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ACE Inhibitor Induced Cough
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Angiotensin-converting enzyme (ACE) inhibitors are widely prescribed for hypertension and heart failure. These drugs are commonly associated with cough, and are less commonly associated with angioedema, which may be potentially life threatening.

Cough and Respiratory Reactions

Although estimates vary, 20% or more of patients who receive ACE inhibitors develop a dry cough, sometimes severe enough to require discontinuation of the drug. With few exceptions, ACE inhibitor cough is an apparent class effect that may occur with all ACE inhibitors. Although resolution of the cough after withdrawal of ACE inhibitors may occur within days, it may require weeks.

Mechanisms of Cough From Angiotensin-Converting Enzyme Inhibitors

The inhibition of ACE (also known as kininase II and bradykinin dehydrogenase) prevents the conversion of angiotension I to angiotensin II, with consequent salutary benefits via the renin-angiotensin system in pathological states. ACE inhibitor cough is thought to be linked to the suppression of ACE, which is proposed to result in an accumulation of substances normally metabolized by ACE: bradykinin or tachykinins (with the consequent stimulation of vagal afferent nerve fibers) and substance P. However, the development of cough may result from a more complex cascade of events than originally believed. Bradykinin has been shown to induce the production of arachidonic acid metabolites and nitric oxide (NO), and there is some evidence that these products, which are subject to regulation by other pathways, may promote cough through proinflammatory mechanisms.

Can Angiotensin II Receptor Blockers be Used in Patients With a History of Angiotensin-Converting Enzyme Inhibitor Cough?

Angiotensin II receptor blockers (ARBs) confer many of the same hemodynamic benefits as ACE inhibitors, but they do not directly inhibit ACE activity or inhibit the breakdown of bradykinin. Theoretically, ARBs would be predicted to be acceptable substitutes for ACE inhibitors in patients who have adverse events such as bradykinin-mediated cough.


A 53-year-old widowed woman comes to the office for a health maintenance examination. She is a new patient who has a history of hypertension. She says that she has no complaints, except for a cough that she began to notice 4 months ago. She denies nasal discharge, "a tickle in the throat," frequent throat clearing, heartburn and the sensation of regurgitation, fever, sputum production, cigarette smoking, illegal drug use, sexual activity, occupational exposures, and any other symptoms associated with a respiratory infection. She says that the cough is not seasonal or associated with wheezing. Her temperature is 37.0 C (98.6 F), blood pressure is 135/90 mm Hg, pulse is 70/min, and respirations are 14/min. Physical examination is unremarkable. The most appropriate next step is to

A. order an electrocardiogram
B. order an x-ray of the chest
C. question her about medications
D. refer her for fiberoptic bronchoscopy
E. schedule her for pulmonary function tests

The correct answer is C. This patient has a chronic cough, which is usually considered chronic because it is lasting more than 3 weeks. It may be due to a variety of things. However, the important lesson in this question is that before you turn to diagnostic studies you need, to make sure that you have obtained a detailed history. The case history will provide the answer to almost every question that you will need to ask her, except what medications she takes. Since she is a new patient, you will need to find out if she is taking an ACE inhibitor, such as captopril or enalapril, which is a frequent cause of a chronic cough in hypertensive patients. They cause a cough in up to 20% of people taking them. The exact mechanism is unknown, but it is thought to somehow be related to bradykinin and substance P. The treatment for the cough is the discontinuation of the ACE inhibitor.

An electrocardiogram (choice A) is unnecessary at this time in this patient, complaining of a chronic cough. She is not complaining of chest pain and there is nothing in her history that suggests an arrhythmia. The most important next step, is to take a detailed history before you order diagnostic tests.

An x-ray of the chest (choice B) may be appropriate in the near future, but it is not the next step at this time. Before you order diagnostic studies, you need to make sure that you ask her any questions that might help you figure out the etiology of her cough. Asking her about medications is very important because ACE inhibitors cause a chronic cough in up to 20% of patients taking this medication.

A fiberoptic bronchoscopy (choice D) is used to obtain histologic and cytologic specimens and to visualize an endobronchial tumor. Before you turn to such a specialized study, you need to first obtain a detailed history. If the patient is not taking an ACE inhibitor, a chest x-ray should usually be performed, and if this is abnormal, sputum cytology, a high resolution CT scan, and fiberoptic bronchoscopy should be considered.

Pulmonary function tests (choice E) are used to assess airway hyperresponsiveness for patients in which you suspect asthma, and lung volumes and diffusion capacity in patients in which you suspect a diffuse interstitial lung disease. A detailed history is necessary before using any of these studies.

A 54-year-old man is admitted to the hospital with chest pain. Based on serial enzyme determinations and his electrocardiogram, he is diagnosed with a myocardial infarction. He is hospitalized for three days and recovers, but left ventricular dysfunction remains. He is prescribed several medications on discharge. A week later, he complains to his doctor about a dry, non-productive, persistent cough. Which of the following medications is most likely responsible for the appearance of this symptom?

A. Aspirin
B. Captopril
C. Metoprolol
D. Procainamide
E. Warfarin

The correct answer is B. Captopril, an angiotensin-converting enzyme inhibitor (ACE inhibitor), reduces the mortality associated with myocardial infarction. ACE inhibitors decrease the amount of ventricular remodeling after infarction and reduce the risk of congestive heart failure; they may also diminish the risk of a second heart attack. ACE inhibitors are known to frequently cause a dry cough. They also cause headache, diarrhea, fatigue, nausea, and dizziness. All of the other agents might be prescribed in this setting, but dry cough is only associated with captopril.

Aspirin (choice A) is a nonsteroidal anti-inflammatory drug associated with increased bleeding time, gastrointestinal bleeding, and tinnitus. Metoprolol (choice C), a beta-1 antagonist, can cause hypoglycemia, peripheral vasoconstriction, and CNS side effects. Procainamide (choice D) is a group IA antiarrhythmic that can cause antimuscarinic and direct depressant effects on the heart, and may produce a reversible syndrome similar to lupus erythematosus. Warfarin (choice E) is an oral anticoagulant that can cause bleeding at therapeutic doses, and bone defects in the developing fetus.
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Vitiligo is a loss of skin melanocytes that causes areas of skin depigmentation of varying sizes. Cause is unknown, but genetic and autoimmune factors are likely. Diagnosis is usually clear based on skin examination. Common treatments include topical corticosteroids (often combined with calcipotriene), calcineurin inhibitors (tacrolimus and pimecrolimus), and narrowband ultraviolet (UV) B or psoralen plus UV A. Widespread disease may be responsive to narrowband UVB treatments. For severe widespread pigment loss, residual patches of normal skin may be permanently depigmented (bleached) with monobenzyl ether or hydroquinone.

Vitiligo affects up to 2% of the population.


Etiology is unclear, but melanocytes are lacking in affected areas. Proposed mechanisms include autoimmune destruction of melanocytes, reduced survival of melanocytes, and primary melanocyte defects.

Vitiligo can be familial (autosomal dominant with incomplete penetrance and variable expression) or acquired. Some patients have antibodies to melanin. Up to 30% have other autoimmune antibodies (to thyroglobulin, adrenal cells, and parietal cells) or clinical autoimmune endocrinopathies (Addison disease, diabetes mellitus, pernicious anemia, and thyroid dysfunction). However, the relationship is unclear and may be coincidental. The strongest association is with hyperthyroidism and hypothyroidism.

Occasionally, vitiligo occurs after a direct physical injury to the skin (eg, as a response to sunburn). Patients may associate the onset of vitiligo with emotional stress.

Symptoms and Signs

Vitiligo is characterized by hypopigmented or depigmented areas, usually sharply demarcated and often symmetric. Depigmentation may be localized, involving 1 or 2 spots or entire body segments (segmental vitiligo); rarely, it may be generalized, involving most of the skin surface (universal vitiligo). However, vitiligo most commonly involves the face (especially around the orifices), digits, dorsal hands, flexor wrists, elbows, knees, shins, dorsal ankles, armpits, inguinal area, anogenital area, umbilicus, and nipples. Cosmetic disfigurement can be especially severe and emotionally devastating in dark-skinned patients. Hair in vitiliginous areas is usually white.


Clinical evaluation

Depigmented skin is typically obvious on examination. Subtle hypopigmented or depigmented lesions are accentuated under a Wood light examination (see Wood light). Differential diagnosis includes postinflammatory hypopigmentation, piebaldism (a rare autosomal dominant disorder in which depigmented patches surrounded by hyperpigmented areas occur most often on the forehead, neck, anterior trunk, and mid-extremities), morphea (localized scleroderma, in which skin is usually sclerotic), leprosy (in which lesions are usually hypoesthetic), lichen sclerosus, pityriasis alba, chemical leukoderma, and leukoderma due to melanoma. Although there are no evidence-based guidelines, it is reasonable for physicians to do CBC, fasting blood glucose, and thyroid function tests.


• Protection of affected areas from sunlight
• Topical corticosteroids and calcipotriene
• Topical calcineurin inhibitors with face or groin involvement
• Narrowband UVB or psoralen plus ultraviolet A (PUVA) therapy

Treatment is supportive and cosmetic. Physicians must be aware of individual and ethnic sensibilities regarding uniform skin coloring; the disease can be psychologically devastating. All depigmented areas are prone to severe sunburn and must be protected with clothing or sunscreen.

Small, scattered lesions may be camouflaged with makeup. With more extensive involvement, treatment is usually aimed at repigmentation. However, little is known about comparative efficacies of such treatments. Traditional first-line therapy is potent topical corticosteroids, which may cause hypopigmentation or atrophy in normal surrounding skin. Calcineurin inhibitors (tacrolimus and pimecrolimus) may be particularly useful for treating areas of the skin (such as the face and groin) where adverse effects of topical corticosteroid therapy most commonly occur. Calcipotriene blended with betamethasone dipropionate may also be helpful and more successful than monotherapy with either drug. Oral and topical PUVA is often successful, but hundreds of treatment sessions may be necessary. Narrowband UVB is as effective as topical PUVA and has few adverse effects, making narrowband UVB preferable to PUVA. Narrowband UVB is often the preferred initial treatment for widespread vitiligo. Excimer laser may be useful, particularly for localized disease that does not respond to initial topical therapy.

Surgery is reasonable only for patients with stable, limited disease when medical therapy has failed. Therapies include autologous micrografting, suction blister grafting, and tattooing; tattooing is especially useful for difficult-to-repigment areas such as the nipples, lips, and fingertips.

Depigmentation of unaffected skin to achieve homogeneous skin tone is possible with 20% monobenzyl ether or hydroquinone applied twice daily. This treatment is indicated only when most of the skin is involved and the patient is prepared for permanent pigment loss and the subsequent increased risks of photo-induced skin damage (eg, skin cancers, photoaging). This treatment can be extremely irritating, so a smaller test area should be treated before widespread use. Treatment for ≥ 1 yr may be required.

Key Points
• Some cases of vitiligo may involve genetic mutations or autoimmune disorders.
• Vitiligo can be focal, segmental, or, rarely, generalized.
• Diagnose by skin examination and consider testing with CBC, fasting blood glucose, and thyroid function tests.
• Consider treatments such as topical calcipotriene plus betamethasone dipropionate, corticosteroid topical monotherapy, narrowband UVB, or a calcineurin inhibitor (tacrolimus and pimecrolimus).


A 57-year-old man comes to your office complaining of "the famous musician" disease on his hands. He denies any family or personal history of diabetes, anemia, thyroid disease, or sudden onset of patches of hair loss. He works as a janitor at a local apartment building. His job involves mostly wiping equipment at the end of the day with antiseptics. Physical examination shows well-demarcated, depigmented patches on his fingers and the dorsum of the hands. Wood's light examination enhances these areas as fluorescent white patches. There are no texture changes or scaling associated with these areas. There is no involvement around the mouth, nipple, upper chest, axillae, groin, and glans penis. The most likely diagnosis is

A. autoimmune vitiligo
B. lichen sclerosis
C. morphea
D. occupational vitiligo
E. pityriasis alba

The correct answer is D. This patient most likely has occupational vitiligo. This type of vitiligo may occur in individuals who work in rubber garments or wear gloves that contain antioxidants. Different chemicals including thiol, phenolic compounds, catechol, and derivatives of catechols can produce depigmentation simulating classic vitiligo associated with autoimmune diseases. One source of a phenolic chemical is the antiseptics used in hospitals. Exam of depigmented areas under Wood's light usually reveal fluorescent white patches of the involved area.

Autoimmune vitiligo (choice A) is incorrect not only because this patient denies history of autoimmune disorders, such as insulin-dependent diabetes, pernicious anemia, Hashimoto's thyroiditis, Grave's disease, and alopecia areata, but also the nature of the localized lesions and his occupation point toward an exogenous cause.

Lichen sclerosis (choice B) and morphea (choice C) are both incorrect. Both of these disorders are associated with hypopigmentation and changes in skin texture.

Pityriasis alba (choice E) is incorrect because this favors the face on young kids, and is usually associated with fine scales on the surface.

A 10-year-old African American boy is brought into the office by his mother because of concerns over "white spots" on his skin that are increasing in size and number. His mother reports the first spot began 2-3 years ago on his right index finger, which was stable until recently when it increased in size. Of more concern to the mother was the increase in number of similar lesions of various size around his mouth, anus, and penile tip. Further questioning reveals a family history of diabetes and thyroid disease. Full skin examination shows depigmented, flat patches that are well demarcated with no scales or surrounding erythema located at the perioral, perianal, tip of penis, and bilateral knees as well as right index and middle fingers. Management of this patient should include

A. complete blood count and chemotherapy
B. ketoconazole shampoo 3 times per week and oral ketoconazole for 2 weeks
C. sunscreen and sun avoidance
D. topical antifungal cream
E. topical corticosteroids and phototherapy

The correct answer is E. Topical steroid and phototherapy are the two main therapeutic modalities in treating vitiligo. Vitiligo is an acquired disorder of depigmentation characterized by loss of melanocytes from the epidermis, the mucous membranes, and other tissues. A vitiliginous lesion usually presents as either a hypopigmented or snow-white, well circumscribed macule or patch. In most cases, a single lesion is initially noticed and new lesions can develop either immediately or over an extended period of time. Lesions progress in size and number. The most common sites are the face, hands, legs, glans of the penis, and the perianal region. Thyroid diseases (both hypo- and hyperthyroidism as well as Graves disease), diabetes mellitus, pernicious anemia, Addison disease, multiglandular insufficiency syndrome, and alopecia areata have been associated with vitiligo.

