AFP Journal Review

1. AFP Journal Review June 15, 2007 issue Lianne Beck, MD Assistant Professor Emory Family Medicine

2. Articles • Fever of Unidentifiable Source in Young Children • Menorrhagia • Schizophrenia • Therapies for Diabetes

3. Fever w/o a Source in Infants • 1 in 5 acutely ill, non-toxic appearing children have an unidentifiable source of fever. • Most infants will have self-limited viral illness. • Rates of occult bacteremia and serious bacterial infections (SBI) have declined since H. fluenza, type B and S. pneumonia vaccines. (10% 1.8%) • SBIs more common in infants < 90 days old, and especially in those younger than 29 days.

4. Definition of Fever and SBI • Rectal temp of 100.4 (38° C) or greater. • Axillary and tympanic temps are unreliable in infants. • Afebrile at time of presentation should not be reassuring. • SBIs include bacteremia, bacterial gastroenteritis, cellulitis, meningitis, osteomyelitis, pneumonia, septic joint, urinary tract infections.

5. History and Physical Exam • History • recent sx’s, vaccinations, sick contacts, birth history, medical problems, maternal fever at time of delivery, GBS colonization, maternal HSV. • Response to antipyretics not correlated with lower risk of SBI. • Physical exam to look for possible source. • Toxic signs • cyanosis, decreased activity, hyper/hypoventilation, inability to interact with parents or surroundings, irritability, lethargy, weak eye contact.

6. Diagnostic Tests • WBC < 15,000 or ANC < 10,000 low risk • UA and Culture via cath or suprapubic aspiration • LP consider w/ emperic abx • Stool testing in pts with diarrhea • CXR if pulmonary signs/sx’s present OR if rectal temp > 102.2 and WBC > 20,000

9. Menorrhagia • Defined as excessive CYCLIC uterine bleeding that occurs at regular intervals over several cycles, or prolonged bleeding that lasts for more than 7 days. • Classic definition of > 80 ml of blood loss per cycle rarely used clinically, due to subjectivity. • Low ferritin, clot size, and rate of pad/tampon change during full flow most predictive of blood loss volume > 80 ml. • Pt distress related to disruption in work, sexual activity, or quality of life and NOT menstrual volume alone are key in determining treatment.

10. Risk Factors • Increased Age • Premenopausal leiomyomata • Endometrial polyps • Platelet Dysfunction (von Willebrand’s) • Parity, BMI and smoking are NOT considered risk factors

11. Diagnostic Testing Royal College ACOG of Ob/Gyn *Only if other historical or clinical features suggest specific condition

12. Endometrial Evaluation Evaluation Type Reliability Comment

13. Treatment

14. Endometrial Ablation

15. Menorrhagia

16. Schizophrenia • Prevalence of 1% in all cultures • Equally common in men and women • Men present in late teens, early 20s • Women present in late 20s, early 30s • Family history is biggest risk factor • Dopamine plays a role, but not entirely

17. Symptoms • Positive symptoms: hallucinations, delusions (paranoid) • Negative symptoms: flattened affect, loss of sense of pleasure, loss of will or drive, social withdrawal • Disorganized speech and behavior: loose associations, schizophasia - “word salad”, difficulty in performing normal daily activities, childlike silliness, outbursts of unpredictable agitation

18. 5 Classic Types • Paranoid – preoccupied with one or more delusions or auditory hallucinations • Disorganized – Speech and behavior disorganized, flat or inappropriate affect • Catatonic – immobility, excessive purposeless motor activity, extreme negativism, peculiar voluntary movement • Undifferentiated – none of criteria of above are met • Residual– continued presence of negative symptoms and at least 2 attenuated positive symptoms, but no significant positive psychotic features • Three-factor dimensional model – psychotic, disorganized, and negative. Symptoms are absent, mild, moderate or severe.

