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Due to concern for a possible “as yet undiscovered” infectious etiology, CFS patients excluded from donating blood by the American Red Cross in 2010

COMMONLYASSOCIATED CONDITIONS

Common comorbidities include:

Fibromyalgia (more common in women)

Irritable bowel syndrome

Gynecologic conditions (pelvic pain, endometriosis) and GYN surgeries (hysterectomy, oophorectomy) (2)

Anxiety disorders

Major depression

Posttraumatic stress disorder (including physical and/or past sexual abuse)

Domestic violence

Attention deficit hyperactivity disorder (ADHD)

Postural orthostatic tachycardia syndrome (POTS)

Sleep disorders, including OSA Reduced left ventricular size and mass

DIAGNOSIS

HISTORY

Athorough medical history and psychosocial history is required for accurate diagnosis. Box 1 shows updated diagnostic criteria proposed by the Institute of Medicine.

ALERT

Box 1. 2015 IOM Criteria for Diagnosis of Myalgic Encephalomyelitis/CFS (1)

Each of the following three symptoms at least half of the time, to at least a moderately severe degree:

Asubstantial reduction or impairment in the abililty to engage in pre-illness levels occupational, educational, social, or personal activities that persists for >6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not a result of ongoing excessive exertion, and is not substantially alleviated by rest

Postexertional malaise*

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Unrefreshing sleep*

Plus at least one of the two following manifestations (chronic, severe):

Cognitive impairment* Orthostatic intolerance

*Frequency and severity of symptoms should be assessed.

Common illnesses to exclude (2):

–Anemias

–Autoimmune diseases (rheumatoid arthritis, lupus)

–Significant cardiac or pulmonary disease

–Endocrine disorders (diabetes, Addison disease, thyroid disorder)

–Infectious disease (tuberculosis, HIV/AIDS, chronic hepatitis, Lyme disease)

–Intestinal diseases (celiac or Crohn)

–Neurologic disorders (such as multiple sclerosis, Parkinson disease, myasthenia gravis)

–Primary psychiatric disorders and substance abuse (clinical depression not included)

–Primary sleep disorders such as sleep apnea

–Malignancies

PHYSICALEXAM

Complete physical exam to rule out other medical causes for symptoms. A complete mental status examination should be performed as well.

DIFFERENTIALDIAGNOSIS

Idiopathic chronic fatigue (i.e., fatigue of unknown cause for >6 months without meeting criteria for CFS)

Psychiatric disorders

–Major depression

–Somatization disorder

Physiologic fatigue (sleep disturbance, menopause)

Pregnancy until 3 months postpartum

Insomnia: primary (no clear etiology) versus secondary (e.g., due to anxiety, depression, environmental factors, poor sleep hygiene)

Other known or defined systemic disease

Endocrine disorder (hypothyroidism, Addison disease, Cushing syndrome, diabetes mellitus)

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Localized infection (e.g., occult abscess)

Chronic or subacute bacterial disease (e.g., endocarditis)

Lyme disease

Fungal disease (e.g., histoplasmosis, coccidioidomycosis)

Parasitic disease (e.g., amebiasis, giardiasis, helminth infestation)

HIV or related disease

Iatrogenic (e.g., medication side effects)

Toxic agent exposure

Obesity

Malignancy

Autoimmune disease

Chronic inflammatory disease (sarcoidosis, Wegener)

Neuromuscular disease (MS, myasthenia gravis)

DIAGNOSTIC TESTS & INTERPRETATION

No validated diagnostic test available and finding an abnormal result is not always the same as discovering the cause of fatigue. Be prepared to renew the search for the cause if the problem is treated and the patient remains fatigued.

Initial Tests (lab, imaging)

Standard laboratory tests are recommended to rule out other causes for symptoms:

–CBC; complete metabolic panel

–Urinalysis

–Thyroid-stimulating hormone (TSH) and free T4

–ESR or C-reactive protein

–Magnesium and phosphorus level

–Screen for drugs of abuse.

–Age-/gender-appropriate cancer screening

Additional studies, if clinical findings are suggestive or patient at risk:

–Creatine kinase

–Anti-nuclear antibodies and rheumatoid factor

–Tuberculin skin test

–Serum cortisol

–HIV; RPR; VDRL

–Lyme serology

–IgAtissue transglutaminase

As domestic violence is a common component of the differential diagnosis,

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screen using:

–“Have you ever been hit, kicked, punched, or otherwise, hurt by someone within the past year? If so, by whom?”

–“Do you feel safe in your current relationship?”

–“Is there a partner from a previous relationship who is making you feel unsafe now?”

No applicable imaging tests available; however, EEG and/or MRI may be useful if patient has CNS symptoms; polysomnography, if patient has increased somnolence (4)

Follow-Up Tests & Special Considerations

Assess for comorbid psychiatric disorders.

Assess for personality and psychosocial factors and maladaptive coping styles. In patients with sleep disturbance, polysomnography may reveal a treatable comorbid disease.