Complete blood count and chemotherapy (choice A) is appropriate if you suspect cutaneous T cell lymphoma. It is a chronic, frequently fatal disease of helper T cells commonly seen in patients in the fifth to seventh decades of life. Clinically, the lesions can present as erythematous, pruritic, brown-to-purple indurated plaques with central clearing or multiple, round, dome-shaped tumors. Pruritus is usually severe and excoriations are prominent.

Topical and oral ketoconazole (choice B) is incorrect because these are the mainstay of therapy in tinea versicolor. It is an extremely common superficial fungal disorder characterized by multiple scaling, oval, macular, and patchy lesions usually distributed over the upper portions of the trunk, proximal arms, and occasionally the face. The lesions are hypopigmented or hyperpigmented, caused by Pityrosporum orbiculare. Generally asymptomatic, the lesions become lighter than the surrounding skin in the summer and relatively darker during winter, hence the name tinea versicolor.

Sunscreen and sun avoidance (choice C) is incorrect because these are treatments for pityriasis alba. This is a common disorder in children, characterized by discrete asymptomatic hypopigmented patches on the face, neck, upper trunk, and proximal extremities. Most cases appear following sun exposure and result from a disturbance in pigmentation of the affected areas.

Topical antifungal cream (choice D) is the treatment for tinea corporis (ringworm), which is characterized by one or more annular, sharply circumscribed scaly patches with a clear center and scaly vesicular, papular, or pustular border. The disorder is most commonly seen in children and in individuals in warm, humid climates.
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Serotonin Syndrome
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Serotonin syndrome is a potentially life-threatening condition resulting from increased CNS serotonergic activity that is usually drug related. Symptoms may include mental status changes, hyperthermia, and autonomic and neuromuscular hyperactivity. Diagnosis is clinical. Treatment is supportive.

Serotonin syndrome can occur with therapeutic drug use, self-poisoning, or, most commonly, unintended drug interactions when 2 serotonergic drugs are used. It can occur in all age groups.

Drugs that can cause Serotonin Syndrome: Anti-depressants: MAO inhibitors, SSRIs, TCAs, 

Complications in severe serotonin syndrome can include metabolic acidosis, rhabdomyolysis, seizures, acute kidney injury, and disseminated intravascular coagulation (DIC). Causes probably include severe hyperthermia and excessive muscle activity.

Symptoms and Signs
In most cases, serotonin syndrome manifests within 24 h, and most occur within 6 h, of a change in dose or initiation of a drug. Manifestations can range widely in severity. They can be grouped into the following categories:

• Mental status alterations: Anxiety, agitation and restlessness, easy startling, delirium
• Autonomic hyperactivity: Tachycardia, hypertension, hyperthermia, diaphoresis, shivering, vomiting, diarrhea
• Neuromuscular hyperactivity: Tremor, muscle hypertonia or rigidity, myoclonus, hyperreflexia, clonus (including ocular clonus), extensor plantar responses

Neuromuscular hyperactivity may be more pronounced in the lower than the upper extremities.

Symptoms usually resolve in 24 h, but symptoms may last longer after use of drugs that have a long half-life or active metabolites (eg, monoamine oxidase inhibitors, SSRIs).

• Clinical criteria

Diagnosis is clinical. Various explicit criteria have been proposed.

The Hunter criteria are currently preferred because of ease of use and high accuracy (almost 85% sensitivity and > 95% specificity compared with diagnosis by a toxicologist). These criteria require that patients have taken a serotonergic drug and have one of the following:

• Muscle hypertonia
• Spontaneous clonus
• Tremor plus hyperreflexia
• Ocular or inducible clonus, plus either agitation, diaphoresis, or temperature > 38° C

Systemic infections, drug or alcohol withdrawal syndromes, and toxicity caused by sympathomimetic or anticholinergic drugs should also be considered in the differential diagnosis. Differentiation of serotoninsyndrome from neuroleptic malignant syndrome may be difficult because symptoms (eg, muscle rigidity, hyperthermia, autonomic hyperactivity, altered mental status) overlap. Clues to serotoninsyndrome include use of serotonergic drugs, rapid onset (eg, within 24 h), and hyperreflexia, in contrast to the often decreased reflex responses in neuroleptic malignant syndrome.

There are no confirmatory tests, but patients should have testing to exclude other disorders (eg, CSF analysis for possible CNS infection, urine testing for drugs of abuse). Also, some tests (eg, serum electrolytes, platelet count, renal function tests, CK, PT, testing for urine myoglobin) may be necessary to identify complications in severe serotonin syndrome.

• Supportive measures
• Sometimes cyproheptadine

When serotonin syndrome is recognized and treated promptly, the prognosis is usually good.

All serotonergic drugs should be stopped. Mild symptoms are often relieved with sedation using a benzodiazepine, with resolution occurring in 24 to 72 hours. If symptoms resolve more rapidly, patients should be observed for at least several hours. However, most patients require hospitalization for further testing, treatment, and monitoring.

In severe cases, admission to an ICU is required. Hyperthermia is treated by cooling. Neuromuscular blockade with appropriate sedation, muscle paralysis, and other supportive measures may be necessary. Drug treatment of autonomic abnormalities (eg, hypertension, tachycardia) should be with shorter-acting drugs (eg, nitroprusside, esmolol) because autonomic effects can change rapidly.

If symptoms persist despite supportive measures, the serotonin antagonist cyproheptadine can be given orally or, after crushing, via NGT (12 mg, then 2 mg q 2 h until response occurs). Chlorpromazine and olanzapine may be effective, but are not routinely used because of the potential for adverse effects. Unlike in malignant hyperthermia or neuroleptic malignant syndrome, dantrolene should not be used.

Consultation with a toxicologist is encouraged.

Key Points
• Drugs that increase serotonergic activity can lead to hyperthermia and neuromuscular hyperactivity, with complications of metabolic acidosis, rhabdomyolysis, seizures, acute kidney injury, and DIC.
• The diagnosis is likely if patients have taken a serotonergic drug and have muscle hypertonia, spontaneous clonus, tremor plus hyperreflexia, or the combination of ocular or inducible clonus, plus either agitation, diaphoresis, or temperature > 38° C.
• Serotonin syndrome can often be differentiated from neuroleptic malignant syndrome by use of serotonergic drugs, rapid onset (eg, within 24 h of its drug trigger), and hyperreflexia.
• Stop all serotonergic drugs and give a benzodiazepine.
• Treat complications aggressively and consider cyproheptadine.


A 25-year-old female has been treated with fluoxetine for depression, monthly hydrochlorothiazide for 1 week before her menses for premenstrual syndrome and omeprazole for gastroesophageal reflux. On the third day of her monthly fluoxetine, she began to complain of muscle spasms about the neck and shoulders. She then grabbed a friend’s tramadol for her “wry neck.” Within 2 hours of her first dose of tramadol, her muscle spasms became worse, and she began to complain of chills, goose bumps and mental agitation. In the nearby ED, she manifests hyperreflexia. Which of the following is the most likely cause of these symptoms and signs?

A. Bacteremia
B. Overt indulgence in cocaine 
C. Drug interaction
D. Thyrotoxicosis
E. Carcinoid syndrome

The answer is C. Patients who are on SSRIs along with serotonin-increasing drugs such as tramadol, meperidine, monoamine oxidase inhibitors (MAOIs), sibutramine, sumatriptan, lithium, St John’s wort and Ginkgo may result in serotonin syndrome. Findings include mental status changes, agitation, myoclonus, hyperreflexia, diaphoresis, goose bumps and shivering, tremor, diarrhea, ataxia, and fever. This can be life threatening. Further, SSRIs can increase the levels or pharmacological effects of warfarin and of the tricyclic antidepressants. Although the other choices are each somewhat plausible in certain details, the drug interaction described is by far the most likely under the circumstances portrayed in the vignette.

Symptoms of acute oral overdose of this medication include diarrhea, myoclonus, diaphoresis, elevated temperature, facial flushing, and tremor. Depending on the dose ingested, the patient may become agitated, confused, and hypertensive. Hyperreflexia can occur and progress to seizures. These symptoms may occur at conventional doses if the patient is also using monoamine oxidase inhibitors.

A. Acetaminophen 
B. Diazepam
C. Scopolamine 
D. Amitriptyline 
E. Sertraline

The answer is E. Given the widespread use of selective serotonin reuptake inhibitors (SSRIs) in the management of major depressive disorders, it is hardly surprising that their toxicity in overdose has been designated “serotonin syndrome.” Diaphoresis, diarrhea, myoclonus, tremor, and confusion are characteristics of overdoses of fluoxetine, sertraline (choice E), and most other SSRIs. In extreme situations, the toxic syndrome may be life- threatening, with seizures, marked hyperthermia, and possible ventricular arrhythmias. The syndrome may occur at conventional doses of the SSRIs with concomitant administration of monoamine oxidase inhibitors, levodopa, meperidine, lithium, or dextromethorphan (in over-the-counter cough medications). Management is supportive, with the possible use of phenytoin or lidocaine for cardiac arrhythmias and benzodiazepines for seizures.
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Nocturnal Enuresis
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Nighttime incontinence (nocturnal enuresis, or bed-wetting) is usually not diagnosed until age 7.  It is defined as involuntary voiding of urine ≥ 2 times/mo during the night. Before this time, nocturnal enuresis is typically referred to as nighttime wetting.

In primary enuresis, children have never achieved urinary continence for ≥ 6 mo. In secondary enuresis, children have developed incontinence after a period of at least 6 mo of urinary control. An organic cause is more likely in secondary enuresis.


Nocturnal enuresis

Organic disorders account for about 30% of cases and are more common in complex compared to monosymptomatic enuresis. The remaining majority of cases are of unclear etiology but are thought to be due to a combination of factors, including

• Maturational delay
• Uncompleted toilet training
• Functionally small bladder capacity (the bladder is not actually small but contracts before it is completely full)
• Increased nighttime urine volume
• Difficulties in arousal from sleep
• Family history (if one parent had nocturnal enuresis, there is a 30% chance offspring will have it, increasing to 70% if both parents were affected)

The factors contributing to organic causes of nocturnal enuresis include

• Conditions that increase urine volume (eg, diabetes mellitus, diabetes insipidus, renal failure, excessive water intake, sickle cell disease and sometimes sickle trait [hyposthenuria])
• Conditions that increase bladder irritability (eg, UTI, pressure on the bladder by the rectum and sigmoid colon [caused by constipation])
• Structural abnormalities (eg, ectopic ureter, which can cause both nocturnal and diurnal enuresis)
• Abnormal sphincter weakness (eg, spinal cord abnormalities, which can cause both nocturnal and diurnal enuresis)


History of present illness inquires about onset of symptoms (ie, primary vs secondary), timing of symptoms (eg, at night, during the day, only after voiding), and whether symptoms are continuous (ie, constant dribbling) or intermittent. Recording a voiding schedule (voiding diary), including timing, frequency, and volume of voids, can be helpful. Important associated symptoms include polydipsia, dysuria, urgency, frequency, dribbling, and straining. Position during voiding and strength of urine steam should be noted. To prevent leakage, children with enuresis may use holding maneuvers, such as crossing their legs or squatting (sometimes with their hand or heel pushed against their perineum). In some children, holding maneuvers can increase their risk of UTIs. Similar to the voiding diary, a stooling diary can help identify constipation.

Review of systems should seek symptoms suggesting a cause, including frequency and consistency of stools; fever, abdominal pain, dysuria, and hematuria (UTI); perianal itching and vaginitis (pinworm infection); polyuria and polydipsia (diabetes insipidus or diabetes mellitus); and snoring or breathing pauses during sleep (sleep apnea). Children should be screened for the possibility of sexual abuse, which, although an uncommon cause, is too important to miss.

Past medical history should identify known possible causes, including perinatal insults or birth defects (eg, spina bifida), neurologic disorders, renal disorders, and history of UTIs. Any current or previous treatments for enuresis and how they were actually instituted should be noted, as well as a list of current drugs.

Developmental history should note developmental delay or other developmental disorders related to voiding dysfunction (eg, attention-deficit/hyperactivity disorder, which increases the likelihood of enuresis).

Family history should note the presence of nocturnal enuresis and any urologic disorders.

Social history should note any stressors occurring near the onset of symptoms, including difficulties at school, with friends, or at home; although enuresis is not a psychologic disorder, a brief period of wetting may occur during stress.

Clinicians also should ask about the impact of enuresis on the child because it also affects treatment decisions.

Physical examination

Examination begins with review of vital signs for fever (UTI), signs of weight loss, and hypertension (renal disorder). Examination of the head and neck should note enlarged tonsils, mouth breathing, or poor growth. Abdominal examination should note any masses consistent with stool or a full bladder.

In girls, genital examination should note any labial adhesions, scarring, or lesions suspicious of sexual abuse. An ectopic ureteral orifice is often difficult to see but should be sought. In boys, examination should check for meatal irritation or any lesions on the glans or around the rectum. In either sex, perianal excoriations can suggest pinworms.

The spine should be examined for any midline defects (eg, deep sacral dimple, sacral hair patch). A complete neurologic evaluation is essential and should specifically target lower-extremity strength, sensation and deep tendon reflexes, sacral reflexes (eg, anal wink), and, in boys, cremasteric reflex to identify possible spinal dysraphism. A rectal examination may be useful to detect constipation or decreased rectal tone.

Interpretation of findings

Usually, primary nocturnal enuresis occurs in children with an otherwise unremarkable history and examination and probably represents maturational delay. A small percentage of children have a treatable medical disorder; sometimes findings suggest possible causes. For children who are being evaluated for nocturnal enuresis, it is important to determine whether diurnal symptoms of urgency, frequency, body posturing or holding maneuvers, and incontinence are present. Children with these symptoms have complex nocturnal enuresis, and management should be directed primarily toward controlling the diurnal symptoms.


Diagnosis is often apparent after history and physical examination. Urinalysis and urine culture are appropriate for both sexes. Further testing is useful mainly when history, physical examination, or both suggest an organic cause. Ultrasonography of the kidneys and bladder is often done to verify urinary tract anatomy is normal. Uroflow testing can show a staccato voiding pattern in patients with dysfunctional voiding.


