Carl M. Allen, DMD, MSD

• Professor and Director, Division of Oral and Maxillofacial
• Surgery, Pathology, and Dental Anesthesiology
• College of Dentistry, The Ohio State University,
• Columbus, Ohio

Hot flashes or sweats can disturb sleep patterns and interfere with sleep quality heart attack clothing buy cheap bystolic line, resulting in fatigue arrhythmia consultants generic bystolic 5 mg without a prescription, irritability blood pressure 9040 buy discount bystolic, and difficulty concentrating hypertension causes 2.5mg bystolic amex. Vaginal dryness and dyspareunia are common symptoms that can interfere with sexual function blood pressure bulb replacement buy bystolic 5mg mastercard. Changes in mood and cognition are common complaints during the menopausal transition heart attack zip buy 5 mg bystolic visa, but a causative link between hormonal fluctuations and mood disturbances and cognitive changes has not been established. Women who do experience significant depression at this time are more likely to have experienced depression earlier in their lives, particularly at times of hormonal change. Mood issues during the perimenopausal transition should be approached in the same manner as at other ages. In addition to mood, many women in perimenopause complain of difficulties with concentration and memory. Most epidemiologic studies do not demonstrate an increased risk of depression or a decline in cognitive skills during the menopausal transition. In the United States, up to 75% of women who experience a natural menopause and 90% of women who experience a surgical menopause have these vasomotor symptoms. If hormone therapy is initiated, the lowest dose needed to treat the symptoms should be used and usually for a short term. For women who have only vaginal dryness, vaginal estrogen can be used instead of oral estrogen. It may be acceptable under some circumstances, provided the woman is aware of the potential benefits and risks, to extend low-dose therapy if the benefits of treatment outweigh the risks, and a woman has failed attempts to stop (level C evidence). Alternative Therapies Interest in nonhormonal and "natural" alternatives in the treatment of menopausal symptoms is extremely high. As many as 75% of menopausal women have used some form of alternative or complementary treatment to relieve menopausal symptoms. Behavioral options such as dressing in layers, regular exercise, stress reduction techniques, and avoidance of known triggers are safe and may be helpful for a number of women. Some of the more common herbal remedies for menopausal symptoms include isoflavones. None of these therapies has consistently been shown to decrease hot flashes beyond placebo in rigorous randomized, controlled trials. There are effective nonhormonal medication options for treatment of hot flashes, although hormone therapy is superior to these alternatives. Gabapentin and clonidine have been shown to reduce hot flash frequency beyond placebo. Women between 45 and 65 years of age are disproportionately affected, just before and after the menopausal transition. Risk factors for dysfunction include depression and anxiety, relationship conflict, stress and fatigue, and a history of abuse. Medical and physical issues, such as pelvic floor disorders, endometriosis, and psychiatric and neurologic disease, can negatively affect sexuality. As women age and enter menopause, the decline in estrogen levels causes thinning of the vaginal epithelium, decreased vaginal elasticity, and decreased vaginal lubrication, resulting in painful intercourse. For most women, vasomotor symptoms are self-limited, lasting on average 1 to 2 years; however, up to 25% of women may have symptoms for longer than 5 years. The exact cause of a hot flash is not understood, although it is related to a disturbance of hypothalamic thermoregulation. Women experience a sudden onset of warmth, ranging from noticeable to markedly uncomfortable, especially over the face and upper body. There are racial and ethnic differences in reported hot flashes, with African American women experiencing increased rates compared with white women and Hispanic and Asian women experiencing lower rates. In the 1950s, it was discovered that estrogen could relieve hot flashes, and its use became widespread. In 1975, a study published in the New England Journal of Medicine showed that women who used estrogen for more than 7 years had a 14-fold increase in uterine cancer. Subsequent research determined that endometrial hyperplasia and cancer is reduced to essentially zero when low-dose progestin is continued for 12 to 13 days per month. Women on estrogen with an intact uterus must use progestin therapy to prevent endometrial hyperplasia and cancer. The conclusion was that estrogen alone should not be recommended for the prevention of chronic disease in postmenopausal women and hormone therapy should not be prescribed for disease prevention. Nonpharmacologic therapies include counseling, lifestyle changes to decrease stress and anxiety, physical therapy for vaginismus and pelvic floor dysfunction, and lubricants and vaginal moisturizers for dyspareunia caused by vaginal dryness. For some women, vaginal lubricants and moisturizers may be sufficient and are the first-line therapy. Pharmacologic therapy for sexual dysfunction has primarily focused on hormonal therapy. Topical vaginal estrogen results in little systemic absorption and is very effective in relieving the symptoms of vaginal atrophy. The endothelium of the urethra and bladder becomes more fragile and less elastic with menopause. Risk also increases as body weight increases due to increased pressure on the bladder. Urinary incontinence and its behavioral and pharmacologic treatment options are discussed in Chapter 26, "Incontinence," in Goldman-Cecil Medicine, 25th Edition. Reproductive and metabolic effects include anovulation, infertility, acne, hirsutism, obesity, and metabolic syndrome. Increased insulin resistance is a significant consequence of the syndrome, increasing the risk of type 2 diabetes, particularly in obese women. The risk of type 2 diabetes mellitus increases with obesity, and like obesity, the incidence of diabetes has been on the rise in the United States. More than 10% of adult Americans carry the diagnosis of diabetes, and many remain undiagnosed. The increased cardiovascular disease risk conferred by diabetes is greater for women than for men, and women with diabetes have lower survival rates and quality of life after a cardiovascular event than their male counterparts. In addition to reviewing traditional risk factors for diabetes, a history of gestational diabetes and infant birth weight greater than 9 pounds should be considered when evaluating female patients for the risk of diabetes. It increases the risk of numerous pregnancy-related complications, including gestational diabetes mellitus, fetal macrosomia, hypertension, shoulder dystocia, and cesarean delivery, and contributes postpartum complications such as thrombosis and infection. The risk of cardiovascular disease related to the metabolic syndrome appears to have a stronger correlation in women. Metabolic syndrome significantly increases the risk of type 2 diabetes and BreastPain,Discharge,andMasses Breast symptoms are common in practice and cause