivid nightmares during first third of deep sleep (non-REM); child screams with terror, is not fully aroused, and does not remember what happened.
o ~6% of children, disappears in adolescence
o In adults age 20-30 it has a chronic course
* Sleepwalking Disorder: Motor activity ranging from sitting up to getting out of bed and walking about while still asleep.
o ~2% of school-aged children sleepwalk at least a few nights a week
o Up to 30% of children sleepwalk at least once
o 1-5% of children have sleepwalking disorder
o Tends to disappear in adolescence; in adults it will have a chronic waxing/waning course.

* Parasomnias Not Otherwise Specified:
o REM sleep behavior disorder: Violent motor behavior during REM sleep
o Sleep paralysis/inability to move during transition from wakefulness and sleep

Primary Sleep Disorders Etiology and Treatment of Dyssomnias
* Etiology: Subclinical anxiety and depression, environmental changes, health and behavioral habits; for some etiology is unknown but may include:
o Cognitions or intrusive, uncontrollable thoughts
o Personality and psychological adjustment problems
o Lifestyle factors
o Nocturnal activities that interfere with sleep
* Treatment for specific disorders:
o Excessive sleepiness (narcolepsy or hypersomnia): Stimulants, though more success with hypersomnia than narcolepsy.
o Insomnia: Sleep pills, which tend to become ineffective over the long-term.
o Sleep apnea: Avoid medications, alcohol and other substances; lose weight if overweight; sleep on side rather than back; pressure mask during sleep may also help with moderate and severe apnea.

* Treatment for RLS and PLMD: Behavioral treatment, medications for RLS
* Treatment for sleep disorders generally:
o Relaxation/focusing procedures
o Changing mental state prior to bedtime
o Slow deep breaths
o Eliminate distractions
o Avoid daytime naps, caffeine late in day, heavy meals/exercise/alcohol/nicotine 2 hours before bedtime.

Eating and Sleeping Disorders.ppt


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

Primary Hypersomnia
* Duration of major sleep episodes range from 8-12 hours
o Often followed by difficulty awakening
* Excessive sleep during normal waking hours takes the form of
o Intentional naps
o Inadvertent episodes of sleep
* Daytime naps
o Are relatively long (lasting an hour or more)
o Are not refreshing
o Do not lead to heightened alertness
* Unintentional sleep episodes occur in low-stimulation and low-activity situations
o Such as?
* Hypersomnia can lead to distress and dysfunction:
o Difficulty in meeting morning obligations
o Unintentional daytime sleep episodes can be dangerous and embarrassing
o Low level of alertness can lead to poor efficiency, poor concentration, and poor memory

* Essential features:
o Repeated irresistible attacks of refreshing sleep
o Cataplexy and/or
o Intrusion of REM sleep between wakefulness and periods of sleep
* For diagnostic purposes, the sleep attacks must occur daily over a period of at least 3 months

* Repeated irresistible attacks of refreshing sleep:
o Sleep is irresistible; results in unintended sleep in inappropriate places
o Sleep episodes usually last 10-20 minutes, but can last up to an hour
o Individuals typically have 2-6 daily episodes
+ some attempt to control sleepiness by taking naps

* Cataplexy: Loss of muscle tone during episodes (usually lasts only seconds):
o Can be subtle or dramatic
o Person is fully conscious/alert during episode
o Occurs in approx. 70% of cases
+ Often develops years after onset
+ Triggered by strong emotions

* Approx. 20-40% experience intense dreamlike imagery:
o Hypnagogic hallucinations – just prior to falling asleep
o Hypnopompic hallucinations – just after awakening
o Most hallucinations are visual and incorporate elements of one’s environment

* Approximately 30-50% of individuals with narcolepsy experience sleep paralysis:
o Occurs just on falling asleep or awakening
o Individual is awake but unable to move or speak
+ Some feel like they can’t breathe
o Hallucinations and paralysis can occur simultaneously
+ Typically lasts seconds–minutes, ends abruptly


* Causes:
o Unknown
o May be genetic – higher degree of incidence among biological relatives
o May be partly due to a loss of certain brain cells in hypothalamus
+ Produce sleep-regulating chemical