The most important part of treatment is family education about the cause and clinical course of enuresis. Education helps decrease the negative psychologic impact of urine accidents and results in increased adherence with treatment.

Treatment should be targeted toward any cause that is identified; however, frequently no cause is found. In such cases, the following treatments may be useful.

Nocturnal enuresis

The most effective long-term strategy is a bed-wetting alarm. Although labor intensive, the success rate can be as high as 70% when children are motivated to end the enuresis, and the family is able to adhere. It can take up to 4 mo of nightly use for complete resolution of symptoms. The alarm triggers when wetting occurs. Although children initially continue to have wetting episodes, over time, they learn to associate the sensation of a full bladder with the alarm and then wake up to void prior to an enuretic event. These alarms are readily available online without prescription. An alarm should not be used by children with complex nocturnal enuresis or children with reduced bladder capacity (as evidenced by voiding diary). These children should be treated the same as children with diurnal enuresis. It is essential to avoid punitive approaches because these undermine treatment and lead only to poor self-esteem.

Drugs such as desmopressin (DDAVP) and imipramine can decrease nighttime wetting episodes. However, results are not sustained in most patients when the treatment is stopped; parents and children should be forewarned of this to help limit disappointment. DDAVP is preferable to imipramine because of the rare potential of sudden death with imipramine use.

Nocturnal Enuresis Medications

Desmopressin (DDAVP): For children ≥ 6 yr, initially 0.2 mg po once/day 1 h before bedtime, increased prn to a maximum of 0.6 mg once/day

Imipramine: For children 6–8 yr, 25 mg po once/day at night, For children > 8 yr, 50 mg po once/day at night

Caution: as side effects of imipramine include possible nervousness, personality change, disordered sleep and cardiac arrhythmias.


A 5-year-old boy is brought to the office by his mother because of recurrence of bed-wetting at night. He has a 3-month-old sister who is healthy. Physical examination is normal. Urinalysis shows: Specific gravity: 1.010 | Glucose: Negative | Protein: Negative | Microscopic: 0-1 WBC/hpf, 0 RBC/hpf. Which of the following is the most important information to share with his parents?

A. This condition will cease if they reprimand him for deliberately wetting the bed
B. The condition is self-limiting, & they should take care to lessen the emotional impact on their child
C. This is a potentially serious problem and could represent chronic inflammation of the kidneys
D. This may be a precursor of diabetes mellitus
E. This signifies a serious underlying emotional disorder

The correct answer is B. In the absence of an organic etiology, emotional stress (possibly arising from the arrival of a new sibling) is the most likely etiology of this child’s secondary enuresis. Complete urinalysis is essential in eliminating disorders such as urinary tract infections, diabetes mellitus, and diabetes insipidus. Most episodes of nocturnal enuresis are self-limited, and may not require additional therapy (choice C). The timing of the boy’s bed-wetting is significant. He has just suffered a major disruption to his world—the birth of a sibling—and may be regressing in reaction to this event. Certainly this behavior is likely to refocus his parent’s attention on him, which may be what he is seeking at an unconscious level. At any rate, the most logical advice from the physician should be reassurance that the bed-wetting will go away, especially if the parents reassure the boy of their continuing love for him. Telling them that he has a serious underlying emotional disorder (choice E) or that this is a precursor of diabetes mellitus (choice D) is inappropriate. Reprimanding him (choice A) may only make the situation worse.

An 8-year-old boy is brought to see you because his parents are concerned about his lifelong history of bedwetting at night. This behavior occurs an average of five or six nights per week. However, he does not have any daytime wetting or incontinence. His parents have tried several tactics to stop this behavior, including fluid restriction, night awakening, and rewards for dry nights, but the behavior has continued. The boy has had no medical problems and is doing well in school and with his friends. His physical examination is normal. Which of the following diagnostic and therapeutic strategies is most reasonable?

A. No further studies and a trial of imipramine
B. IV pyelogram and use of a moisture-sensitive alarm at night
C. Reassurance that he will grow out of this behavior
D. Urinalysis and use of a moisture-sensitive alarm at night
E. Urinalysis and a trial of imipramine

The answer is D. Enuresis is the involuntary loss of urine after an age of continence has been achieved in the majority of children, which typically occurs at 5 years of age in girls and 6 years of age in boys. In school-age children, the incidence of enuresis is 5% to 8%, and it generally decreases with age. The etiology of enuresis is multifactorial and likely involves physical immaturity, sleep disturbances, psychologic factors, and, possibly, genetic factors. It is critical that organic factors be sought and excluded. These include urinary tract infections, urinary tract obstructions, meningomyelocele, diabetes mellitus, diabetes insipidus, chronic stool retention, and sickle cell disease (secondary to defects in urinary concentrating mechanism). However, these organic causes are secondary and account for no more than 5% of all cases.

Evaluation necessitates a careful history, which should involve questions about the pattern of enuresis, history of constipation, and psychologic stressors. The physical examination should focus on a careful neurologic and genital examination. Laboratory studies may be limited to urinalysis to check for specific gravity, glucose, and the possibility of a urinary tract infection. If any abnormalities are evident on physical examination or urinalysis, more detailed studies are appropriate.

Treatment for enuresis centers on behavioral approaches, such as charting, night awakening by parents, and bladder stretching exercises. The use of a moisture-sensitive alarm is one of the most successful treatment modalities and eliminates the condition in 70% of children within the first several months of use. Pharmacologic agents are useful in decreasing the number of episodes of bedwetting but have a high relapse rate. They should be used only when the temporary, rapid elimination of bedwetting is required. Both tricyclic antidepressants and desmopressin acetate are effective. An IV pyelogram would be indicated, if the boy had a history of recurrent urinary tract infections, to investigate any possible structural abnormalities of the genitourinary tract. Enuresis is a stigmatizing condition; most families desire a solution and are not satisfied with reassurance.

A 2-year-old boy is brought to the emergency department because of increasing and profound lethargy during the past 4 hours. The past medical history is unremarkable. However a 7-year-old brother who is a bed wetter has an upper respiratory infection. There have been no other contacts with individuals who are sick. On physical examination, the child’s temperature is 37.4􏰦C (99.3􏰦F), and he is noted to be hypotensive. There is no history or evidence of trauma. The cardiac monitor demonstrates a ventricular dysrhythmia, and the child begins to have a seizure. Which of the following is the most likely cause for this child’s problem?

A. Shaken baby syndrome  |  B. Meningitis  |  C. Imipramine
D. Congenital heart disease  |  E. Febrile seizure

The answer is C. The patient is a toddler and at risk for accidental ingestion. Imipramine (choice C) is an antidepressant some- times used to treat nocturnal enuresis. Children who have ingested tricyclic antidepressants primarily present with status epilepticus, coma, and dysrhythmias.

Seizures may also be associated with shaken baby syndrome (choice A), but retinal hemorrhages are usually noted on physical examination. Congenital heart disease (choice D) usually manifests itself earlier than 2 years of age. Febrile seizures (choice E) are associated with a rapid rise in temperature and usually develop when the core temperature reaches 39.0􏰦C (102.2􏰦F) or above. This patient is afebrile. Although meningitis (choice B) should be included in the differential diagnosis of a lethargic child, it is less likely given the fact that the child presents with symptoms associated with tricyclic antidepressant ingestion, and the child’s brother is a bed wetter.
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Zollinger-Ellison syndrome
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A gastrinoma is a gastrin-producing tumor usually located in the pancreas or the duodenal wall. Gastric acid hypersecretion and aggressive, refractory peptic ulceration result (Zollinger-Ellison syndrome). Diagnosis is by measuring serum gastrin levels. Treatment is proton pump inhibitors and surgical removal.

Gastrinomas are a type of pancreatic endocrine tumor that arises from islet cells but can also arise from the gastrin-producing cells in duodenum and, much less rarely, other sites in the body. Gastrinomas occur in the pancreas or duodenal wall 80 to 90% of the time. The remainder occur in the splenic hilum, mesentery, stomach, lymph node, or ovary. About 50% of patients have multiple tumors. Gastrinomas usually are small (< 1 cm in diameter) and grow slowly. About 50% are malignant. About 40 to 60% of patients with gastrinoma have multiple endocrine neoplasia.

Symptoms and Signs
Zollinger-Ellison syndrome typically manifests as aggressive peptic ulcer disease, with ulcers occurring in atypical locations (up to 25% are located distal to the duodenal bulb). However, as many as 25% do not have an ulcer at diagnosis. Typical ulcer symptoms and complications (eg, perforation, bleeding, obstruction) can occur. Diarrhea is the initial symptom in 25 to 40% of patients.

• Serum gastrin level
• CT, scintigraphy, or PET to localize

Gastrinoma is suspected by history, particularly when symptoms are refractory to standard acid suppressant therapy.

The most reliable test is serum gastrin. All patients have levels > 150 pg/mL; markedly elevated levels of > 1000 pg/mL in a patient with compatible clinical features and gastric acid hypersecretion of > 15 mEq/h establish the diagnosis. However, moderate hypergastrinemia can occur with hypochlorhydric states (eg, pernicious anemia, chronic gastritis, use of proton pump inhibitors), in renal insufficiency with decreased clearance of gastrins, in massive intestinal resection, and in pheochromocytoma.

A secretin provocative test may be useful in patients with gastrin levels  < 1000 pg/mL. An IV bolus of secretin 2 μg/kg is given with serial measurements of serum gastrin (10 and 1 min before, and 2, 5, 10, 15, 20, and 30 min after injection). The characteristic response in gastrinoma is an increase in gastrin levels, the opposite of what occurs in patients with antral G-cell hyperplasia or typical peptic ulcer disease. Patients also should be evaluated for Helicobacter pylori infection, which commonly results in peptic ulceration and moderate excess gastrin secretion.

Once the diagnosis has been established, the tumor or tumors must be localized. The first test is abdominal CT or somatostatin receptor scintigraphy, which may identify the primary tumor and metastatic disease. PET or selective arteriography with magnification and subtraction is also helpful. If no signs of metastases are present and the primary is uncertain, endoscopic ultrasonography should be done. Selective arterial secretin injection is an alternative.

• Acid suppression
• Surgical resection for localized disease
• Chemotherapy for metastatic disease
• Acid suppression

Proton pump inhibitors are the drugs of choice: omeprazole or esomeprazole 40 mg po bid. The dose may be decreased gradually once symptoms resolve and acid output declines. A maintenance dose is needed; patients need to take these drugs indefinitely unless they undergo surgery.

Octreotide injections, 100 to 500 mcg sc bid to tid, may also decrease gastric acid production and may be palliative in patients not responding well to proton pump inhibitors. A long-acting form of octreotide (20 to 30 mg IM once/mo) can be used.

Surgical removal should be attempted in patients without apparent metastases. At surgery, duodenotomy and intraoperative endoscopic transillumination or ultrasonography help localize tumors. Surgical cure is possible in 20% of patients if the gastrinoma is not part of a multiple endocrine neoplasia syndrome.

In patients with metastatic disease, streptozocin in combination with 5-fluorouracil or doxorubicin is the preferred chemotherapy for islet cell tumors. It may reduce tumor mass (in 50 to 60%) and serum gastrin levels and is a useful adjunct to omeprazole. Newer chemotherapies under investigation for insulinoma include temozolomide-based regimens, everolimus, or sunitinib. Patients with metastatic disease are not cured by chemotherapy.

Key Points
• Most gastrinomas manifest with peptic ulcer symptoms, but some patients present with diarrhea.
• About half of patients have multiple gastrinomas and about half have multiple endocrine neoplasia syndrome; half of gastrinomas are malignant.
• Serum gastrin levels are usually diagnostic, but patients with borderline elevated levels may need a secretin provocative test.
• Tumors can usually be localized with CT, somatostatin receptor scintigraphy, or PET.
• Acid secretion is suppressed with a proton pump inhibitor, sometimes also with octreotide, pending surgical removal.


A patient complains of daily burning epigastric pain of 4-months duration. He states that he is sometimes awakened at night by coughing spells and a burning in his throat. He has also been having diarrhea. Basal acid output, using a nasogastric tube, is measured to be 15 meq/hr (normal < 5 meq/hr). An antral biopsy is negative for H. pylori. Fasting serum gastrin is measured at 1,000 pg/mL (normal <150 pg/mL). Which of the following is the most likely explanation for these symptoms?

A. Type A chronic gastritis
B. Routine duodenal ulcer
C. Routine gastric ulcer
D. Vipoma
E. Zollinger-Ellison syndrome

The correct answer is E. Zollinger-Ellison syndrome results from hypersecretion of gastric acid due to a gastrin-secreting neoplasm (gastrinoma). The esophageal symptoms, epigastric pain, and duodenal ulcers are all due to excessive acid secretion. Diarrhea occurs in about half of Zollinger-Ellison patients. It is partly due to the excess gastric secretions delivered to the intestines, and partly due to maldigestion because the low pH in the duodenal lumen creates a poor environment for function of pancreatic enzymes. Furthermore, the low duodenal pH can damage the intestinal mucosa and flatten the villi, leading to malabsorption.

Type A chronic gastritis (choice A) is another cause of increased circulating gastrin. In this case, the autoimmune destruction of the acid-secreting mucosa leads to achlorhydria. A major factor that normally suppresses acid secretion by the parietal cells is the low pH of gastric juice. With achlorhydria, the pH of the juice rises and gastrin secretion increases (it can be as high as in Zollinger-Ellison syndrome). However, with chronic gastritis the basal secretion of acid would be decreased, not increased. Furthermore, duodenal ulcer is unlikely.

Most often the plasma concentration of gastrin is not significantly increased with routine duodenal ulcer (choice B), however it can be increased in about 10% of the patients with this disorder. Provocative testing using secretin infusion will markedly increase gastrin secretion from a gastrinoma, but have little effect with benign duodenal ulcer. H. pylori is present in virtually 100% of duodenal ulcers and multiple ulcers are less common than in Zollinger-Ellison syndrome.

The endoscopic examination failed to provide evidence of a gastric ulcer (choice C). Furthermore, the incidence of H. pylori infection is very high with gastric ulcer. Patients with gastric ulcer often exhibit decreased basal acid secretion and the ulcer is usually due to breakdown of the gastric mucosal barrier. 