significant anxiety to patients. Although most breast complaints are about benign conditions, it is important to evaluate breast symptoms thoroughly to ensure that breast cancers are not being missed. Initial evaluation starts with obtaining a history and asking when symptoms began and how they evolved. For instance, a mass that is prominent premenstrually and then decreases in size in the follicular phase of menses is likely a benign cyst. Localized breast pain is the only symptom in 10% to 15% of women with newly diagnosed breast cancer. Approximately two thirds of breast pain is cyclical in nature and related to the normal hormonal variations in the menstrual cycle. Noncyclical breast pain does not follow the usual menstrual pattern and is usually unilateral. Causes of noncyclical breast pain include large breasts, diet and lifestyle factors. If mammography and the physical examination are normal, reassurance can be provided. In women younger than 35 years of age, normal examination results can obviate the need for further testing. Concern for malignancy is increased if the discharge occurs without provocation, is persistent, and is unilateral; if the discharge is serous, serosanguineous, or bloody; if it occurs in an older patient; or if it is associated with a mass or lump. Interstitial cystitis or painful bladder syndrome is a clinical diagnosis consisting of pain, pressure, or discomfort related to the bladder and associated with lower urinary tract symptoms lasting more than 6 weeks and occurring in the absence of infection or other identifiable causes. Physical examination should assess for focal areas of pain, scars, hernias, or masses in the abdomen, and a pelvic examination should be performed. After the most likely diagnosis has been identified, an empirical, targeted treatment may be instituted and followed for efficacy. Further work-up should be considered if the patient does not respond or symptoms change. If empirical therapy and a thorough investigation do not yield a diagnosis, laparoscopy may be considered to identify pelvic pathology. Depending on the underlying cause, management strategies may include heat therapy (for musculoskeletal pain), counseling and psychiatric referral, gastrointestinal referral, medications. Multidisciplinary approaches, including medications and interventions that address dietary and psychosocial factors, may be superior to medical treatment alone. However, a benign intraductal papilloma is the most common cause of bloody nipple discharge. Most bilateral discharge that occurs only with manipulation is a normal physiologic response. Galactorrhea, bilateral milk production occurring in a nonlactating woman, can be seen in many conditions, including prolactinomas, thyroid dysfunction, and chronic renal failure. It can be a response to many drugs, including antipsychotics, oral contraceptives, and marijuana. Initial evaluation for breast discharge includes a pregnancy test, prolactin level determination, and thyroid tests. If there is concern about malignancy, a breast specialist performs cytology, immunology, and occult blood testing on the discharge and obtains mammography and ultrasound studies. There are four categories of breast masses: abscesses, benign masses, benign tumors, and cancer. Although breast cancers have characteristically been described as hard and immobile with irregular borders, no examination finding reliably distinguishes between a benign and cancerous mass. If the mass is solid and is not characteristic of a fibroadenoma (which can be observed or biopsied), a biopsy is indicated to rule out malignancy. In women older than 30 years of age, mammography is the first diagnostic test that should be ordered, even if the woman had a recent negative screening mammogram. Ultrasound is often done simultaneously to further evaluate the mass or an area of abnormality detected on the mammogram. Negative imaging results should not preclude further work-up of a clinically suspicious mass. Have you ever been in a relationship in which your partner threatened you with violence Have you ever been in a relationship in which your partner has thrown, broken, or punched things A self-administered questionnaire may be even more effective than face-to-face questioning. They may blame themselves for the abuse, or they may not be emotionally ready to acknowledge the abuse. PelvicPain Pelvic pain is characterized as acute or chronic, and both types are commonly encountered in primary care practice. Acute pelvic pain usually manifests over hours to days and may be gynecologic, gastrointestinal, or urologic in origin. Life-threatening conditions, including ruptured ectopic pregnancy and appendicitis, need to be ruled out. Gynecologic causes include complications of pregnancy, acute pelvic infection, and ovarian pathology, including cyst and torsion. After identification, a woman may be referred to a mental health provider or social worker. PsychiatricIssues Fewer than one half of people who meet the diagnostic criteria for psychological disorders are identified. Only two of every five people with a mood, anxiety, or substance use disorder seek assistance within a year of onset of the disorder. However, substantial gender differences exist in the rates of common mental disorders, including depression, anxiety, and somatic complaints. In the United States, the estimated lifetime prevalence is 21% for women and 13% for men. Depression occurring at these times may represent a specific biologic response to the effects of hormonal fluctuations in the brain and may require different treatments from depression unrelated to these periods. The disability associated with mental illness is worse for individuals with three or more comorbid disorders. Women are more likely than men to have comorbid conditions, including anxiety disorders, eating disorders, and somatization. Gender-specific risk factors for common mental disorders that disproportionately affect women include gender-based violence, low income and income inequality, low or subordinate social status, and the responsibility as caretaker of others. Somatoform disorders are associated with significant disability and a significantly greater number of clinic and emergency room visits than for other psychiatric diagnoses. Generalized anxiety disorder and panic disorder are about twice as prevalent among women than men, with lifetime prevalences of 5% and 3. Although there is a higher prevalence of social anxiety disorder among women than men, more men may seek treatment for the disorder. There is a strong association between eating disorders and mood disorders, particularly depression. There are no marked gender differences in the rates of severe mental disorders such as schizophrenia and bipolar disorder, which affect less than 2% of the population. Women are more likely to seek help from and disclose mental health problems to their primary health care physician, whereas men are more likely to seek specialist mental health care and are the principal users of inpatient care. Evidence exists for possible gender bias in the treatment of psychological disorders. Physicians are more likely to diagnose depression in women than men, even when they have similar scores on standardized measures of depression or have identical symptoms at presentation.