TREATMENT

No treatment yet proven effective by large randomized trials; recommendations based on expert opinion and standard symptom management (1,2)

Focus on changes in lifestyle and insight, with a goal to avoid complicating treatments (e.g., addictive medications, invasive testing) or interventions that support secondary gain.

Amulti-disciplinary approach is recommended.

GENERALMEASURES

ALERT

No definitive cure. Treatment involves symptom management and guided selfmanagement. The aim is to reduce symptoms and improve quality of life by establishing a good therapeutic relationship. It is helpful to identify troublesome symptoms (pain and insomnia) and address those first. Both cognitive-behavioral therapy (CBT) and graded exercise therapy (GET) are effective. Medication is often of little value.

Individual CBT: Challenge fatigue-related cognition; plan social and occupational rehabilitation.

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GET: Track amount of exercise patient can do without exacerbating symptoms and gradually increase intensity and duration. Both involve a careful balance between activity and rest. Fear of movement and avoidance of physical activity are common in CFS.

Patients learn how to gradually increase activity in a way that will not exacerbate their illness. Vigorous exercise can trigger relapse, perhaps related to immune dysregulation.

Improves functional capacity and diminishes fatigue

GET is more effective with educational interventions using telephone reminders.

Duration of illness does not predict treatment outcome; aggressive combined care indicated for all

MEDICATION

No established pharmacologic treatments

If medications are needed, use the lowest effective dose and increase cautiously.

Studies have been conducted with antivirals, antidepressants, immunoglobulins, hydrocortisone, and modafinil; none show clear benefit

Agomelatine, an antidepressant with agonist activity at melatonin receptors, is promising in early studies.

If insomnia is present, use of nonaddicting sleep aids (hydroxyzine, trazodone, doxepin, etc.) may improve outcomes.

ISSUES FOR REFERRAL

Psychiatrist to help manage comorbid behavioral disorders

Rehabilitative medicine

Sleep or pain management specialist

COMPLEMENTARY& ALTERNATIVE MEDICINE

Treatment such as acupuncture, massage, and chiropractic have been shown to be beneficial for some patients suffering from pain (2)[B].

Other helpful nonpharmacologic interventions may include physical therapy, stretches, hydrotherapy, yoga, Tai Chi, and meditations. Hot or cold packs, warm baths as well as electrical massagers, transcutaneous electrical nerve stimulations can also be considered.

Equivocal evidence for homeopathy and biofeedback

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ONGOING CARE

FOLLOW-UPRECOMMENDATIONS

Patient Monitoring

Although no consensus exists, periodic reevaluation is appropriate for support, relief of symptoms, and assessment for other possible causes of symptoms.

DIET

Good nutrition and well balanced diet is advisable.

Ensure patient obtains at least the recommended daily allowance of vitamins and minerals.

No particular diet program has been shown to be effective for treatment of CFS.

Whether weight loss improves symptoms in obese CFS patients, it has yet to be tested.

PATIENT EDUCATION

Gradual increase in physical exercise

Avoid extended periods of rest but ensure adequate rest between sessions.

Patient education is an important part of treatment of CFS, such as education on the benefits of cognitive therapies, lifestyle changes, and pharmacologic therapy directed at specific-associated symptoms. Job modification should also be proposed as needed.

Chronic Fatigue and Immune Dysfunction Syndrome Association of America: http://solvecfs.org/

CDC, Chronic Fatigue Syndrome: http://www.cdc.gov/cfs/

PROGNOSIS

Fluctuating course is common.

Generally, improvement is slow, with a course of months to years.

An estimated 15% full recovery rate

Patients with poor social adjustment, a strong belief in an organic etiology, financial secondary gain, or age >50 years are less likely to improve.

COMPLICATIONS

CFS patients may reduce physical activity out of fear that it may worsen symptoms.

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Depression

Unemployment: Although studies document improvement with treatment, <1/3 of patients in trials return to work.

The Social Security Administration considers CFS to be a disability.

Receipt of third-party disability payments (secondary gain) has been associated with treatment nonresponse.

Polypharmacy

Chronic immune activation or an associated infection may play a role in an increased risk for non-Hodgkin lymphoma in elderly (>80 years) CFS patients.

REFERENCES

1.Unger ER, Lin JS, Brimmer DJ, et al. CDC grand rounds: chronic fatigue syndrome—advancing research and clinical education. MMWR Morb Mortal Wkly Rep. 2016;65(5051):1434–1438.

2.Friedberg F, Bateman L, Bested AC, et al. ME/CFS: A Primer for Clinical Practitioners. Chicago, USA: International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis; 2014.

3.Lievesley K, Rimes KA, Chalder T. Areview of the predisposing, precipitating and perpetuating factors in chronic fatigue syndrome in children and adolescents. Clin Psychol Rev. 2014;34(3):233–248.

4.Duffy FH, McAnulty GB, McCreary MC, et al. EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients—a case control study. BMC Neurol. 2011;11:82.