Breathing-Related Sleep Disorder
* Essential feature:
o Sleep disruption, leading to excessive sleepiness or insomnia, that is due to abnormalities of ventilation during sleep
o Daytime sleepiness is the most frequently reported complaint

* Obstructive sleep apnea syndrome
o Temporary cessation of breathing during sleep
+ Seems to be a result of blocked upper air passages, causing breathing to stop temp.
# Enlargement of soft tissue may cause airways to narrow
+ May also be the result of structural deformities
+ Cessation of breathing lasts from 15-90 seconds
+ Individual may wake up as many as 500x/night
o Individual may wake up gasping for air, making a loud snorting sound, and go back to sleep
+ Individual is usually not aware of these interruptions of sleep
o Approx. 20 million Americans suffer from this disorder; men are 2x as like as women to suffer from it; usually occurs in overweight people

* Things that may help:
o Dieting
o Surgery (tonsils and adenoids)
o Dental appliances which reposition the tongue
o Ventilating machines

Circadian Rhythm Sleep Disorder
* Essential features:
o Disruption of normal sleep wake pattern
o Must be severe enough to cause severe distress or impairment of social, occupational or other important functioning
o Result of jet lag, working swing shifts, etc

* Sleep disorders characterized by abnormal behavior or physiological events that occur in association with:
o Sleep
o Specific sleep stages or
o Sleep-wake transitions
* Usually complain of unusual behavior during sleep


* Parasomnias include:
o Nightmare Disorder
o Sleep Terror Disorder
o Sleepwalking Disorder

Nightmare Disorder

* Essential Feature:
o Repeated occurrence of frightening dreams that lead to awakenings from sleep
o Must result in significant distress or result in social or occupational dysfunction

* Nightmares defined:
o A lengthy, elaborate dream sequence that is highly anxiety provoking or terrifying
* Dream content:
o Usually focuses on imminent danger to the individual
+ Sometimes the danger is more subtle, as involving personal failure or embarrassment

* Nightmares may replicate a real life traumatic experience a person had
o But not usually
* Individuals are alert upon wakening
o Can describe the dream in detail
* Occur almost exclusively during REM sleep
* Believed to be caused by stress

* Upon awakening, the individual experiences a lingering sense of anxiety or fear  difficulty returning to sleep
* Some individuals avoid sleeping, resulting in
o Excessive sleepiness
o Poor concentration, irritability
o Depression/anxiety

Sleep Terror Disorder
* Def: repeated abrupt awakenings from NREM sleep accompanied by:
o Intense physiological arousal
o Feelings of panic
* Often occurs during times of stress
* Most frequently occurs in children (up to 6%); rare in adults (<1%)
* Typical experience (lasts 1-10 minutes):
o Wake up in a state of panic, screaming
+ Body is in full physiological arousal
o Child may thrash about while still sleeping
o If awakened, the child is usually confused and incoherent
+ Soon fall back into deep sleep

Sleep Terror Disorder

o Children do not remember the incident in the morning; more terrifying to the parent
o Sleepwalking and sleep-talking may accompany sleep terror disorder
* Typically outgrown by adolescence
o Though some cases last into adulthood
* Cause is unknown
o But it is thought to be associated with stress

Sleepwalking Disorder

* Essential features:
o Arising from bed and walking about while asleep
* During episodes, the person has
o Reduced alertness/responsiveness
o A blank stare
o Is unresponsive to communication with others or efforts to wake them

Sleepwalking Disorder

* Individual typically has little recall of the incident upon awakening
* For diagnosis, the sleepwalking must cause severe distress or impairment of social or occupational functioning

* Sleepwalking episodes can include a variety of behaviors:
o May sit up in bed, look around, pick at blankets
o May walk into closets, out of the room, down stairs and even out of a building
o Some use the bathroom, eat or talk
o On occasion, some run from a perceived threat
o Some have operated machinery

* Particularly during childhood, sleepwalking can include inappropriate behavior
o E.g. Urinating in a closet
* Individuals often wake up in another place
o Or with evidence they performed some activity
* Most episodes last minutes to half an hour
* Cause: Unknown
o Genetics and environment may be involved