Syndromes

• A tube through the mouth into the stomach to wash out the stomach (gastric lavage)
• Heart -- abnormal heart rhythms or heart failure (rare)
• Cleft soft palate
• Problems with your eyesight
• X-rays of the arteries (angiogram)
• Presbyopia
• Lose weight. You are more likely to feel winded if you are overweight. You are also at greater risk for heart disease and heart attack.

Additional side effects in children include slipped capital femoral epiphysis and hydrocephalus blood pressure 120 0 order discount bystolic. The incidence of hypopituitarism 10 years after irradiation of the sellar region is approximately 50% heart attack female discount bystolic 5mg line. Treatment often requires the use of multiple modalities to achieve adequate control of the disease blood pressure under 120 buy discount bystolic 2.5 mg online. Primary therapy is almost always transsphenoidal surgery arrhythmia treatment guidelines order bystolic 2.5 mg without prescription, with the cure rate being directly proportional to tumor size hypertension code for icd 9 purchase bystolic 2.5 mg amex. Approximately 40% to 60% of tumors are not controlled with surgery alone because of cavernous sinus invasion or intracapsular intra-arachnoid invasion arteria inominada generic bystolic 2.5 mg. Additional treatment options include primary medical therapy or primary surgical debulking of the tumor followed by medical therapy for hormonal control and/or radiation therapy for treatment of residual tumor. Focused single-dose gamma knife radiotherapy has a 5-year remission rate of 29% to 60%. Hypopituitarism is seen in more than 50% of patients within 5 to 10 years after radiotherapy. Cabergoline is the most efficacious of the dopamine agonists for treatment of acromegaly, but it is effective in fewer than 10% of patients. The incidence of acromegaly is about 2 to 4 per million population, and the mean age at diagnosis is 40 to 50 years. Clinical Presentation Acromegaly is a rare disease, and the rate of change of symptoms and signs is slow and insidious. Characteristic clinical findings of this disease include physical changes of the bone and soft tissue and with multiple endocrine and metabolic abnormalities Table 62-4). In addition, it is subject to the negative feedback of thyroid hormones released from the thyroid gland. Clinical Presentation the most common age of presentation is in the early fifth decade, and there is no gender bias. Presenting symptoms can be the result of a mass effect of the tumor or, most commonly, there are symptoms and signs of hyperthyroidism, including weight loss, tremors, heat intolerance, and diarrhea. Many times, these tumors are initially misdiagnosed as primary hyperthyroidism and patients are mistakenly treated with radioactive iodine. Treatment and Prognosis Surgery (transsphenoidal resection) is the first-line treatment and should be performed by an experienced neurosurgeon. Most patients do well and achieve control of symptoms of thyrotoxicosis as well as reduction in tumor burden. Pathology Hypopituitarism due to encroachment of a tumor on the normal pituitary can cause deficiency of one or more pituitary hormones. Radiation treatment of the pituitary gland can also cause hypopituitarism over time. Clinical Presentation the usual signs and symptoms of hypothyroidism are weight gain, fatigue, cold intolerance, and constipation. If the condition is caused by an underlying sellar tumor, symptoms of mass effect may also be present, depending on the size of the tumor. The differential diagnosis includes euthyroid sick syndrome, which is often seen in the setting of an acute illness. This syndrome does not require any intervention, and the laboratory results normalize on repeat testing after resolution of the acute illness. Treatment and Prognosis Management focuses on replacement of the thyroid hormones, as in primary hypothyroidism. Underlying adrenal insufficiency should always be excluded and treated before treatment of secondary hypothyroidism to avoid precipitating an adrenal crisis. Aldosterone secretion from the adrenal glands is not impaired because it is maintained via the renin-angiotensin axis. Secondary or tertiary adrenal insufficiency is most commonly iatrogenic, caused by the use of steroids for other disease processes. Mineralocorticoids are usually not needed in patients with central adrenal insufficiency. Both primary and secondary adrenal insufficiency are characterized by weight loss, fatigue, muscle weakness, orthostatic symptoms, nausea, vomiting, diarrhea, and abdominal pain. Biochemical abnormalities include hyponatremia, azotemia, eosinophilia, and anemia. Diagnosis and Differential Diagnosis the gold standard for diagnosis of secondary adrenal insufficiency has been an insulin tolerance test. The test is contraindicated in elderly patients and in those with a history of seizures, cardiovascular disease, or cerebrovascular disease. Treatment Glucocorticoid replacement therapy in the form of hydrocortisone (10 mg in am and 5 mg in pm) or prednisone (5 to 7. G, Striae in a 24-year-old patient with congenital adrenal hyperplasia treated with excessive doses of dexamethasone as replacement therapy. A 24-hour urine collection may show an elevated cortisol level, but this test is not reliable in patients with renal dysfunction. A second test, the 1-mg dexamethasone suppression test, measures an 8 am fasting cortisol level after a dose of 1 mg dexamethasone given at 11 pm the night before. Another diagnostic test is the late-night salivary cortisol measurement, using saliva collected at 11 pm on two consecutive nights. Individuals who are using inhaled or topical steroids are not good candidates because of a high rate of false-positive results. A single positive finding is not sufficient to make this diagnosis and must be repeated and confirmed by doing additional tests. Pathologic hypercortisolism should be differentiated from physiologic activation of the