A vasoactive intestinal peptide-secreting tumor (VIPoma) (choice D) produces a watery diarrhea because of excessive cAMP-dependent secretion of chloride and water by intestinal cells in the crypts of Lieberkühn. However, the symptoms of dyspepsia, presence of duodenal ulcers, and hypersecretion of acid and gastrin are not present. In fact, the excessive vasoactive intestinal peptide usually suppresses gastric acid secretion.

39-year-old man comes to the office because of "gnawing" abdominal pain and diarrhea for the past 2 months. He states that the pain is worst about 3 hours after a meal and it often wakes him at night. He says, "surprisingly, the pain is relieved by food." He takes a nonsteroidal antiinflammatory drug every couple of weeks for a headache or back ache, does not smoke cigarettes, and has a couple of glasses of wine on the weekends. He vaguely recalls that his father and brother have had similar symptoms in the past. Physical examination shows epigastric tenderness, midway between the xiphoid process and the umbilicus. There is no rebound tenderness. You prescribe amoxicillin, bismuth, and metronidazole, and tell him to return in 2 months. He returns for his follow-up appointment and says that his diarrhea is still present and that the abdominal pain has not decreased in intensity or quality. Physical examination is unchanged. Laboratory studies show hypercalcemia. At this time the most appropriate management is to

A. measure serum gastrin levels
B. measure serum secretin levels
C. order a CT scan of the abdomen
D. order an MRI of the abdomen
E. order an ultrasound of the abdomen

The correct answer is A. This patient most likely has Zollinger-Ellison syndrome (ZES), which is typically characterized by peptic ulcers, increased gastrin secretion, and a tumor in the pancreas (gastrinoma). Many patients with ZES have multiple endocrine neoplasia I (MEN I), which is an autosomal dominant disorder consisting of tumors in the parathyroid gland, pancreas, and pituitary gland. Individuals with ZES often have multiple recurrent or treatment-resistant peptic ulcers, hypercalcemia, diarrhea, and a family history of pancreatic, parathyroid, or pituitary tumors. The first study used to evaluate an individual for ZES is serum gastrin levels. Individuals with ZES typically have markedly elevated levels of serum gastrin.

The first study used to diagnosis ZES is measuring serum gastrin levels, not serum secretin levels (choice B). A CT scan of the abdomen (choice C) or an ultrasound (choice E) may be helpful in localizing the gastrinoma, after establishing the diagnosis with elevated serum gastrin levels. An MRI (choice D) is useful in identifying hepatic metastases of gastrinomas. However, it is not the most appropriate first step in establishing the diagnosis of a gastrinoma.

A 40-year-old white man has been treated for peptic ulcer disease (PUD) symptoms for several weeks. The patient also has diarrhea, a problem he had not had in the past. He denies taking nonsteroidal anti-inflammatory medication either by prescription or over the counter. You treated the patient with a 3-week course of the histamine 2 receptor blocking agent (H2 receptor blocker) ranitidine, but the patient’s symptoms only slightly improved and recurred fully within days after discontinuance of the drug. You then pre- scribed the hydrogen pump blocking agent omeprazole for 3 weeks with similar disappointing results. Esophagogastroduodenoscopy then demonstrated a large ulcer (3-cm diameter) distal to the duodenal bulb. During the procedure, studies were done for H. pylori that were negative. Which of the following would be the next logical action?

A. Draw blood for a gastrin level
B. Refer for lower endoscopy to rule out ulcerative colitis
C. Order barium upper GI series with small bowel follow-through to rule out Crohn disease
D. Order stool cultures for bacterial cause of infectious diarrhea
E. Order stool studies for ova and parasites

The answer is A. Association of refractory PUD and diarrhea, especially when one or more ulcers include(s) a lesion larger than usual, located distal to the duodenal bulb, suggests Zollinger–Ellison syndrome. Gastrinomas occur in the pancreas, duodenal wall, or lymph nodes, or, when associated with multiple endocrine neoplasia, type 1, occur in multiples in endocrine organs such as the parathyroid glands. One-third of gastrinomas are malignant. Over 90% of patients with gastrinomas develop PUD and one-third will have watery diarrhea that can be quite severe and, of course, refractory to usual treatment. Although each of the other choices are causes of diarrhea, they would have to coexist with PUD in this case, none of which is found in that association.
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Supratherapeutic INR
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The rationale for intervening in patients with elevated INRs without bleeding is to minimize the risk of developing hemorrhagic complications. Care must also be taken not to overcorrect the INR. Choice of treatment in this patient population depends on the degree of coagulopathy, and on the clinical impact of potential blood loss should bleeding occur. One option is to simply hold the warfarin until the INR again is within therapeutic range. Alternatively, vitamin K may be given as a more active management strategy. Vitamin K safely and effectively corrects the INR but does not necessarily reduce bleeding events compared with warfarin withdrawal alone. If used, intravenous (iv.) and oral (p.o.) vitamin K are preferred over subcutaneous administration. Choice of therapeutic strategy in these clinical scenarios is often further guided by the degree of INR elevation above the therapeutic target.

INR Between 3.0 & 4.5
Spontaneous bleeding events with minimal INR elevation are uncommon. A review by Oake et al. in 2008 calculated the relative risk of bleeding events to be 2.7 with INR values between 3.0 and 5.0, compared with a relative risk of 21.8 if the INR was greater than 5.0. However, as there is only a slightly increased risk of bleeding when the INR is between 3.0 and 4.5, the published literature and most guidelines support withholding warfarin until the INR is again within therapeutic range and/or lowering the daily dose, without treating with vitamin K.

Mild coagulopathy is more likely to be an issue around the time of surgery and other invasive procedures. Current guidelines suggest discontinuing warfarin 5 days before surgery, or longer if the INR is above 3.5. This recommendation is based on a study by White et al. that documented INR normalization to below 1.2 after four omitted warfarin doses, as long as the baseline INR was between 2.0 and 3.0.

INR Between 4.5 & 10.0
Rates of spontaneous and procedure-based bleeding events increase once the INR exceeds therapeutic targets more significantly. A prospective cohort study found a 14-day major bleeding rate of approximately 5% in patients presenting with INR values over 6.0. Other groups have documented bleedings rates lower than this. A prospective cohort study by Garcia et al. reported an overall rate of major hemorrhage of 1.3% in patients with INR values above 5.0, and 0.96% in those with INRs between 5.0 and 9.0.

The correction of supratherapeutic INRs in patients with mechanical heart valves is an important subgroup to consider. Ageno et al. randomized a group of 59 such patients with INRs ranging from 6.0 to 12.0 to receive either 1 mg p.o. vitamin K or no treatment. No major bleeding events were recorded in either group, but the vitamin K cohort did achieve more rapid INR correction. One other important finding, however, is that three of the patients given vitamin K overcorrected to INRs of less than 1.8, potentially increasing their risk of thromboembolic complications. More recently, we conducted a randomized controlled trial of low-dose (1.25 mg) oral vitamin K versus placebo in nonbleeding patients with INRs ranging from 4.5 to 10.

INR Values Above 10.0
Vitamin K may again be used alone in the situation of highly excessive INR values, but its action is not immediate, requiring 6–24 h before an effect is seen. Larger doses can also lead to difficulty achieving therapeutic targets once warfarin is restarted, particularly if more than one dose is required for correction. However, at lower doses, such warfarin resistance is uncommon, although trials directly exploring this issue are few in number and further limited by inconsistent definitions of the phenomenon.

Guidelines have historically recommended that higher doses (e.g., 2.5–5 mg) of vitamin K be used in excessively elevated INRs; however, several studies have now demonstrated effectiveness of lower doses. Gunther et al. reported on 75 patients assessed with INRs over 10.0 and, of those 51 episodes treated with low-dose (2 mg) p.o. vitamin K, no significant major bleeding events occurred, compared with three clinically significant bleeds in the 24 episodes treated with only warfarin discontinuation.


Management of Minor Bleeding
Management of the bleeding anticoagulated patient depends on the severity and location of the bleed. Patients with supratherapeutic INRs and non-life-threatening bleeding can usually be treated with local measures, close monitoring and either warfarin interruption alone or in conjunction with low-dose vitamin K. Correcting the underlying defect is also required whenever bleeding is an issue, as warfarin-associated coagulopathy (WAC) predisposes but does not directly cause bleeding. For example, minor cutaneous bleeding or epistaxis can usually be managed with external compression or packing. Oral cavity bleeds can often be controlled with topical antifibrinolytics (e.g., tranexamic acid mouth rinse) in addition to warfarin withdrawal. However, there is little in the way of guidelines or evidence for the standardization of treating minor bleeds, and clinical judgement must be used.

Management of Major Bleeding
When urgent reversal of anticoagulation is needed, such as with active severe bleeding or imminent surgery, more immediate measures are required. The aim should be to correct the INR to normal or near-normal (<1.5) levels regardless of the initial INR, including supratherapeutic, therapeutic or even slightly subtherapeutic values. INR correction in this setting is accomplished with intravenous factor replacement. Current options available include fresh-frozen plasma (FFP), recombinant activated factor VII (rFVIIa) and prothrombin complex concentrates (PCCs). of disseminated intravascular coagulopathy, transfusion-related or other complications.

To avoid ‘rebound’ over-anticoagulation, vitamin K should be administered with FFP or PCC to provide an enduring correction of the INR. Intravenous vitamin K is the preferred formulation when treating the bleeding patient due to its faster onset of action, with a first effect on the INR noted within 2 h and a maximum effect within 6–12 h, compared with 12–24 h for oral preparations. The systematic review by Dentali et al. concluded that all patients with major bleeding should receive iv. vitamin K over other preparations owing to its rapidity of action and predictable delivery. A dose of 10 mg of iv. vitamin K is recommended for any patients with major or life-threatening bleeds.


Supratherapeutic INR Without Bleeding

• INR: 3.0 - 4.5 
Stop Warfarin (usually for 5 days)

INR 4.5 - 10.0
Stop Warfarin
Give Vitamin K low 0.5mg - 1.0mg (given oral - PO)

INR > 10.0
Stop Warfarin
Give higher does of Vitamin K (2.0mg - 5mg). Note: Vitamin K takes 6 - 24 hours to take effect

Supratherapeutic INR With Bleeding


Stop Warfarin immediately
Urgent reversal with FFP (Fresh Frozen Plasma). It contains all the clotting factors needed.
Also give Vitamin K high dose (5-10mg) IV

If there is life threatening bleeding, then also give: Prothrombin Complex


A 49-year-old man comes to clinic for follow up and monitoring of his oral anticoagulation levels. The patient is postoperative day 62 from a left total knee replacement. On postoperative day number 2 he suffered a pulmonary embolism. He was placed on intravenous unfractionated heparin and then oral warfarin. He was discharged home with follow-up instructions to return to the clinic for monitoring of his prothrombin time/international normalized ratio (INR) every 3 weeks. On return to the clinic today his PT/INR is found to be 22.4/7.3. His physical examination is unremarkable. The most appropriate management at this time is to

A. admit the patient to the hospital
B. instruct the patient to discontinue warfarin and return in 1 week
C. instruct the patient to discontinue warfarin week until his next visit in 3 weeks
D. give protamine sulfate, intravenously
E. give vitamin K and follow up with the patient at his next visit

The correct answer is A. This patient has a supratherapeutic INR and is at great risk of spontaneous bleeding. He requires hospitalization, vitamin K administration, and if there is bleeding, fresh frozen plasma. Because he is within 2 months of a pulmonary embolism, his risk of recurrent PE off of warfarin is high and he will therefore need to be restarted on heparin as soon as his INR falls below 2.0. This management can only be accomplished in the hospital.

Although withholding warfarin is appropriate, not admitting the patient to the hospital (choice B) and (choice C) is incorrect for the reasons stated above. Protamine sulfate (choice D) is an antagonist of unfractionated heparin. It has no effect on warfarin, which interferes with the carboxylation of factors 2, 7, 9, and 10. Again, administration of vitamin K (choice E) is appropriate in this setting, but because the patient's risk of bleeding is so high, he should be admitted to the hospital for the management.

While on call, you are paged to evaluate a 91-year-old woman with shortness of breath. She had been admitted several days ago for congestive failure in the setting of rapid atrial fibrillation. Her past medical history is significant for atrial fibrillation and hypertension. Her medications include warfarin, atenolol, and furosemide. On arrival, you find her in moderate respiratory distress. Her physical exam and laboratory data including an INR of 4.1 are consistent with a pulmonary hemorrhage. You consult the patient's primary care physician and inform her of the patient's condition. You both agree that the patient's coagulopathy needs to be addressed. The patient's coagulopathy will be most rapidly corrected by

A. administering dextran
B. giving intramuscular vitamin K
C. intravenous fresh frozen plasma
D. intravenous protamine sulfate
E. subcutaneous vitamin K

The correct answer is C. The patient's coagulopathy consists of a supra therapeutic INR. Fresh frozen plasma will most rapidly provide all of the necessary clotting factors needed to normalize coagulation.

Dextran (choice A) is an anticoagulant with an antiplatelet effect. It also has no place in the correction of a supra therapeutic INR.

Intramuscular vitamin K (choice B) or subcutaneous vitamin K (choice E) while being able to correct the supra therapeutic INR associated with warfarin use over time, are unable to correct it acutely. They are, therefore, inappropriate for the acute correction of the coagulopathy associated with inappropriate warfarin use. Protamine sulfate (choice D) is used to reverse the effects of heparin and has no place in the correction of a supra therapeutic INR.

An 80 year old man who is taking warfarin because of a history of atrial fibrillation, is found on routine blood work to have an INR of 7.2. He reports no bleeding. Which one of the following is the best immediate management of this problem?
A. Hold the warfarin for 3 days
B. Vitamin K 1 mg orally 
C. Vitamin K 10 mg intravenously
D. Fresh frozen plasma intravenously
E. Desmopressin (DDAVP)

Answer: B. If the INR is between 5.0-9.0 and bleeding is absent, you should cease warfarin therapy; consider reasons for elevated INR and patient-specific factors. If bleeding risk is high, give vitamin K (1.0-2.0 mg orally or 0.5-1.0 mg intravenously). Measure INR within 24 hours, resume warfarin at a reduced dose once INR is in therapeutic range.