19. DSM IV Diagnostic Criteria • 2 or more symptoms*, each present for a one month period (or less if treated) • Marked social/occupational dysfunction • Continuous signs of disturbance persists for at least 6 months • Schizoaffective and mood disorder w/ psychotic features have been ruled out • Substance abuse, medications, general medical conditions have been rule out • If there is history of PDD, diagnosis is made only if delusions or hallucinations are also present for at least a month (or less if tx’d) *Only one symptom required if delusions are bizarre or hallucinations consist of running commentary on person’s behaviors/thoughts, or 2 or more voices conversing w/each other

20. Differential Diagnosis • Brief psychotic disorder – last < 1 month • Delirium - acute, fluctuating change in mental status, with inattention and altered levels of consciousness. • Delusional disorder – not bizarre, no other characteristics • Medical illness - hepatic encephalopathy, hypoglycemia, electrolyte abnormalities, sepsis • Medication-induced - anticholinergics, anxiolytics, digoxin, phenytoin, steroids, narcotics, and cimetidine • Mood disorder w/ psychotic features - major depressive, manic, or mixed episodes

21. Differential Diagnosis • Pervasive developmental disorder - recognized during infancy or early childhood; absence of delusions and hallucinations • Psychotic disorder NOS - insufficient information • Schizophreniform disorder - Lasts one to six months; diagnosis does not require a decline in functioning • Schizotypal personality disorder - Pervasive patterns of social and interpersonal deficits beginning in early adulthood; accompanied by eccentric behavior and cognitive or perceptual distortions • Substance abuse and/or withdrawal

22. Drug Treatment • First generation antipsychotics • “Neuroleptics” • Dopamine D2 antagonists • Haloperidol (Haldol) • Thiothixene (Navane) • Atypical antipsychotics • Low affinity D2 antagonists • High affinity 5HT2A antagonists • Clozapine (Clozaril), Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel), Ziprasidone (Geodon), Aripiprazole (Abilify)

23. Neurologic Side Effects of First Generation Antipsychotics Side effect Features Onset Treatment

24. Adverse effects of Second Generation Antipsychotics (Atypicals) • Weight gain (occur with both classes) • Diabetes (reversible) • Hyperlipidemia (TC, TG) • Hyperuricemia • Clozapine and Olanzapine highest risk

25. Prognosis • Individual, group, family treatments show promise, but more studies needed • Intensive Psychiatric Rehab Treatment has resulted in improved functioning • CBT reduces + and – symptoms, but no evidence it reduces relapse rates • Higher rates of substance abuse • Accelerated heart disease is most common cause of death • Suicide is a common cause of death: 10% lifetime risk

27. Therapies for Diabetes • Pramlintide (Symlin) and Exenatide (Byetta) are new injectable drugs approved in 2005. • Symlin is indicated for BOTH type I and type II DM, is a synthetic analogue of human Amylin. Used WITH insulin, metformin and/or sulfonlyurea. • Byetta indicated for type II DM, a GLP-1 mimetic, a synthetic form of exendin-4 (found naturally in saliva of Gila monster.) Used with metformin and/or sulfonylurea.

28. Mechanism of Action of Amylin Buse J. B., et al. Clinical Diabetes 20:137-144, 200

29. Mechanism of Action of Incretin Byetta Januvia

30. Therapies for Diabetes • Sites of Action • Brain – Improves satiety • Liver – Inhibits release of glucagon • Stomach – Delays gastric emptying • Pancreas – Stimulates release of insulin and beta cell proliferation and differentiation (exenatide only)

31. Therapies for Diabetes • Pramlintide (Symlin) • Type I DM • 15 mcg SC QAC, increase by 15 mcg every 3-7 days to target of 60 mcg • Type II DM • 60 mcg SC QAC, increase to target of 120 mcg • Adverse effects - nausea, HA, anorexia, abd pain, vomiting, severe hypoglycemia • Cost - $382/month • Pregnancy Category C

32. Therapies for Diabetes • Exenatide (Byetta) • Dose – 5 mcg BID one hour before morning and evening meals. Target 10 mcg BID. • Adverse effects – GI, dizziness, HA, hypoglycemia • Costs - $176 - $207/month • Not recommended for pts w/ GFR < 30 mL/min, children, or pts with severe GI disease.