hypothalamic-pituitary-adrenal axis, which can be observed in conditions such as critical illness, eating disorders, alcoholism, pregnancy, severe neuropsychiatric illness, and poorly controlled diabetes. Treatment and Prognosis the treatment involves removal of the pituitary tumor by an experienced neurosurgeon. Options after a failed resection include reoperation, bilateral adrenalectomy, radiotherapy, or pharmacotherapy. Pharmacotherapeutic agents include ketoconazole, metyrapone, mitotane, cabergoline, pasireotide, and mifepristone. In severe cases, intravenous etomidate may be used to stabilize patients for surgery. Long-term remission after resection of a pituitary microadenoma ranges from 69% to 98%, with a recurrence rate of 3% to 19%. Clinical Presentation Signs and symptoms depend on the time of onset and the extent of gonadotropin deficiency. If deficiency occurs after birth but before puberty, it can cause delayed or absent sexual development. Onset after puberty often causes insidious changes and may remain undiagnosed for years, especially in men. The usual presentation after puberty includes symptoms of hypogonadism as well as infertility. Treatment For women, replacement therapy in the form of oral or transdermal estrogen should be continued until the age of natural menopause. Progesterone addition to induce withdrawal bleeding is essential in women with an intact uterus to prevent endometrial hyperplasia. For men, testosterone replacement is available in multiple forms, including an intramuscular injection product, several gels, and a patch. Gonadotropin-SecretingPituitaryTumors Definition and Epidemiology Gonadotropin-secreting pituitary tumors are usually large and typically manifest with signs and symptoms of mass effect. Patients can also have symptoms of hypogonadism and other pituitary hormone deficiencies. Immunoperoxidase staining on surgical specimens is also needed to establish the diagnosis, especially in the case of postmenopausal women. Radiation therapy may be used as an adjunct treatment because of the size and more aggressive nature of these tumors, compared with true nonsecretory pituitary tumors. They are both composed of an alpha and a beta subunit, the latter of which gives each its specific biologic function. These hormones bind to the receptors in the gonads (ovaries and testes) and modulate gonadal function. The response to a synthetic analogue of vasopressin is analyzed if the normal rise in urine osmolality and decrease in urine volume are not seen. Patients with primary polydipsia concentrate their urine without the need for synthetic vasopressin. It can also be acquired secondary to intrasellar and suprasellar tumors, infiltration of the hypothalamus and posterior pituitary, infection, trauma or surgery, or as part of an autoimmune condition. Swearingen B, Biller B: Diagnosis and management of pituitary disorders, New York, 2008, Humana Press. Microscopically, the thyroid is composed of several follicles that contain colloid surrounded by a single layer of thyroid epithelium. Biosynthesis of T4 and T3 occurs by iodination of tyrosine molecules in thyroglobulin. Iodine, after conversion to iodide in the stomach, is rapidly absorbed from the gastrointestinal tract. After active transport from the bloodstream across the follicular cell basement membrane, iodide is enzymatically oxidized by thyroid peroxidase, which also mediates the iodination of the tyrosine residues in thyroglobulin, to form monoiodotyrosine and diiodotyrosine. The iodotyrosine molecules couple to form T4 (3,5,3,5tetraiodothyronine) or T3 (3,5,3-triiodothyronine). Once iodinated, thyroglobulin containing newly formed T4 and T3 is stored in the follicles. Thyroid hormones also have specific effects on several organ systems Table 63-1). These effects are exaggerated in hyperthyroidism and lacking in hypothyroidism, accounting for the wellrecognized signs and symptoms of these two disorders. The unbound or free fractions are the biologically active fractions; they represent only 0. Most of the circulating T3 is derived from deiodination of circulating T4 in the peripheral tissues. Deiodination of T4 can occur at the outer ring (5-deiodination), producing T3 (3,5,3-triiodothyronine), or at the inner ring (5-deiodination), producing reverse T3 (3,3,5triiodothyronine). Similarly, total T4 and T3 are low despite euthyroidism in conditions associated with low levels of thyroid-binding proteins. Therefore, further tests to assess the free hormone levels, which reflect biologic activity, must be performed. Free T4 and free T3 levels can be measured directly or by dialysis or ultrafiltration. In hyperthyroidism, the free T3 may be elevated in the presence of a normal free T4. Serum thyroglobulin measurements are useful in the follow-up of patients with papillary or follicular carcinoma. After thyroidectomy and iodine-131 (131I) ablation therapy, thyroglobulin levels should be less than 0. Levels in excess of this value indicate the possibility of persistent or metastatic disease. Calcitonin is produced by the C cells of the thyroid and has a minor role in calcium homeostasis. Calcitonin measurements are invaluable in the diagnosis of medullary carcinoma of the thyroid and for monitoring the effects of therapy for this entity. ThyroidImaging Technetium-99m (99mTc) pertechnetate is concentrated in the thyroid gland and can be scanned with a gamma camera, yielding information about the size and shape of the gland and the location of the functional activity in the gland (thyroid scan). The thyroid scan is often performed in conjunction with a quantitative assessment of radioactive iodine (123I) uptake by the thyroid. Functioning thyroid nodules are called warm or hot nodules; cold nodules are nonfunctioning. Malignancy is usually associated with a cold nodule; 16% of surgically removed cold nodules are malignant. Thyroid ultrasound evaluation is useful in the differentiation of solid nodules from cystic nodules. Clinical