However, if there is any clinically significant bleeding where warfarin-induced coagulopathy is considered a contributing factor, you should cease warfarin therapy, give 5.0-10.0 mg vitamin K intravenously, as well as fresh frozen plasma (150-300 mL), assess patient continuously until INR < 5.0, and bleeding stops. 

An 80 year old man, who is taking warfarin because of a history of atrial fibrillation, presents to the emergency room with a syncopal episode. His stool has been black. His hemoglobin is 65 g/L and INR 7.2. Which one of the following is the best immediate approach to the management of raised INR? 
A. Vitamin K, 1 mg orally. 
B. Vitamin K, 10 mg intravenously 
C. Hold warfarin for 3 days 
D. Desmopressin (DDAVP) 
E. 4 units of fresh frozen plasma 

Answer: E. If the INR is between 5.0-9.0 and bleeding is absent, you should cease warfarin therapy; consider reasons for elevated INR and patient-specific factors. If bleeding risk is high, give vitamin K (1.0-2.0 mg orally or 0.5-1.0 mg intravenously). Measure INR within 24 hours, resume warfarin at a reduced dose once INR is in therapeutic range.

However, if there is any clinically significant bleeding where warfarin-induced coagulopathy is considered a contributing factor, you should cease warfarin therapy, give 5.0-10.0 mg vitamin K intravenously, as well as fresh frozen plasma (150-300 mL), assess patient continuously until INR < 5.0, and bleeding stops. 
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Nursemaid's Elbow (Subluxation of Radial Head)
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Nursemaid's Elbow - Radial head subluxation, common among toddlers, is caused by traction on the forearm and usually manifests as refusal to move the elbow (pseudoparalysis).

In adults, the radial head is wider than the radial neck; consequently, the head cannot fit through the ligaments that tightly surround the neck. However, in toddlers (about 2 to 3 yr old), the radial head is no wider than the radial neck and can easily slip through these ligaments (radial head subluxation).

Subluxation results from traction on the forearm, as when a caregiver pulls a reluctant toddler forward or catches the toddler by the wrist during a fall—actions many caregivers do not remember.


Symptoms may include pain and tenderness. Most patients cannot describe their symptoms and simply present with unwillingness to move the affected arm. The radial head may be only mildly tender.


• Usually history

Plain x-rays are normal and considered unnecessary by some experts when patients have a clear history of a traction injury, unless an alternate diagnosis is clinically suspected.

Using a reduction maneuver may be diagnostic and therapeutic.


• Reduction

Reduction may be done using

• Supination-flexion

• Hyperpronation

Neither technique requires sedation or analgesia; the child experiences pain only for a few seconds.

In supination-flexion, the elbow is completely extended and supinated, then flexed. A subtle palpable pop or click is often detected when the radial head resumes its normal position.

In hyperpronation, the practitioner supports the child's arm at the elbow and places moderate pressure with a finger on the radial head. The practitioner then grips the distal forearm with the other hand and hyperpronates the forearm. A pop can be felt at the radial head when it is reduced.

Children usually start to move the elbow after about 10 to 20 min. If they do not move it, x-rays of the elbow should be taken. If they do move it, x-rays and immobilization are unnecessary.

If pain or dysfunction lasts > 24 h, incomplete reduction or an occult fracture should be suspected. Radial head subluxation recurs in 20 to 40% of children.


A 2-year-old child stumbles, but his mother keeps him from falling by pulling up on his right hand. An hour later the child refuses to use his right arm and cries when his mother tries to move it. The most likely diagnosis is

A. dislocation of the ulna
B. dislocation of the olecranon epiphysis
C. subluxation of the head of the radius
D. subluxation of the head of the ulna
E. anterior dislocation of the humeral head

ANSWER: C. “Nursemaid’s elbow” is one of the most common injuries in children under 5 years of age. It occurs when the child’s hand is suddenly jerked up, forcing the elbow into extension and causing the radial head to slip out from the annular ligament.

A 6-year-old boy is brought to the office by his parents who are concerned because he has been refusing to use his right arm for 1 day. The parents report that he has been in good health and has not suffered any recent falls or injuries to the arm that they are aware of. The father does recall one incident 2 days ago when he pulled upward on the boy's right arm to prevent him from tripping as they descended a flight of stairs. The boy is holding his right arm with the elbow flexed and the forearm pronated. He begins to cry when you attempt to examine the arm. The most appropriate next step is

A. closed reduction and cast immobilization
B. a CT of the right arm
C. measurement of compartment pressure of the forearm
D. supination of the forearm with the elbow flexed
E. a trial of compressive bandage on the right arm

The correct answer is D. This boy has the signs and symptoms of a very common injury in little children. "Nursemaid's elbow" or subluxation of the radial head, which occurs when there is longitudinal traction on the pronated extended elbow. This traction can cause the radial head to slip from beneath the annular ligament. Children will often refuse to move the arm following this injury. X-rays of the forearm and elbow are usually normal and treatment involves supination of the forearm with the elbow flexed. Recurrence is uncommon and no immobilization of the affected arm is necessary.

Closed reduction and cast immobilization (choice A) is necessary for fractures of the forearm, not for subluxation of the radial head. Fractures of the forearm are also very common in children, but usually have an antecedent history of fall or injury.

Obtaining a CT of the right arm (choice B) is not necessary for this patient. X-rays of the right arm can be done to rule out a fracture or hemarthrosis. A CT of the extremity is sometimes performed if the x-ray demonstrates a fracture. The history given by the boy's parents and the boy's presenting symptoms strongly suggest subluxation of the radial head. X-rays of the forearm and elbow are usually normal in this setting and are not necessary to make the diagnosis.

There is no reason to suspect compartment syndrome (choice C) in this child. Signs of compartment syndrome include severe pain in the limb especially with active or passive stretching of the ischemic muscle, cyanosis, and numbness. This syndrome is an uncommon complication of any traumatic injury to the extremities. Subluxation of the radial head is not associated with compartment syndrome.

A trial of a compressive bandage (choice E) is not necessary in this patient. Supination of the forearm should reduce the subluxation of the radial head. Compressive bandages or immobilization are not necessary after reduction of the subluxation.
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Trichotillomania is characterized by recurrent pulling out of one's hair resulting in hair loss.

Patients with trichotillomania repeatedly pull or pluck out their hair for noncosmetic reasons. Most commonly, they pull hair from their scalp, eyebrows, and/or eyelids, but any body hair may be pulled out. Sites of hair pulling may change over time.

For some patients, this activity is somewhat automatic (ie, without full awareness); others are more conscious of the activity. Hair pulling is not triggered by obsessions or concerns about appearance but may be preceded by a feeling of tension or anxiety that is relieved by the hair pulling, which is often then followed by a feeling of gratification.

Hair pulling typically begins just before or after puberty. At any given point in time, about 1 to 2% of people have the disorder. About 90% of them are female.

Symptoms and Signs

Hair pulling is usually chronic, with waxing and waning of symptoms.

Patterns of hair loss vary from patient to patient. Some have areas of complete alopecia or missing eyelashes and/or eyebrows; others merely have thinned hair.

A range of behaviors (rituals) may accompany hair pulling. Patients may search fastidiously for a particular kind of hair to pull; they may try to ensure that hair is pulled out in a particular way. They may roll the hair between their fingers, pull the strands between their teeth, or bite the hair once it is pulled. Many patients swallow their hair.

Patients may feel embarrassed by or ashamed of their appearance. Many try to camouflage the hair loss by covering the bald areas (eg, wearing wigs or scarfs). Some patients pull out hair from widely scattered areas to disguise the loss. They may avoid situations in which other people may see the hair loss; typically, they do not pull hair out in front of others, except for family members.

Some patients pull hair from others or from pets or pull strands from fibrous materials (eg, clothing, blankets). Most patients also have other body-focused repetitive behaviors, such as skin picking or nail biting.


• Clinical criteria

Diagnostic criteria typically include the following:

• Removing hair

• Making repeated attempts to stop the hair pulling

• Experiencing significant distress or impairment from the activity

The distress can include feelings of embarrassment or shame (eg, at loss of control of one's behavior, at the cosmetic consequences of the hair loss).


• SSRIs or clomipramine

• Cognitive-behavioral therapy

SSRIs or clomipramine (a tricyclic antidepressant with potent serotonergic effects) may be useful for coexisting depression or anxiety disorders. For hair pulling, clomipramine appears to be more effective than desipramine (a tricyclic antidepressant that inhibits reuptake of norepinephrine). However, SSRIs have been disappointing. Some evidence suggests that N -acetylcysteine (a partial glutamatergic agonist) is effective. There is also limited evidence that low-dose dopamine blockers are effective, but risk:benefit ratio must be carefully assessed.

Cognitive-behavioral therapy that is tailored to treat the specific symptoms of hair-pulling disorder is currently the psychotherapy of choice. For example, habit reversal, a predominantly behavioral therapy, can be used; it includes awareness training (eg, self-monitoring, identification of triggers for the behavior), stimulus control (modifying situations—eg, avoiding triggers—to reduce the likelihood of initiating pulling), and competing response training (substituting other behaviors for hair pulling).


A 16-year-old female presents to your office for treatment of her hair pulling. She reports a depressed mood and significant hair loss. Her problem developed at age 10 when she would pull hair when she was upset about her parents fighting and when feeling sad, lonely or bored. She reported that she usually pulled her hair ‘without thinking’ or when under stress related to school, family and relationship problems. Sometimes, however, she reported a significant urge to pull, with some relief when she engaged in the behavior. At those times she found the hair pulling enjoyable. The most likely diagnosis is

A. Alopecia Areata
B. Obsessive-Compulsive Disorder
C. Tinea Capitis
D. Traction Alopecia
E. Trichotillomania

Answer: E. Trichotillomania is characterized by recurrent pulling out of one's hair resulting in hair loss.

Patients with trichotillomania repeatedly pull or pluck out their hair for noncosmetic reasons. Most commonly, they pull hair from their scalp, eyebrows, and/or eyelids, but any body hair may be pulled out. Sites of hair pulling may change over time.

For some patients, this activity is somewhat automatic (ie, without full awareness); others are more conscious of the activity. Hair pulling is not triggered by obsessions or concerns about appearance but may be preceded by a feeling of tension or anxiety that is relieved by the hair pulling, which is often then followed by a feeling of gratification.

Hair pulling typically begins just before or after puberty. At any given point in time, about 1 to 2% of people have the disorder. About 90% of them are female.

An 18-year-old girl is brought to the clinic because she periodically pulls her hair and puts it in her mouth. She has several bald patches on both sides of her head. Initially the mother thought it was some sort of infection but the dermatologist "did not find anything." The patient describes a sense of relief when she does it and claims that she really does it when upset, anxious. or overwhelmed. She admits that she has been doing it on and off for at least 2 years and thinks that it started after her parents got divorced. She is doing well in school. Which of the following is the most appropriate initial step in management?

A. Prescribe a benzodiazepine to relieve tension
B. Prescribe a tricyclic antidepressant
C. Rule out the presence of comorbid conditions
D. Start interpersonal psychotherapy
E. Start treatment with carbamazepine

The correct answer is C . When it is suspected that a patient has trichotillomania, the most appropriate initial step is to rule out the presence of comorbid conditions. The most frequent ones would be obsessive-compulsive, borderline, and depressive disorders.

Prescribing a benzodiazepine (choice A) does not address the problem and may only episodically relieve symptoms of anxiety. The potential for addiction is greater than the potential benefit.

Prescribing a tricyclic antidepressant (choice B) is not the appropriate next step. Comorbid conditions need to be ruled out first Tricyclics have many side effects and more appropriate treatment with SSRI might be available.

Interpersonal therapy (choice D) is not an appropriate choice for impulse-control disorder. Some forms of behavior therapy are more appropriate.

Treatment with carbamazepine (choice E) should be considered for intermittent explosive disorder, but it is usually not used for trichotillomania.
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Neonatal Jaundice
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Jaundice is a yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration). The serum bilirubin level required to cause jaundice varies with skin tone and body region, but jaundice usually becomes visible on the sclera at a level of 2 to 3 mg/dL (34 to 51 μmol/L) and on the face at about 4 to 5 mg/dL (68 to 86 μmol/L). With increasing bilirubin levels, jaundice seems to advance in a head-to-foot direction, appearing at the umbilicus at about 15 mg/dL (258 μmol/L) and at the feet at about 20 mg/dL (340 μmol/L). Slightly more than half of all neonates become visibly jaundiced in the first week of life.

Hyperbilirubinemia may be harmless or harmful depending on its cause and the degree of elevation. Some causes of jaundice are intrinsically dangerous whatever the bilirubin level. Among term infants, the threshold typically is considered to be a level > 18 mg/dL (> 308 μmol/L).

Kernicterus is the major consequence of neonatal hyperbilirubinemia. Although it is now rare, kernicterus still occurs and can nearly always be prevented. Kernicterus is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei, caused by either acute or chronic hyperbilirubinemia.

The majority of bilirubin is produced from the breakdown of Hb into unconjugated bilirubin (and other substances). Unconjugated bilirubin binds to albumin in the blood for transport to the liver, where it is taken up by hepatocytes and conjugated with glucuronic acid by the enzyme uridine diphosphogluconurate glucuronosyltransferase (UGT) to make it water-soluble. The conjugated bilirubin is excreted in bile into the duodenum. In adults, conjugated bilirubin is reduced by gut bacteria to urobilin and excreted. Neonates, however, have sterile digestive tracts. They do have the enzyme β-glucuronidase, which deconjugates the conjugated bilirubin, which is then reabsorbed by the intestines and recycled into the circulation. This is called enterohepatic circulation of bilirubin.

Most cases involve unconjugated hyperbilirubinemia. Some of the most common causes of neonatal jaundice include

• Physiologic hyperbilirubinemia
• Breastfeeding jaundice or Breast milk jaundice
• Pathologic hyperbilirubinemia due to hemolytic disease

Physiologic hyperbilirubinemia occurs in almost all neonates. Shorter neonatal RBC life span increases bilirubin production; deficient conjugation due to the deficiency of UGT decreases clearance; and low bacterial levels in the intestine combined with increased hydrolysis of conjugated bilirubin increase enterohepatic circulation. Bilirubin levels can rise up to 18 mg/dL by 3 to 4 days of life (7 days in Asian infants) and fall thereafter.