33. Therapies for Diabetes • Pramlintide has been shown to cause statistically significant weight loss (B) and reduction of A1C (C) when used in conjunction with insulin, metformin or a sulfonylurea. • Exenatide shown to cause a statistically significant weight loss (B), reduction in fasting and postprandial plasma glucose and A1C levels (C) when used with metformin or sulfonylurea. • No studies have examined drugs effects on diabetic complications, CVD, or overall mortality.

34. Quiz • Which one of the following statements about the use of chest radiography in febrile children is correct? A. It is recommended for all febrile children younger than 36 months. B. It is recommended for all febrile children younger than 90 days. C. It is recommended for all febrile infants younger than 29 days. D. It is recommended only when a child up to three months of age presents with pulmonary symptoms.

35. Quiz • A 32-year-old patient states she has had heavy periods for years. She often misses work because of discomfort and leakage. Which one of the following is the most patient-oriented estimate of the extent of her menorrhagia? A. A pictorial chart assessing blood loss. B. The patient's description of the amount of blood lost. C. Number and size of clots. D. A low serum ferritin level. E. The patient's statement that her lifestyle is impaired.

36. Quiz • A patient with normal hormone levels has been diagnosed with fibroids. A pelvic examination reveals a large, boggy uterus. Which one of the following is the best test to confirm the diagnosis? A. Transvaginal ultrasonography. B. Thyroid-stimulating hormone. C. Endometrial biopsy. D. Saline infusion sonohysteroscopy.

37. Quiz • Which one of the following statements about the diagnosis of schizophrenia is correct? A. Onset is usually abrupt with no prodromal phase. B. At least one symptom or sign must be present for more than two years to make the diagnosis. C. The diagnosis rarely changes over time. D. There are both positive and negative symptoms.

38. Quiz • Which one of the following statements about risk factors for schizophrenia is correct? A. The emotional climate of the family environment has little or no effect in persons with a genetic risk of schizophrenia. B. The diagnosis is more common in Hispanics than in other ethnic groups. C. Family history is the most important risk factor. D. Socioeconomic status is the most important risk factor.

39. Quiz • Which one of the following is the most common adverse effect associated with exenatide (Byetta) use? A. Nausea. B. Dizziness. C. Headache. D. Hypoglycemia.

40. Quiz (X-Type) • Which of the following increase the risk of serious bacterial infection in febrile children? A. Age older than 90 days. B. Failure to respond to antipyretics. C. Rectal temperature of 103° F (39.4°C) or higher. D. Toxic appearance.

41. Quiz • If a patient with menorrhagia wants to maintain her childbearing potential, which of the following treatment options is/are known to be effective? A. Continuous progestin from days 5 to 26 of the menstrual cycle. B. Levonorgestrel-releasing intrauterine device (Mirena). C. Nonsteroidal anti-inflammatory drugs. D. Thermal balloon ablation.

42. Quiz • Which of the following side effects is/are associated with atypical antipsychotic therapy for schizophrenia? A. Drowsiness. B. Hypercholesterolemia. C. Diabetes. D. Weight gain.

43. Quiz • Clinical trials have shown that exenatide (Byetta) reduces which of the following in patients with diabetes? A. A1C levels. B. Fasting plasma glucose levels. C. Diabetic complications D. Mortality rate.

44. Quiz • Clinical trials have shown that pramlintide (Symlin) decreases which of the following in patients with diabetes? A. Mortality rate. B. A1C levels. C. Macrovascular complications. D. Body weight.

45. Sources • Sur D, Bukont E. Fever of Unidentifiable Source in Young Children. American Family Physician. June 15, 2007. • Apgar B, Kaufman A, Nwogu U, Kittendorf A. Menorrhagia. American Family Physician. June 15, 2007. • Shultz S, North S, Shields C. Schizophrenia. American Family Physician. June 15, 2007. • Jones M. Therapies for Diabetes. American Family Physician. June 15, 2007