manifestations of thyrotoxicosis result from the direct physiologic effects of the thyroid hormones as well as the increased sensitivity to catecholamines. Tachycardia, tremor, stare, sweating, and lid lag are all caused by catecholamine hypersensitivity. Ophthalmopathy results from inflammatory infiltration of the extraocular eye muscles by lymphocytes with mucopolysaccharide deposition. Older patients often do not have the florid clinical features of thyrotoxicosis, and the condition termed apathetic hyperthyroidism is exhibited as flat affect, emotional lability, weight loss, muscle weakness, SignsandSymptoms Table 63-3 lists the signs and symptoms of hyperthyroidism. Thyrotoxic crisis, or thyroid storm, is a life-threatening complication of hyperthyroidism that can be precipitated by surgery, radioactive iodine therapy, or severe stress. Patients develop fever, flushing, sweating, significant tachycardia, atrial fibrillation, and cardiac failure. Hyperpyrexia out of proportion to other clinical findings is the hallmark of thyroid storm. However, it may be the result of excessive ingestion of thyroid hormone or, rarely, thyroid hormone production from an ectopic site (as in struma ovarii).

Blood pressure blood pressure normal limit discount 2.5 mg bystolic otc, serum electrolytes and glucose heart attack or anxiety generic 2.5 mg bystolic visa, and patient mood should be monitored during corticosteroid therapy pulse pressure low values purchase 5 mg bystolic amex. Plasma exchange was followed by rapid functional improvement in over 40% heart attack heart rate order generic bystolic on line, with early initiation of plasma exchange treatment the single factor most associated with significant improvement (level A) pulse pressure 15 discount 2.5mg bystolic fast delivery. As there are currently no biomarkers that direct the choice of disease modifying therapies for an individual patient blood pressure medication beginning with r bystolic 5 mg low cost, selection of the disease modifying therapy for an individual is based on disease course and severity, patient comorbidities, and individual preferences. They differ in dosage, side effects, and incidence of neutralizing antibody induction. Common side effects include a "flu-like" feeling for several hours after a dose, which is usually improved by nonsteroidal anti-inflammatory medications or acetaminophen. It is considered immunomodulatory not immunosuppressive, although its mechanism of action is not fully understood. Glatiramer acetate has no known drug interactions, and laboratory monitoring is not needed. Side effects include injection site reactions and an uncommon transient tachycardia reaction that occurs soon after an injection. Down-modulates sphingosine-1-phosphate receptors, lymphocytes unable to migrate out of lymphoid tissue. Beneficial effects were still measurable 12 months after treatment discontinuation. Because of these risks and with the advent of more targeted medications, mitoxantrone is not commonly used in the United States. A 2-year phase 3 trial of natalizumab showed 68% reduction in annualized relapse rate, 42% reduction in sustained disability, and over 90% reduction in gadolinium-enhancing lesions compared with placebo (level A). Patients receiving it must take part in a risk-mitigation program and can only be infused at certified infusion centers. Fingolimod has several risks, including macular edema, pulmonary dysfunction, bradycardia, and herpetic infections. Medical monitoring for potential bradycardia for at least 6 hours is necessary for the first dose. Teriflunomide can cause hepatotoxicity, and it is contraindicated in pregnancy (pregnancy category X). If necessary, teriflunomide can be rapidly eliminated from the body using cholestyramine, otherwise it persists for long periods. Teriflunomide is closely related to the drug leflunomide, approved for rheumatoid arthritis in 1998. Patients treated with alemtuzumab had lower annualized relapse rate (by 49% and 53. Alemtuzumab leads to a profound drop in the white blood cell count, which may last for months or even years. In trials, secondary autoimmune diseases developed in a sizeable proportion of alemtuzumab-treated subjects, with autoimmune thyroid disease being most common. It is occasionally "benign" in which case the disease has little impact on quality of life. In one non-randomized study, early initiation of disease modifying therapies within a year of symptom onset was associated with better long-term outcomes. In the brain, they are most common in the hypothalamus and around the fourth ventricle. Older lesions display demyelination, axon loss, and death of oligodendroglia and neurons. Control of bladder and bowel is often affected, as is autonomic function below the level. West Nile virus can cause a myelopathy that resembles poliomyelitis, with flaccid paralysis due to infection and death of anterior horn cells. Nitrous oxide anesthesia can precipitate an acute onset myelopathy in the case of borderline vitamin B12 deficiency. The history and physical examination should be performed with these disorders in mind. When response to intravenous methylprednisolone is suboptimal, plasma exchange should be considered. Several short case series have pointed toward possible efficacy of azathioprine plus prednisone, rituximab, and mycophenolate mofetil for prevention of future attacks (level C). Over one year, 85% had no relapses and no patient progressed in disability (level B). These can include encephalopathy, which may manifest as reduced level of consciousness (even coma), or as behavioral changes. No randomized prospective treatment trials for acute disseminated encephalomyelitis are reported. Classically, optic neuritis presents over hours with loss of vision together with pain exacerbated by eye movement. Other diseases that might present similarly, such as sarcoidosis and giant cell arteritis, should be ruled out. Successful long-term treatment with "steroid