Breastfeeding jaundice develops in one sixth of breastfed infants during the first week of life. Breastfeeding increases enterohepatic circulation of bilirubin in some infants who have decreased milk intake and who also have dehydration or low caloric intake. The increased enterohepatic circulation also may result from reduced intestinal bacteria that convert bilirubin to nonresorbed metabolites.

Breast milk jaundice is different from breastfeeding jaundice. It develops after the first 5 to 7 days of life and peaks at about 2 wk. It is thought to be caused by an increased concentration of β-glucuronidase in breast milk, causing an increase in the deconjugation and reabsorption of bilirubin.

Pathologic hyperbilirubinemia in term infants is diagnosed if

• Jaundice appears in the first 24 h, after the first week of life, or lasts > 2 wk
• Total serum bilirubin (TSB) rises by > 5 mg/dL/day
• TSB is > 18 mg/dL
• Infant shows symptoms or signs of a serious illness

Some of the most common pathologic causes are: Immune and nonimmune hemolytic anemia, G6PD deficiency, Hematoma resorption, Sepsis, Hypothyroidism

History of present illness should note age of onset and duration of jaundice. Important associated symptoms include lethargy and poor feeding (suggesting possible kernicterus), which may progress to stupor, hypotonia, or seizures and eventually to hypertonia. Patterns of feeding can be suggestive of possible breastfeeding failure or underfeeding. Therefore, history should include what the infant is being fed, how much and how frequently, urine and stool production (possible breastfeeding failure or underfeeding), how well the infant is latching on to the breast or taking the nipple of the bottle, whether the mother feels that her milk has come in, and whether the infant is swallowing during feedings and seems satiated after feedings.

Review of systems should seek symptoms of causes, including respiratory distress, fever, and irritability or lethargy (sepsis); hypotonia and poor feeding (hypothyroidism, metabolic disorder); and repeated episodes of vomiting (intestinal obstruction).

Past medical history should focus on maternal infections (toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex [TORCH] infections), disorders that can cause early hyperbilirubinemia (maternal diabetes), maternal Rh factor and blood group (maternofetal blood group incompatibility), and a history of a prolonged or difficult birth (hematoma or forceps trauma).

Family history should note known inherited disorders that can cause jaundice, including G6PD deficiency, thalassemias, and spherocytosis, and also any history of siblings who have had jaundice.

Physical examination
The skin is inspected for extent of jaundice. Gentle pressure on the skin can help reveal the presence of jaundice. Also, ecchymoses or petechiae (suggestive of hemolytic anemia) are noted.

The physical examination should focus on signs of causative disorders.

The general appearance is inspected for plethora (maternofetal transfusion); macrosomia (maternal diabetes); lethargy or extreme irritability (sepsis or infection); and any dysmorphic features such as macroglossia (hypothyroidism) and flat nasal bridge or bilateral epicanthal folds (Down syndrome).

For the head and neck examination, any bruising and swelling of the scalp consistent with a cephalohematoma are noted. Lungs are examined for crackles (rales), rhonchi, and decreased breath sounds (pneumonia). The abdomen is examined for distention, mass (hepatosplenomegaly), or pain (intestinal obstruction). Neurologic examination should focus on signs of hypotonia or weakness (metabolic disorder, hypothyroidism, sepsis).


Diagnosis is suspected by the infant’s color and is confirmed by measurement of serum bilirubin. Noninvasive techniques for transcutaneous measurement of bilirubin levels in infants are being used increasingly, with good correlation with serum bilirubin measurements. Risk of hyperbilirubinemia is based on age-specific TSB levels.

A bilirubin concentration> 10 mg/dL (> 170 μmol/L) in preterm infants or > 18 mg/dL in term infants warrants additional testing, including Hct, blood smear, reticulocyte count, direct Coombs’ test, TSB and direct serum bilirubin concentrations, and blood type and Rh group of the infant and mother.

Other tests, such as blood, urine, and CSF cultures to detect sepsis and measurement of RBC enzyme levels to detect unusual causes of hemolysis, may be indicated by the history and physical examination. Such tests also may be indicated for any neonates with an initial bilirubin level > 25 mg/dL (> 428 μmol/L).


• Physiologic jaundice usually is not clinically significant and resolves within 1 wk. Frequent formula feedings can reduce the incidence and severity of hyperbilirubinemia by increasing GI motility and frequency of stools, thereby minimizing the enterohepatic circulation of bilirubin. The type of formula does not seem important in increasing bilirubin excretion.

• Breastfeeding jaundice may be prevented or reduced by increasing the frequency of feedings. If the bilirubin level continues to increase > 18 mg/dL in a term infant with early breastfeeding jaundice, a temporary change from breast milk to formula may be appropriate; phototherapy also may be indicated at higher levels. Stopping breastfeeding is necessary for only 1 or 2 days, and the mother should be encouraged to continue expressing breast milk regularly so she can resume nursing as soon as the infant’s bilirubin level starts to decline. She also should be assured that the hyperbilirubinemia has not caused any harm and that she may safely resume breastfeeding. It is not advisable to supplement with water or dextrose because that may disrupt the mother’s production of milk.

• Phototherapy

This treatment remains the standard of care, most commonly using fluorescent white light. (Blue light is most effective for intensive phototherapy.) Phototherapy is the use of light to photoisomerize unconjugated bilirubin into forms that are more water-soluble and can be excreted rapidly by the liver and kidney without glucuronidation. It provides definitive treatment of neonatal hyperbilirubinemia and prevention of kernicterus. Phototherapy is an option when unconjugated bilirubin is > 12 mg/dL (> 205.2 μmol/L) and may be indicated when unconjugated bilirubin is > 15 mg/dL at 24 to 48 h, 18 mg/dL at 49 to 72 h, and 20 mg/dL at> 72 h. Phototherapy is not indicated for conjugated hyperbilirubinemia. Because visible jaundice may disappear during phototherapy though serum bilirubin remains elevated, skin color cannot be used to evaluate jaundice severity. Blood taken for bilirubin determinations should be shielded from bright light, because bilirubin in the collection tubes may rapidly photo-oxidize.

• Exchange transfusion

This treatment can rapidly remove bilirubin from circulation and is indicated for severe hyperbilirubinemia, which most often occurs with immune-mediated hemolysis. Small amounts of blood are withdrawn and replaced through an umbilical vein catheter to remove partially hemolyzed and antibody-coated RBCs as well as circulating Igs. The blood is replaced with uncoated donor RBCs. Only unconjugated hyperbilirubinemia can cause kernicterus, so if conjugated bilirubin is elevated, the level of unconjugated rather than total bilirubin is used to determine the need for exchange transfusion.

Specific indications are serum bilirubin ≥ 20 mg/dL at 24 to 48 h or ≥ 25 mg/dL at > 48 h and failure of phototherapy to result in a 1- to 2-mg/dL (17- to 34-μmol/L) decrease within 4 to 6 h of initiation or at the first clinical signs of kernicterus regardless of bilirubin levels. If the serum bilirubin level is > 25 mg/dL when the neonate is initially examined, preparation for an exchange transfusion should be made in case intensive phototherapy fails to lower the bilirubin level. An alternative approach uses the weight of the neonate in grams divided by 100 to determine the bilirubin level (in mg/dL) at which exchange transfusion is indicated. Thus, a 1000-g neonate would receive an exchange transfusion at a bilirubin level of ≥ 10 mg/dL, and a 1500-g neonate would receive an exchange transfusion at a bilirubin level of ≥ 15 mg/dL.


A neonate of approximately 36 weeks gestational age is born to a primigravida mother. Pregnancy and delivery are uncomplicated, with Apgar scores of 9 at 1 and 5 minutes. Mother's and baby's blood groups are both O+. Mother chooses to exclusively breastfeed the neonate. At 24 hours of life, the neonate is noted to be jaundiced and the total serum bilirubin is noted to be 7 mg/dL. He is discharged home later the same day with an appointment for follow-up with the pediatrician at 1 week of age. However, 48 hours later, the neonate is brought to the emergency room. History from the mother reveals that the neonate has progressively become more jaundiced, is not breastfeeding well and is lethargic. Examination also reveals evidence of moderate volume depletion and significant jaundice (including the soles). The neurologic exam is normal and total serum bilirubin is 20 mg/dL. The most likely diagnosis is

A. Neonatal Jaundice
B. Carotenemia
C. Breast Milk Jaundice
D. Cholestasis
E. Hemolytic Disease of Newborn

Answer: A. This is a typical clinical vignette to describe a case of neonatal jaundice. The baby is at 3 days of life and has a serum bilirubin of 20 mg/dL. Breast milk jaundice develops after 5 - 7 days of life.

A full-term newborn boy was born to a gravida 3, para 3 woman who had not committed to regular prenatal care. There is a history of neonatal jaundice in her second baby caused by a minor blood group incompatibility. Assuming this baby exhibits jaundice in the first few days of life, which of the following cutoff points is satisfactory for alerting the primary care physician to the likely need for phototherapy?

A. unconjugated bilirubin is > 10 mg/dL
B. unconjugated bilirubin is > 15 mg/dL at 24 to 48 h
C. unconjugated bilirubin is > 15 mg/dL at 49 to 72 h
D. unconjugated bilirubin is > 15 mg/dL at > 72 h

The answer is B.  Phototherapy is an option when unconjugated bilirubin is > 12 mg/dL (> 205.2 μmol/L) and may be indicated when unconjugated bilirubin is > 15 mg/dL at 24 to 48 h, 18 mg/dL at 49 to 72 h, and 20 mg/dL at> 72 h. Phototherapy is not indicated for conjugated hyperbilirubinemia. Exchange transfusion may be necessary if phototherapy does not obviate that need.

You are the doctor on call in the well baby nursery at the community hospital. One of the nurses calls you to ask about one of your patients. The baby is now 30 hours old and was born full term via vaginal delivery to a healthy 28-year-old mother. There were no complications at the delivery and the baby has been feeding well. The nurse is concerned that the baby looks "yellow". You ask her to send for a bilirubin level. A few hours later she calls to tell you that the total bilirubin level has come back at 18 mg/dL with a direct bilirubin level of 0.6 mg/dL. The parents are now concerned about the baby's discoloration. The most appropriate next step is to

A. reassure the mother that this is completely normal and no additional studies or treatment are indicated
B. repeat the bilirubin level immediately as the result must be a lab error
C. start phototherapy and repeat the bilirubin level in 6 hours
D. transfer to the nearest neonatal intensive care unit for an exchange transfusion
E. wait 6 hours and repeat the bilirubin level

The correct answer is C. Jaundice is a common occurrence in the first week of life. "Physiologic jaundice" is usually transient and is due to an increased bilirubin load from increased red blood cell volume, decreased survival time of the red blood cell, and an increased enterohepatic circulation. Other factors include defective hepatic uptake of bilirubin and inadequate conjugation of bilirubin to bilirubin glucuronide for excretion. A normal cord blood bilirubin level is about 1.5 mg/dl, and a neonate's serum bilirubin normally increases by a maximum of 5mg/dl in 24 hours to a maximum of about 15mg/dl at 3 days of life. A level of 18mg/dl at 30 hours of life is not normal and requires phototherapy to bring the level down. Phototherapy should bring the level down by 1-2mg/dl within 4-6 hours. The level should be checked at that time to ensure that the level has not continued to rise. Besides phototherapy, an investigation into the cause for the rapid rise of bilirubin should be undertaken. The most important consideration is the blood type of the mother and the blood type of the infant. A direct Coombs test should also be performed. Other things to keep in mind include a red cell defect such as an hemoglobinopathy, polycythemia, extravascular blood loss, bacterial sepsis, increased enterohepatic circulation (from an intestinal obstruction), disorder of bilirubin metabolism, or an endocrine disorder such as hypothyroidism.

Reassurance that this is completely normal (choice A) is incorrect. This baby needs to be treated for hyperbilirubinemia and more blood will need to be drawn to follow the levels. The mother should be reassured that this is a common occurrence, that is usually transient, and has no future implications on the baby's development, if treated appropriately.

Repeating the labs (choice B) is not correct because although lab error is something to keep in mind when interpreting all test results, this baby is jaundiced and therefore it is unlikely to have a normal bilirubin level. Jaundice usually becomes apparent at levels of 5mg/dl in the neonate. As levels get higher, the jaundice usually progresses from the face to the trunk and then down the body.

An exchange transfusion (choice D) is not yet warranted in this baby. If the level were greater than 25mg/dl or started at greater than 20 mg/dl and did not improve with phototherapy, this baby would require an exchange transfusion. During this procedure, blood is removed from the baby (usually from an umbilical artery catheter), and the baby is transfused with cross matched blood through a venous catheter. The exchange is done in 15ml increments. There are multiple risks to the procedure including thromboemboli, dysrhythmias, hyperkalemia, hypernatremia, DIC, and transfusion reaction. And thus answer D is not correct.

Wait 6 hours and repeat the level (choice E) is incorrect because the bilirubin level is too high to allow you to wait and watch. If the bilirubin level is allowed to rise unchecked the baby is put at risk for kernicterus. When the level of unconjugated bilirubin reaches higher than 20mg/dl in a full-term neonate, it can become neurotoxic by accumulating in the basal ganglia, pons, or cerebellum causing kernicterus. Clinically, it manifests as a variety of neurologic symptoms ranging from lethargy and hypotonia to severe encephalopathy and death. At the present rate of rise, the bilirubin is likely to be higher than 20 mg/dl in 6 hours.
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Toxic Shock Syndrome
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Toxic shock syndrome (TSS) is caused by staphylococcal or streptococcal exotoxins. Symptoms include high fever, hypotension, diffuse erythematous rash, and multiple organ dysfunction, which may rapidly progress to severe and intractable shock. Diagnosis is made clinically and by isolating the organism. Treatment includes antibiotics, intensive support, and immune globulin.

TSS is caused by exotoxin-producing cocci. Strains of phage-group 1 Staphylococcus aureus elaborate the TSS toxin-1 (TSST-1) or related exotoxins; certain strains of Streptococcus pyogenes produce at least 2 exotoxins.