ADDITIONALREADING

Centers for Disease Control and Prevention. Diagnosis and management of chronic fatigue syndrome, CDC course for clinicians. http://www.cdc.gov/cfs/education/diagnosis/course.html. Accessed October 11, 2016.

Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Board on the Health of Select Populations, Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Washington, DC: National Academies Press; 2015.

Social Security Administration. Providing medical evidence to the social security administration for individuals with chronic fatigue syndrome fact sheet. https://www.socialsecurity.gov/disability/professionals/cfs-pub063.htm.

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Accessed October 11, 2016.

Yancey JR, Thomas SM. Chronic fatigue syndrome: diagnosis and treatment. Am Fam Physician. 2012;86(8):741–746.

SEE ALSO

Algorithm: Fatigue

CODES

ICD10

R53.82 Chronic fatigue, unspecified

CLINICALPEARLS

No pharmacologic agents (e.g., antidepressants, immune modulators) have been shown to be consistently effective in treating CFS.

~70% of patients show improvement with CBT; 55% with GET; in many cases, the combination of these two treatments is helpful.

There are many more patients with idiopathic chronic fatigue than true CFS. To diagnose CFS, use the IOM diagnostic criteria.

Standardized instruments (SF-36, symptom index, and Multidimensional Fatigue Inventory [MFI]) are of use in the diagnosis of CFS and help to follow patient progress.

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CHRONIC KIDNEYDISEASE

Crystal Verdick, DO, MS James E. West, MD

BASICS

Chronic kidney disease (CKD) is defined as structural or functional abnormalities of the kidney for ≥3 months, as determined by either pathologic abnormalities or markers of damage—including abnormalities in blood or urine tests, histology, imaging studies, or history of kidney transplant—or a GFR <60

mL/min/1.73 m2 for ≥3 months.

DESCRIPTION

In 2012, Kidney Disease: Improving Global Outcome (KDIGO) classified CKD in six categories by GFR estimation (in mL/min/1.73 m2):

–G1: kidney damage with normal or increased GFR ≥90

–G2: mild ↓ GFR 60 to 89

–G3a: mild to moderate ↓ GFR 45 to 59

–G3b: moderate to severe ↓ GFR 30 to 44

–G4: severe ↓ GFR 15 to 29

–G5: kidney failure: GFR <15 or dialysis

CKD per albumin-to-creatinine ratio (ACR) category:

–A1: normal to mildly increased: <30 mg/g or <3 mg/mmol

–A2: moderately increased: 30 to 300 mg/g or 3 to 30 mg/mmol

–A3: severely increased: >300 mg/g or >30 mg/mmol

Risk of progression depends on comorbid conditions.

System(s) affected: renal/urinary, cardiovascular, skeletal, endocrine, metabolic, hematologic, lymphatic, immune, neurologic

Synonym(s): chronic renal failure; chronic renal insufficiency

Geriatric Considerations

GFR normally decreases with age, despite normal creatinine (Cr). Adjust renally cleared drugs for GFR in the elderly.

Pediatric Considerations

CKD definition is not applicable for children <2 years because of lower GFR even when corrected for body surface area. Calculated GFR based on serum Cr

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is used in this age group.

Pregnancy Considerations

Renal function in CKD may deteriorate during pregnancy. Cr >1.5 and hypertension (HTN) are major risk factors for worsening renal function.

Increased risk of premature labor, preeclampsia

ACE inhibitors and angiotensin receptor blockers (ARBs) are contraindicated due to teratogenicity. Use diuretics with caution.

EPIDEMIOLOGY

African Americans are 3.6 times more likely to develop CKD than Caucasians.

Predominant sex: similar in both sexes; however, incidence rate of end-stage renal disease (ESRD) is 1.6 times higher in males than females.

Incidence

Estimated annual incidence of 1,700/1 million population

Prevalence

Overall prevalence of CKD is 14.2%. Unadjusted prevalence/incidence rates of ESRD (stage 5) are 1,752 and 362.4/1 million, respectively. Numbers do not reflect the burden of earlier stages of CKD (stages 1 to 4), which are estimated to affect 13.1% of the population nationwide or 26.3 million in the United States.

ETIOLOGYAND PATHOPHYSIOLOGY

Progressive destruction of kidney nephrons; GFR will drop gradually, and plasma Cr values will approximately double, with 50% reduction in GFR and 75% loss of functioning nephrons mass. Hyperkalemia usually develops when GFR falls to <20 to 25 mL/min. Anemia develops from decreased renal synthesis of erythropoietin.

Renal parenchymal/glomerular

–Nephritic: hematuria, RBC casts, HTN, variable proteinuria

Focal proliferative: IgAnephropathy, systemic lupus erythematosus (SLE), Henoch-Schönlein purpura, Alport syndrome, proliferative glomerulonephritis, crescenteric glomerulonephritis

Diffuse proliferative: membranoproliferative glomerulonephritis, SLE, cryoglobulinemia, rapidly progressive glomerulonephritis (RPGN), Goodpasture syndrome

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