sparing" agents such as methotrexate, azathioprine, or mycophenolate mofetil has been reported. The underlying pathology is not yet known, but the disease appears inflammatory based on clinical presentation, imaging, and specific medication response. After recovery from the acute episode, the optic disk may appear pale, and the relative afferent pupillary defect may persist. Visual acuity initially recovered faster in the intravenous methylprednisolone group, but by 6 months later there was no difference among the three groups (level A). Patients from this trial were examined 10 years later and acuity in the affected eyes was 20/20 or better in 74% and less than 20/200 in only 3%. However, recurrence of optic neuritis was common, and had occurred in either eye in 35% of the patients. Five diagnostic 121 Neuromuscular Diseases: Disorders of the Motor Neuron and Plexus and Peripheral Nerve Disease Carlayne E. Motor neuron and peripheral nerve diseases are considered in this chapter; myopathies are considered in Chapter 122, and neuromuscular junction diseases are considered in Chapter 123. The symptoms and signs of the neuromuscular diseases are at times indistinguishable. However, some useful general rules apply to assist with localization based on the distribution of weakness, presence or absence of sensory symp- ss toms, reflex abnormalities, and specific associated clinical features Table 121-2). The measurement of electrical activity arising from muscle fibers is performed by inserting a needle electrode percutaneously into a muscle. Spontaneous activity during complete relaxation occurs in myotonic disorders, in inflammatory myopathies, and in denervated muscles. Spontaneous activity of a single muscle fiber is called a fibrillation, and such activity of part of or an entire motor unit is called a fasciculation. In myotonia, repeated muscle depolarization and contraction occur despite voluntary relaxation. Conversely, in muscle diseases such as the muscular dystrophies and other diseases that destroy scattered fibers within a motor unit, the motor unit action potentials are of lower amplitude and shorter duration and are polyphasic. A reduced recruitment (interference) pattern from maximum voluntary effort occurs in denervation. Conversely, in patients with primary muscle disease, submaximal voluntary effort produces a full recruitment pattern despite marked weakness. The resulting action potential is recorded by electrodes placed over the nerve more proximally in the case of large sensory nerve fibers and over the muscle distally in the case of motor nerve fibers in a mixed motor sensory nerve. B,Inthismyopathicunit,onlytwofibersremainactive; the other three (shrunken and unshaded) have been destroyed by a muscledisease. Notethatonlyunderthese abnormal circumstances do fibers in the same unit lie next to one another. The incidence is approximately 2 per 100,000 population, and there is a slight male predominance. The peak age of onset is in the sixth decade, although the disease can occur at any time throughout adulthood. Clinical Presentation Clinical symptoms relating to the upper motor neuron degeneration include loss of dexterity, slowed movements, muscle weakness, stiffness, and emotional lability. Lower motor neuron signs and symptoms caused by anterior horn cell degeneration include weakness, muscle atrophy, fasciculation, and cramps. Fasciculations in the absence of associated muscle atrophy or weakness are usually benign and may be aggravated by sleep deprivation, stress, and excessive caffeine ingestion. It may also be limited initially to the bulbar region, resulting in difficulty with swallowing, speech, and movements of the face and tongue. For unclear reasons, ocular motility is spared until the very late stages of the illness. Bowel and bladder function and sensation remain spared throughout the course of the disease. Degeneration of the corticobulbar projections innervating the brainstem can lead to pseudobular affect causing difficulty controlling laughter and/or tearfulness. The mechanism of this effect is not known with certainty; however, riluzole may reduce excitotoxicity by diminishing presynaptic glutamate release. A cough-assist device can be used to assist with clearing upper airway secretions and has been shown to minimize the risk of pneumonia in clinical trials (Level C). Symptomatic therapy for spasticity, pseudobulbar affect, muscle cramping, and sialorrhea is also essential in maintaining patient dignity and quality of life Table 121-4). Augmentative speech devices can assist patients with communication and computer access. Prognosis Mean survival from onset of symptoms is 2 to 5 years, with 10% of patients surviving beyond 10 years. The majority of deaths are related to respiratory muscle failure and aspiration pneumonia. The mechanism by which disruption of the androgen receptor gene alters the function of bulbar and spinal motor neurons is not known. Affected individuals exhibit chin fasciculations, midline furrowing and atrophy of the tongue, and proximal weakness. Dysphagia and dysarthria are common, and up to 90% of patients demonstrate gynecomastia and infertility. Diseases of these plexuses (plexopathies) tend to be focal in symptoms and signs, whereas many diseases of the peripheral nerves and muscles are generalized. Lower trunk lesions may result from malignant tumor invasion, thoracic outlet syndrome, or as a complication of sternotomy. If the entire plexus is involved, radiation injury, trauma, and late metastatic disease are the most common causes. The acute pain generally subsides after a few days to a week; by this time, weakness of the proximal arm becomes apparent. The serratus anterior, deltoid, and supraspinatus are the most commonly affected muscles, but other muscles of the shoulder girdle may also be affected. Sensory loss is usually slight and generally involves the axillary nerve distribution. Weakness lasts weeks to months and be