Staphylococcal toxic shock

Women who have preexisting staphylococcal colonization of the vagina and who use tampons or other devices inserted and left in the vagina (eg, contraceptive sponges, diaphragms) are at highest risk. Mechanical or chemical factors related to tampon use probably enhance production of the exotoxin or facilitate its entry into the bloodstream through a mucosal break or via the uterus. 

When women leave tampons in place for a long time, they may become infected with Staphylococcus aureus. This bacteria breeds in the tampons and produces toxins that induce septic shock. The tampons are a perfect growth medium, the environment is warm and moist, and the blood is a rich source of nutrients.

Estimates made from small series suggest about 3 cases/100,000 menstruating women still occur, and cases are still reported in women who do not use tampons and in women who have infection after childbirth, abortion, or surgery. About 15% of cases occur postpartum or as a complication of postoperative staphylococcal wound infections, which frequently appear insignificant. Cases have also been reported in both men and women with any type of S. aureus infection.

Mortality from staphylococcal TSS is < 3%. Recurrences are common among women who continue to use tampons during the first 4 mo after an episode.

• Streptococcal toxic shock

The syndrome is similar to that caused by S. aureus, but mortality is higher (20 to 60%) despite aggressive therapy. In addition, about 50% of patients have S. pyogenes bacteremia, and 50% have necrotizing fasciitis (neither is common with staphylococcal TSS). Patients are usually otherwise healthy children or adults. Primary infections in skin and soft tissue are more common than in other sites. In contrast to staphylococcal TSS, streptococcal TSS is more likely to cause acute respiratory distress syndrome (ARDS) and less likely to cause a typical cutaneous reaction.

S. pyogenes TSS is defined as any group A β-hemolytic streptococci (GABHS) infection associated with shock and organ failure. Risk factors for GABHS TSS include minor trauma, surgical procedures, viral infections (eg, varicella), and use of NSAIDs.

Symptoms and Signs
Onset is sudden, with fever (39° to 40.5°C, which remains elevated), hypotension, a diffuse macular erythroderma, and involvement of at least 2 other organ systems.

Staphylococcal TSS is likely to cause vomiting, diarrhea, myalgia, elevated CK, mucositis, hepatic damage, thrombocytopenia, and confusion. The staphylococcal TSS rash is more likely to desquamate, particularly on the palms and soles, between 3 and 7 days after onset.

Streptococcal TSS commonly causes ARDS (in about 55% of patients), coagulopathy, and hepatic damage and is more likely to cause fever, malaise, and severe pain at the site of a soft-tissue infection.

Renal impairment is frequent and common to both. The syndrome may progress within 48 h to syncope, shock, and death. Less severe cases of staphylococcal TSS are fairly common.

• Clinical evaluation
• Cultures

Diagnosis is made clinically and by isolating the organism from blood cultures (for Streptococcus) or from the local site. TSS resembles Kawasaki disease, but Kawasaki disease usually occurs in children < 5 yr of age and does not cause shock, azotemia, or thrombocytopenia; the rash is maculopapular. Other disorders to be considered are scarlet fever, Reye syndrome, staphylococcal scalded skin syndrome, meningococcemia, Rocky Mountain spotted fever, leptospirosis, and viral exanthematous diseases. These disorders are ruled out by specific clinical differences, cultures, and serologic tests.

Specimens for culture should be taken from any lesions, the nose (for staphylococci), throat (for streptococci), vagina (for both), and blood. MRI or CT of soft tissue is helpful in localizing sites of infection. Continuous monitoring of renal, hepatic, bone marrow, and cardiopulmonary function is necessary.

• Local measures (eg, decontamination, debridement)
• Fluid resuscitation and circulatory support
• A β-lactam (eg, penicillin) plus clindamycin

Patients suspected of having TSS should be hospitalized immediately and treated intensively. Tampons, diaphragms, and other foreign bodies should be removed at once. Suspected primary sites should be decontaminated thoroughly. Decontamination includes reinspection and irrigation of surgical wounds, even if they appear healthy; repeated debridement of devitalized tissues; and irrigation of potential naturally colonized sites (sinuses, vagina). Fluids and electrolytes are replaced to prevent or treat hypovolemia, hypotension, and shock. Because fluid loss into tissues can occur throughout the body (because of systemic capillary leak syndrome and hypoalbuminemia), shock may be profound and resistant. Aggressive fluid resuscitation and circulatory, ventilatory, and/or hemodialysis support are sometimes required.

Obvious infections should be treated. Pending culture results, vancomycin, daptomycin, linezolid, or ceftaroline—empiric choices that cover the most likely etiologic organisms—should be used. If S. pyogenes is isolated, a β-lactam (eg, penicillin) plus clindamycin (900 mg IV q 8 h) continued for 14 days is the most effective antibiotic treatment. If methicillin-resistant S. aureus (MRSA) is suspected or confirmed, vancomycin, daptomycin, linezolid, or tigecycline is indicated. Antibiotics given during the acute illness may eradicate pathogen foci and prevent recurrences. Passive immunization to TSS toxins with IV immune globulin (2 g/kg, followed by 0.4 g/kg daily for up to 5 days) has been helpful in severe cases of both types of TSS and lasts for weeks, but the disease may not induce active immunity, so recurrences are possible.

If a test for seroconversion of the serum antibody responses to TSST-1 in acute- and convalescent-phase paired sera is negative, women who have had staphylococcal TSS should probably refrain from using tampons and cervical caps, plugs, and diaphragms. Advising all women, regardless of TSST-1 antibody status, to change tampons frequently or use napkins instead and to avoid hyperabsorbent tampons seems prudent.


A 26-year-old woman planned to go biking. As she was dressing, she noticed her period had just started, so she inserted a tampon. While biking, a car turned right immediately in front of her; she crashed into it and catapulted over the hood. She was unable to get up, and when she looked at her right leg, she found that her knee had traveled more than half way up her thigh. The paramedics approximately realigned the femur, splinted it, and transported her to a local hospital, where they set the fracture by implanting a metal rod down the shaft of the bone. Because of her blood loss she was administered two units of blood, after which her hemoglobin level was 7 g/dL. After 2 days in the hospital, the surgical wound continued to seep blood, but she seemed on the road to recovery and was transferred to a neighboring rehabilitation facility. Because of everything else going on, nobody thought of replacing the tampon. The morning after arriving at the rehabilitation facility, she complains of dizziness and a feeling of weakness and seems somewhat disoriented. She has a temperature of 103􏰍F (39.4􏰍C) and has a generalized rash that even covers her hands and the soles of her feet. Her skin is warm to the touch, and her blood pressure is 150/90 mm Hg. The duty nurse calls in a physician, who arrives 45 minutes later. By the time the physician gets there, the patient’s skin appears gray and is cold and clammy, she has tachycardia and the heart sounds are weak, she has a shallow and rapid rate of breathing, her blood pressure is 74/49 mm Hg, her eyes are lusterless, and she is staring without showing signs of recognizing anything. At this time, which of the following choices represents the most probable diagnosis?

A. Hypovolemic shock  |  B. Toxic shock syndrome  |  C. Cardiogenic shock
D. Anaphylactic shock  |  E. Shock cause by a gram-negative organism

The answer is B. Shock is a condition in which peripheral blood flow is compromised, depriving cells of adequate oxygen sup- ply. Several different conditions can cause shock, but there is commonality in the symptoms produced. By the time she is seen by the physician, the patient described is suffering from toxic shock syndrome (TSS; choice B) due to failure to remove the tampon over the course of 4 days. The early phase, including high temperature, rash, hypertension, and warm skin, reflects the inflammatory effects of toxins caused by bacteria growing in the tampon. In TSS, this phase generally lasts about 30 minutes and is then followed by the more typical symptoms of shock due to a toxin-induced shutdown of the vascular system. These typical shock symptoms include pale or gray skin that is cold and clammy to the touch; tachycardia with weak heart sounds; shallow, rapid breathing; hypotension; lack of focus with confusion; and possibly delirium. In the 1980s, a small epidemic of TSS was associated with a specific brand of “super-absorbant” tampons that allegedly could be left in place for an extended period. Since that brand was removed from the market, the condition has become much less common. TSS more often occurs in response to factors other than tampon use in menstruating women. The hypothesis regarding tampon-induced TSS is that, when women leave tampons in place for a long time, they may become infected with Staphylococcus aureus. This bacteria breeds in the tampons and produces toxins that induce septic shock. The tampons are a perfect growth medium, the environment is warm and moist, and the blood is a rich source of nutrients. Moreover, while in the tampon, the bacteria cannot be affected by normal physiologic defense mechanisms and are largely immune even to the influence of antibiotics.

Hypovolemic shock (choice A) can be caused by loss of blood (either externally as by a wound or internally as in gastrointestinal bleeding or a fractured femur) or by dehydration from loss of fluid from extravascular compartments (as in vomiting or diarrhea). The symptoms are the same as those described for this patient, but the onset of shock would not be preceded by the early reaction to toxins. Cardiogenic shock (choice C) occurs when the supply of blood to peripheral tissues falls below a critical level because of inadequate pumping ability of the heart. The symptoms again are as those described, and the condition may be caused by a myocardial infarct, heart failure, cardiac arrhythmias, or cardiac tamponade. Anaphylactic shock (choice D) is caused by an allergic reaction to any of a host of potential allergins. As in TSS, shock is preceded by a brief inflammatory period. However, there is no reason to suspect an allergic reaction in the case presented. Shock caused by a gram-negative organism (choice E) would represent classic septic shock, likely caused by an ingested pathogen or infection from gastrointestinal or urinary tract pathogens. As in TSS and anaphylactic shock, the onset of shock is preceded by a brief inflammatory period. However, gram-negative bacteria are rarely, if ever, associated with tampon-induced shock.

A 36-year-old man complains of diffuse macular rash, headache, and reddened eyes developing over 3 days. Today, his palms and soles show faintly and finely vesicular changes. He complains also of the recurrence over 4 days of soreness and focal redness on the left side of his nose, manifesting a flame-shaped region of erythema involving the left naris. He denies sore throat, and a rapid flocculation test for beta-hemolytic streptococcus is negative. In the past 24 hours, he has developed vomiting and diarrhea. Which of the following is the most likely diagnosis?

A. Scarlatina  |  B. Kawasaki syndrome  |  C. Secondary syphilis 
D. Toxic shock syndrome  |  E. Cirrhosis of the liver

The answer is D. Toxic shock syndrome now occurs as frequently in non-female menstrual situations as in the originally described association with the retained tampon. The vesicular changes of the palms and soles lead to the well-known desquamation seen in the late stages. Toxic shock, which may carry a case mortality as high as 15% as a result of hypotension and heart failure, is due to the toxin elaborated. Thus, early cultures may be unhelpful. Scarlatina may be considered long enough to rule out quickly because the rash of scarlatina is quite different, described as pampiniform (pinpoint red spots). Kawasaki syndrome occurs nearly always in children 5 years old or younger, albeit characterized by desquamation of the palms and the soles. Although secondary syphilis manifests palmar and solar changes, they are nonvesicular and consist of macules, papules, and pustules. Cirrhosis of the liver is mentioned because of palmar erythema seen in the face of patients with advanced compromise of liver function. Again, however, vesicle formation and desquamation is not characteristic of such a situation.
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Conversion Disorder
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Conversion disorder consists of neurologic symptoms or deficits that develop unconsciously and nonvolitionally and usually involve motor or sensory function. The manifestations are incompatible with known pathophysiologic mechanisms or anatomic pathways. Onset, exacerbation, or maintenance of conversion symptoms is commonly attributed to mental factors, such as stress. Diagnosis is based on history after excluding physical disorders as the cause. Treatment begins by establishing a consistent, supportive physician-patient relationship; psychotherapy can help, as may hypnosis.

Conversion disorder tends to develop during late childhood to early adulthood but may occur at any age. It is more common among women.

Symptoms and Signs

Symptoms often develop abruptly, and onset can often be linked to a stressful event. Typically, symptoms involve apparent deficits in voluntary motor or sensory function but sometimes include shaking movements and impaired consciousness (suggesting seizures) and abnormal limb posturing (suggesting another neurologic or general physical disorder). For example, patients may present with impaired coordination or balance, weakness, paralysis of an arm or a leg, loss of sensation in a body part, seizures, unresponsiveness, blindness, double vision, deafness, aphonia, difficulty swallowing, sensation of a lump in the throat, or urinary retention.

The symptoms are severe enough to cause significant distress or impair social, occupational, or other important areas of functioning. Patients may have a single episode or sporadic repeated ones; symptoms may become chronic. Typically, episodes are brief.


• Clinical evaluation

The diagnosis is considered only after a comprehensive medical examination and tests to rule out neurologic or general medical disorders that can fully account for the symptoms and their effects. An important characteristic is that the symptoms and signs are not consistent with neurologic disease. For example, they may not follow anatomic distributions (eg, sensory deficits that involve parts of multiple nerve roots), or findings may vary at different examinations or when assessed in different ways, as in the following:

A patient may have marked weakness of plantar flexion when tested in bed but can walk normally on tiptoes.

In a prone patient, the examiner's hand under the heel of a "paralyzed" leg detects downward pressure when the patient lifts the unaffected leg against resistance (Hoover sign).

Tremor changes or disappears when the patient is distracted (eg, by having the patient copy a rhythmic movement with the unaffected hand).

Resistance to eye opening is detected during an apparent seizure.

A visual field deficit is tubular (tunnel vision).


• Sometimes hypnosis or cognitive-behavioral therapy

A consistently trustful and supportive physician-patient relationship is essential. Collaborative treatment that involves a psychiatrist and a physician from another field (eg, neurologist, internist) seems most helpful. After the physician has excluded a general medical disorder and reassured patients that the symptoms do not indicate a serious underlying disorder, patients may begin to feel better, and symptoms may fade.

The following treatments may help:

Hypnosis may help by enabling patients to control the effects of stress and their mental state on their bodily functions.

Narcoanalysis is a rarely used procedure similar to hypnosis except that patients are given a sedative to induce a state of semisleep.

Psychotherapy, including cognitive-behavioral therapy, is effective for some people.

Any coexisting psychiatric disorders (eg, depression) should be treated.


A 31-year-old man presents to the emergency department with the sudden onset of weakness in his right hand. Two weeks ago, his wife filed a complaint of spousal abuse with the local police, and yesterday, he gave several guns to a friend of his because he “didn’t trust himself with them.” Mental status examination reveals a peculiar calmness and lack of concern about his weakness. Which of the following is the most likely diagnosis?