Eating Disorders, Obesity & Sleep Disorders.ppt


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 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

The Polysomnogram

* 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

* Primary Insomnia
* Narcolepsy
* Sleep Apnea
* Circadian Rhythm Sleep Disorder (jet lag, et al.)
* Restless Legs Syndrome (RLS)
* Medical/Substance related insomnia

Primary Insomnia
* “Primary”, meaning no underlying medical cause
* Onset often with stressor or disruption to sleep schedule or environment
* Results from poor sleep hygiene, along with classical conditioning-
o Faulty learning/association of sleep environment with state of arousal

INSOMNIA- an epidemic?
* Definition: “Subjective” experience of poor sleep quality or quantity that adversely affects daily functioning
* Extremely common complaint in general practice
* 30-40% adults have occasional poor sleep
* 15-20% adults have chronic insomnia

Consequences of Insomnia
* Depression
* Irritability
* Decreased cognitive functioning
* Decreased productivity
* Injuries and accidents

* A dyssomnia characterized by poor sleep quality (restless, fragmented) and dysfunction in the transitions between sleep and wakefulness
* Presents with Excessive Daytime Sedation (EDS)

Narcolepsy Tetrad

* Classic tetrad of associated findings:
o 1. Sleep attacks
o 2. Cataplexy
o 3. Sleep paralysis
o 4. Sleep hallucinations

1. Sleep Attacks
* Most common symptom of the tetrad
* Brief (10-20min) “power-naps”- refreshing and restful
* Average 10-20/wk

2. Cataplexy
* Sudden loss of muscle tone (rarely full body paralysis) caused by intrusion of REM activity into daytime wakefulness
* Triggered by heightened emotion
* Average duration: 30 seconds
* No loss of consciousness

3. Sleep Paralysis
* Brief paralysis upon waking
* Remain alert with full eye movements Can occur in the absence of Narcolepsy (ie, normal variant)

4. Sleep Hallucinations
* Hypnogogic hallucinations- occur during transition into sleep
* Hynopompic hallucinations- occur upon awakening from sleep
* Can occur in the absence of Narcolepsy (ie, normal variant)

Narcolepsy: Etiology
* CNS lesions: brain trauma, stroke, tumor, Multiple Sclerosis
* Familial/idiopathic: onset in adolescence or young adulthood

Sleep Apnea
* Dyssomnia characterized by poor sleep quality due to frequent awakenings (apneas)
* Apneas last sec-minutes- produce brief arousal
* Presents with excessive daytime sedation- EDS

Sleep Apnea: Two Types
* Obstructive Sleep Apnea: most common
* Central Sleep Apnea

Obstructive Sleep Apnea
* Classic- obese, middle-aged male with thick neck or enlarged tonsils
* Apneas- brief gasps…silence, followed by loud “resuscitative” snores, and sometimes body movements (restless)
* Usually unaware of snoring, arousals…but sleep partner is aware

Central Sleep Apnea
* Apneas- episodic cessation of central ventilation drive
o Thus snoring is less common
* More in elderly, with underlying CNS lesions- ex. tumor, stroke

Sleep Apnea: Consequences
* Depression
* Anxiety
* Morning headaches
* Cognitive dysfunction
* Hypertension

Restless Legs Syndrome
* Paresthesias and/or dysesthesias in the legs, relieved by movements
* Usually occur in transition from wakefulness to sleep

RLS Causes
* Peripheral neuropathies
* Peripheral vascular disease
* Medication side effects
* Anemia
* Pregnancy
* Renal failure

Circadian Rhythm Disorders
* Delayed Sleep Phase Syndrome
* Jet Lag
* Accelerated Sleep Phase Syndrome
* Shift Work Sleep Disorder

Insomnia from Medical Conditions
* Reflux (GERD)
* Nocturia
* Peripheral neuropathies
* Breathing problems- Asthma, COPD
* Heart Disease/Failure
* Pain conditions

Psychiatric Causes of Insomnia
* Depression
* Anxiety
* Psychosis
* Substance intoxication/withdrawal

Sleep and Sleep Disorders.ppt

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