accompanied by severe atrophy of the shoulder girdle. No therapy has been shown to alter or shorten the clinical course, although steroids and analgesics may reduce pain. The disorder frequently follows an upper respiratory infection or an immunization, but in many instances no antecedent illness occurs. It is bilateral in one third of cases but is always asymmetrical; it may recur in 5% of patients. These divide within the plexus into ventral and dorsal branches that form the femoral, sciatic, and obturator nerves. Clinical features include proximal pain and weakness in anterior thigh muscles (femoral) or posterior thigh muscles and the buttocks. Diabetes, malignant invasion, radiation therapy, infection (herpes zoster), psoas abscess, trauma, and retroperitoneal hemorrhage are common causes. When more than one peripheral nerve is involved, the term mononeuropathy multiplex or multiple mononeuropathies is often used. Multiple mononeuropathies are most commonly seen in diabetes mellitus and vasculitis but also occur in leprosy, vasculitis, sarcoidosis, hereditary neuropathy with predisposition to pressure palsies, and amyloidosis. Polyneuropathies are a group of disorders affecting the motor, sensory, and autonomic nerves. These disorders may predominantly affect the nerve axon (axonal neuropathies), myelin sheath (demyelinating neuropathies), or the small- to medium-sized blood vessels supplying the nerves (vasculitic neuropathies). The clinical features of the polyneuropathies reflect the pathology of the underlying process. Pathology In the symmetrical axonal polyneuropathies, the underlying pathology is usually a slowly evolving type of axonal degeneration that involves the ends of long nerve fibers first and preferentially. With time, the degenerative process involves more proximal regions of long fibers, and shorter fibers are affected. This pattern of distal axonal degeneration or dying back of nerve fibers results from a wide variety of metabolic, toxic, and endocrinologic causes. In the demyelinating polyneuropathies, the underlying pathology involves the myelin sheath. Demyelination of a peripheral nerve at even a single site can block conduction, resulting in a functional deficit identical to that seen after axonal degeneration. In contrast to repair by regeneration, however, repair by remyelination can be rapid. Peripheral neuropathies are prevalent neurologic conditions, affecting 2% to 8% of adults, with the incidence increasing with age. Mononeuropathies are disorders in which only a single peripheral nerve is affected.

BacterialFoodPoisoning Bacterial food poisoning is caused by ingestion of preformed toxins in food; this results in a toxic illness rather than an enteric infection blood pressure 75 over 55 buy bystolic 5 mg mastercard. Pathogens that produce bacterial food poisoning include Staphylococcus aureus heart attack early symptoms purchase bystolic without prescription, Clostridium perfringens blood pressure medication and breastfeeding buy bystolic pills in toronto, and Bacillus cereus blood pressure 50 over 70 generic bystolic 5mg without a prescription. These organisms grow in food and produce toxins that are ingested directly in the food blood pressure for 12 year old safe 2.5mg bystolic. Symptoms occur soon after food ingestion normal pulse pressure 60 year old purchase 5 mg bystolic overnight delivery, with incubation periods of 1 to 16 hours and high attack rates. The illness is rarely associated with fever, and symptoms usually resolve within 12 to 24 hours after onset. Ingestion of the bacteria with subsequent Salmonella Salmonella typhi causes typhoid fever, but not diarrhea. Nontyphoidal salmonellosis results from ingestion of contaminated meat, dairy, or poultry products or from direct contact with animals such as birds, pet turtles, snakes, and other reptiles. An oral inoculum of 105 to 108 organisms is needed but smaller inocula can cause disease in patients with impaired gastric acidity or compromised immunity. For mild to moderate illness, metronidazole 500 mg tid for 10 days; for severe illness, vancomycin 125 mg qid for 10-14 days Fluoroquinolone orally for 3 days. Complications include bacteremia and metastatic seeding of atherosclerotic plaques and prostheses. Antimicrobial treatment does not shorten the duration of diarrhea and may prolong intestinal carriage in stools; therefore, antibiotics are indicated only for cases of severe disease or extraintestinal involvement. Campylobacter jejuni Disease caused by Campylobacter jejuni usually results from ingestion of undercooked poultry or direct contact with animals. The infective dose is 104 to 106 organisms, with an incubation period of 1 to 5 days. Acute watery diarrhea is the most common presentation; less frequently, systemic symptoms including fever may occur. Prodromal symptoms such as fever, myalgia, headache, and malaise may precede diarrhea. Diarrhea progresses to voluminous watery stools which have been described as "rice water" because they are clear with flecks of mucus. The characteristics of noncholeraic Vibrio species are covered in Tables 96-1 and 96-2. It results in an enterotoxinmediated watery diarrhea with abdominal cramps and vomiting. The oral inoculum is 10 to 100 organisms, with an incubation period of 3 to 4 days. It is classically associated with bloody diarrhea, abdominal pain, and fecal leukocytes. The infectious oral inoculum is about 105 to 108 organisms, with an incubation period of 6 hours to 5 days. Spores occur in the environment and are resistant to alcohol-based handwashing solutions. Patients often have abdominal pain and watery diarrhea but may also have bloody stools. Markers of severe infection include pseudomembranous colitis, acute renal failure, marked leukocytosis, hypotension, and toxic megacolon. The indigenous intestinal microbiota is important for colonization resistance and for recovery from antibiotic-associated C. Other bacterial causes include