A. Conversion disorder
B. Specific phobia
C. Obsessive-compulsive disorder 
D. Hypochondriasis
E. Melancholic depression

The answer is A. Conversion disorder (choice A) is suggested by loss of motor control or sensory function that is not fully explained by physiologic mechanisms and is associated with psychologic conflict. Affected individuals often demonstrate an emotional blandness that is sometimes referred to as la belle indifférence.

Specific phobias (choice B), obsessive-compulsive disorder (choice C), and hypochondriasis (choice D) are often associated with anxiety. Melancholic depression (choice E) may be associated with decreased psychomotor activity.

A 22-year-old woman has been brought home from a private college on a medical basis because of the occurrence of seizures that often occurred in her room in a women’s dormitory and, as described, would seem to be grand mal seizures. She is hospitalized and her family doctor visits her at her hospital bed. He witnesses a seizure and suspects that they are not organically based; that is, they are “hysterical” or pseudoseizures. Which of the following somatoform disturbances is present in this patient?

A. Conversion disorder 
B. Somatization disorder 
C. Pain disorder
D. Hypochondriasis
E. Malingering

The answer is A. Conversion disorder. This picture, taken from a real case, is fairly typical of that condition. The student had learned early that she could escape certain responsibilities by deflecting attention to herself in a sympathetic manner. She was treated in a manner that walked the tightrope between reinforcement of neurosis and cure by allowing her self-respect and suggesting, without being direct, that she knew what to do to get herself reinstated at the college.

A 20-year-old woman presents with sudden loss of sensation and flaccid paralysis of her entire left arm. Many patients with this disorder described in this question:

A. Have comorbid body dysmorphic disorder
B. With an obvious stressful precipitant have a poor prognosis
C. Respond to benzodiazepines
D. Are later diagnosed with a physical illness that explains their symptoms
E. Intentionally produce their symptoms

The answer is D. The sudden onset of a sensory and motor loss in the left arm could be caused by a neurologic illness (e.g., multiple sclerosis, stroke, cervical injury) but would be unlikely given the overlapping distribution of the sensory and motor losses, which do not follow more specific nerve distributions. There is no alteration of the patient’s perceptions or consciousness necessary for any dissociative disorder. Likewise, no mood symptoms are mentioned, so major depression is unlikely.

Between 15% and 30% of patients diagnosed with conversion disorder have an underlying physical illness that is later diagnosed. Between 30% and 50% of patients with conversion disorder have a comorbid psychiatric diagnosis, but there is no specific association with body dysmorphic disorder. A good prognosis is associated with an obvious stressor, acute onset, and good premorbid functioning. There is no evidence to support the use of benzodiazepines in patients with conversion disorder. One criterion of conversion disorder is that the symptoms are not intentionally produced.
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Post-Splenectomy Infection
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Overwhelming post-splenectomy infection (OPSI) is a serious disease that can progress from a mild flu-like illness to fulminant sepsis in a short time period. Although relatively rare, it has a high mortality rate with delayed or inadequate treatment, and therefore it is important for Emergency Physicians to be familiar with it. Patients who are asplenic or hyposplenic are at an increased risk for infection and death from encapsulated organisms and other dangerous pathogens.

Case Report
A 5-month-old girl was brought to the Emergency Department (ED) by her mother with a chief complaint of fever (38.1°C oral), fussiness, and cough for several hours. The patient had a history of duodenal atresia, midgut malrotation, congenital asplenia, and an undiagnosed liver disorder. She was born at 36 weeks gestation and spent some time in the neonatal intensive care unit. She was hospitalized 1 month before presentation for a fever of unknown origin that was treated with empiric intravenous (i.v.) antibiotics, from which she recovered without incident. Her immunizations were up to date. The patient's mother denied sick contacts, diarrhea, bloody stools, difficulty breathing, rhinorrhea, or lethargy. The patient was taking oral feeds with adequate urine output and had a single episode of vomiting. She was given a dose of acetaminophen before arrival. On examination, the patient was afebrile (37.6°C [99.8°F] rectal), non-toxic, smiling, and interactive. She was diffusely jaundiced and had scleral icterus that had been present for weeks. The remainder of her physical examination was unremarkable. Laboratory tests were significant for a white blood cell count (WBC) of 36,000 cells/mm3 with 23% bands, and venous hemoglobin of 6 gm/dL. Liver function studies were grossly abnormal, with coagulation times mildly prolonged. Venous lactate was 2.1. Urinalysis and serum chemistry were unremarkable. Two sets of blood cultures were also obtained. A chest radiograph was normal. After discussion with a pediatric infectious disease specialist, ceftriaxone 50mg/kg i.v. was ordered. The patient was admitted to the pediatric service, where several hours later she developed respiratory depression, lethargy, and signs of septicemia and disseminated intravascular coagulopathy (DIC). She was intubated and central venous access was obtained. Ceftriaxone dose was increased to 100mg/kg and vancomycin was added. Crystalloid and blood product resuscitation was initiated along with vasopressor agents. A lumbar puncture was unremarkable. In<24h from the time they were obtained, the blood cultures were positive for Gram-positive, lancet-shaped diplococci, presumed to be Streptococcus pneumoniae. She was transferred to a pediatric intensive care unit at another institution where, after a prolonged hospital course, she recovered.

This case is an illustrative example of how OPSI can present. A patient may not be ill-appearing initially, but can quickly decompensate into fulminant sepsis. The spleen is the largest accumulation of lymphoid tissue in the body, filtering 10–15% of the body's blood volume per minute. When its function is absent or reduced, the ability to fight off infection is impaired, particularly from encapsulated bacterial organisms. Mortality rates from OPSI range from 50% to 70%; however, with aggressive and early medical care, the mortality rate may be as low as 10%. There are few infectious conditions that progress as rapidly as OPSI, making it especially important for Emergency Physicians to identify it and start appropriate antibiotics and other critical interventions.

When examining the pathophysiology of OPSI, two factors must be considered: the conditions that predispose to asplenism or hypopslenism, and the organisms that thrive in these patients. The spleen has an abundance of lymphoid tissue, including splenic macrophages that attack encapsulated organisms. In their absence, the ability to fight off these pathogens is severely diminished. The spleen is also a major site of early immunoglobulin M production, which is important in the acute clearance of pathogens from the bloodstream. The most common etiologies of asplenia or hyposplenism are congenital and splenectomy after trauma or hematologic disease. Children aged 2 years or less and those splenectomized secondary to hematologic disease have poorer outcomes than those patients with splenectomy after trauma. This may be due to trauma patients retaining an accessory spleen or splenic implants, giving them some ability to mount an immune response. Younger patients are thought to lack the circulating antibodies present to encourage opsonization by macrophages during phagocytosis. 

Several conditions are associated with functional hyposplenism, indicating the situation where the patient has a spleen but it is not functioning in a normal capacity. The most common conditions associated with functional hyposplenia are severe liver disease, ulcerative colitis, celiac sprue, and lupus. Hemoglobinopathies such as sickle cell disease and the thalassemias must also be remembered as an important cause of functional hyposplenia. As the spleen filters out abnormal red blood cells from the circulation, splenomegaly will develop in these patients due to increased splenic sequestration. Eventually, the spleen is no longer able to filter and the patients have essentially succumbed to autosplenectomy.

Encapsulated organisms are the most virulent pathogens to patients with decreased or absent splenic function. The most important pathogen is Streptococcus pneumoniae, but Haemophilus influenza and Neisseria meningitidis are also significant. These are all encapsulated organisms that thrive in the absence of the opsonization and phagocytosis provided by splenic macrophages. Interestingly, asplenic patients account for around one-third of all cases of babesiosis. This is likely due to the fact that Babesia microti is an intraerythrocytic parasite. The spleen serves as a filter to defective erythrocytes, and the asplenic patient is therefore more susceptible to these types of infections. More recently, Capnocytophaga canimorsus has been recognized as causing OPSI after dog bites.

A key element of the history in a patient with known asplenia is their vaccination status. The Centers for Disease Control and Prevention recommends that patients with asplenia receive the 23-valent pneumococcal vaccine to prevent OPSI, as this covers around 73–90% of strains causing OPSI. Asplenic children are revaccinated every 3–6 years, as levels of circulating antibodies to the pneumococcal antigens are lower 5 years after vaccination in asplenic children compared to children with intact splenic function. Other vaccines available to asplenic patients are the Haemophilus influenzae type B vaccine and the meningococcal vaccine. Unfortunately, these vaccines do not completely protect a patient from developing OPSI, and the treatment should still be aggressive and aimed at the encapsulated organisms mentioned above.

The initial prodrome of OPSI is usually mild, consistent with a flu-like illness that can be representative of many other disease processes. The earliest symptoms may be fatigue, abdominal pain, or nausea, and may progress to fever, headache, rigors, myalgias, and vomiting. Rash will likely become present as the disease progresses. The rash may be mild and non-specific, but may also progress rapidly and appear similar to meningococcemia. A rapid clinical deterioration is the hallmark of this disease.

On examination, the patient may be febrile, tachycardic, hypotensive, and in extremis, or, if in early stages of the disease process, well appearing. It is important to localize the source of infection. For example, meningitis or pneumonia may be the inciting disease process, but can quickly become systemic as bacteremia develops. A petechial or purpuric rash may be seen, evident of DIC. OPSI's clinical course may be similar to that of meningococcemia, which also may present with a petechial or purpuric rash. Post-mortem examination of patients with OPSI may reveal bilateral adrenal hemorrhages, which are also found in Waterhouse-Friderichsen syndrome from severe meningococcemia. Respiratory distress and multi-system organ failure may ensue and rapidly progress to coma and death within 24–48h. The exact timeline of symptoms and physical examination findings is variable. Patients with suspected OPSI therefore require frequent reassessment while in the ED, even when appearing non-toxic.

ED Work-up
The ED work-up of a patient with suspected OPSI is quite extensive. A complete blood count may show an elevated or depressed WBC count with bandemia. Peripheral blood smear may show Howell-Jolly bodies present in erythrocytes of patients without a spleen, although therapy usually must be started before the return of such studies. Coagulation studies may reveal signs of DIC. If multi-system organ failure is present, elevations of serum creatinine, liver function studies, and lactate will be present. Blood and urine cultures should be obtained to help focus antimicrobial therapy at a later time. Urinalysis may help localize the infection, as will a chest X-ray study. Lumbar puncture should be done only if there is heightened suspicion for meningitis, keeping in mind that DIC is a contraindication, and performing it should not delay treatment in a critically ill patient.

Treatment and Disposition in the ED
As with any case of sepsis, supportive care is very important. Optimizing tissue perfusion through aggressive fluid resuscitation and possibly vasopressor agents is key. Perhaps the most critical action in the treatment of OPSI is the immediate use of broad-spectrum i.v. antibiotics, ideally after blood cultures have been collected. Diagnostic work-up should never delay the initiation of empiric antibiotics. The initial empiric antibiotic choice for adults with normal renal function presenting with OPSI is vancomycin 1g i.v. every 12h and ceftriaxone 2g i.v. daily. However, it must be noted that vancomycin dosing is weight based, depending on creatinine clearance (CrCl). Patients with CrCl over 60mL/min are dosed at 10–15mg/kg i.v. every 12h, which approximates to 1g i.v. for a 70-kg patient. Vancomycin has excellent Gram-positive coverage, including against penicillin-resistant S. pneumoniae. Ceftriaxone is added for double coverage of Gram-positive organisms, but includes Gram-negative coverage for N. meningitidis and H. influenzae. 

OPSI is an extremely serious infection that often quickly progresses to fulminant sepsis, resulting in high mortality rates. Emergency Physicians are well trained to diagnose and treat sepsis, but not specifically in asplenic patients. This subclass of patients progress from healthy to clinically septic so quickly that it is imperative that Emergency Physicians not only recognize OPSI, but effectively treat it early. Current literature suggests a combination of i.v. vancomycin and ceftriaxone in combination with early goal-directed therapy. Implementation of these strategies may reduce mortality from 70% to around 10–40%.


Which of the following organisms is associated with increased mortality after splenectomy?

A. Moraxella catarrhalis 
B. Influenza
C. Aspergillosis
D. Pneumococcus
E. E. coli

The answer is D. Patients with a history of splenectomy are at particular risk of infection by encapsulated organisms such as Pneumococcus, Haemophilus influenzae, and Neisseria species. Infection with Babesia or Capnocytophaga canimorsus puts patients at particular risk of increased mortality.

A 33-year-old man is in the hospital recovering from a motor vehicle accident from which he sustained a liver laceration, right pneumothorax, and a splenic laceration. He is 2-weeks status post an exploratory laparotomy with splenectomy. His postoperative course has been unremarkable and he is now preparing to return home. He describes feeling "well". His only current medication is a daily multivitamin. His temperature is 37.0 C (98.6 F), blood pressure is 124/78 mm Hg, pulse is 78/min, and respirations are 21/min. His cardiac rhythm is regular and his lungs are clear to auscultation bilaterally. Prior to his discharge, the patient should receive a vaccination against the

A. Bordetella pertussis
B. hepatitis B virus
C. influenza virus
D. Streptococcus pneumoniae
E. varicella virus

The correct answer is D. The spleen constitutes a major site of immune response against encapsulated organisms such as Streptococcus pneumoniae, (pneumococcus). Patients following traumatic splenectomies are especially at risk for sepsis with such organisms. Therefore, this population should be routinely vaccinated against encapsulated organisms including pneumococcus.

Multi trauma victims are not at an elevated risk of developing pertussis. It is also likely that this patient was adequately immunized against pertussis with the DPT vaccine as a child. Therefore, the Bordetella pertussis vaccine (choice A) is not warranted at this juncture. Multi trauma victims are not at an elevated risk of acquiring hepatitis B infection, (when blood products are adequately screened). Therefore, the hepatitis B vaccine (choice B) is not routinely used in their care. Young patients, even with a history of multi trauma, are not at an elevated risk of influenza. Therefore, the influenza vaccine (choice C), especially given the season (mid-summer), is not warranted in this situation. Multi trauma victims are not at an elevated risk for developing varicella. Therefore, the varicella vaccine (choice E) is not warranted in this instance.
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