Shigella, Salmonella, Campylobacter, Aeromonas, noncholeraic Vibrio, and Plesiomonas. The initial evaluation should consider the severity of illness, signs of dehydration, and intestinal inflammation indicated by the fever, abdominal pain, blood in stools (dysentery), or tenesmus. Important epidemiologic clues in the history include age, travel history, ingestion of undercooked or raw food and meat, antibiotic use, sexual activity, daycare attendance, and outbreaks involving others with similar exposure (see Table 96-1). The examination should determine the severity of dehydration and need for rehydration as well as the likely cause. Signs of dehydration or hypovolemia include lax skin turgor and tenting, dry mucus membranes, decreased urination, tachycardia, and hypotension. Oral inoculation requires 109 organisms for infection, with an incubation period of 3 to 7 days. The illness may mimic acute appendicitis and may be complicated by ileal perforation, mesenteric adenitis, or terminal ileitis. ViralCausesofDiarrhea Viruses tend to cause diarrhea by adhering to the intestinal mucosa and disrupting the absorptive and secretory processes without causing inflammation. Rotavirus was the most common cause of severe diarrhea in children in the past, but the incidence has fallen dramatically with widespread use of the rotovirus vaccine. Norovirus is highly contagious and is a very common cause of foodborne gastroenteritis in adults and children in the United States. Other viruses that cause diarrhea are adenoviruses, sapoviruses, and astroviruses. The incubation period is usually longer than 14 hours, and vomiting may be a prominent feature of diarrheal disease caused by viral agents. Examination of stools for erythrocytes and white blood cells (leukocytes) using methylene blue staining or the lactoferrin test can help differentiate diarrhea caused by invasive pathogens from that caused by noninvasive pathogens. Most cases of diarrheal illnesses are self-limited, and almost half resolve within 1 day. Therefore, microbiologic investigation is usually not necessary for patients who are seen within 24 hours of the onset of illness unless certain conditions are present. The indications for stool culture include severe diarrhea (six or more stools per day), diarrhea lasting longer than 1 week, fever, dysentery, hospitalization, inflammatory diarrhea, and multiple cases in a suspected outbreak. Routine stool culture will identify Shigella, Salmonella, Campylobacter, and Aeromonas. Bloody diarrhea, in the absence of fecal leukocytes, suggests enterohemorrhagic Escherichia coli or amebiasis (where leukocytes are destroyed by the parasite). Ingestion of inadequately cooked seafood prompts consideration of Vibrio infections or noroviruses. Persistence of diarrhea (>10 days) with weight loss prompts consideration of giardiasis, cryptosporidiosis, or inflammatory bowel disease. In the United States, fluids containing sodium in the range of 45 to 75 mEq/L (such as Pedialyte or Rehydrolyte solutions) are recommended. Fluid should be administered in large quantities until there is clinical evidence that fluid balance is restored, and then as maintenance therapy. Oral rehydration therapy can be life-saving for patients in developing countries with severe diarrhea. Oral rehydration is often adequate unless the patient is comatose or severely dehydrated. IntravenousFluidTherapy Massive fluid loss due to diarrhea should be rapidly replaced by the administration of intravenous fluids. The rate of fluid administration and maintenance should be guided by clinical signs including vital signs, appearance of the mucosa, neck veins, and skin turgor. OralFluidTherapy In most patients with diarrhea, fluid repletion can be achieved with oral rehydration therapy using isotonic fluids containing glucose and electrolytes. An effective solution can be prepared by the addition of 2 tablespoons of sugar, one fourth of a teaspoon AntimicrobialTherapy Most cases of infectious diarrhea do not require antimicrobial therapy. In uncomplicated salmonellosis, antibiotics may prolong the shedding of salmonella. The choice and dose of antimicrobials for specific pathogens are described in Table 96-2. The first-line therapy is metronidazole 500 mg three times a day orally for 10 to 14 days. For severely ill patients, oral vancomycin 125 mg four times a day for 10 to 14 days should be initiated. Serious disease and death is usually seen in individuals who become severely dehydrated, infants, elderly patients, and those with underlying medical conditions or immunosuppression. SymptomaticTherapy Antidiarrheal agents such as loperamide and bismuth subsalicylate can be used in some instances for symptomatic relief. Antimotility agents should be avoided in patients with bloody or suspected inflammatory diarrhea. The use of these agents has been implicated in prolonging the duration of fever in shigellosis, development of toxic megacolon in C. Associated structures such as tendons, ligaments, and bursae can also become infected, especially if they involve prosthetic or biografted material. Osteomyelitis and septic arthritis can each occur as a result of seeding during an episode of bacteremia, as a consequence of vascular insufficiency, as a complication of trauma, or by extension from a contiguous focus of infection in an adjacent tissue or structure. In the case of hematogenous infection, the bacteremia itself may be relatively transient and of little clinical consequence. Hematogenous osteomyelitis is common in children but accounts for only about 20% of osteomyelitis in adults. Peripheral vascular disease leading to tissue hypoxia, often related to diabetes, hypertension, hyperlipidemia, or smoking, is the biggest risk factor for the development of osteomyelitis in adults older than 50 years of age. There is often antecedent soft tissue infection or destruction as a result of vascular insufficiency and neuropathy. It is most common in the lower extremities, particularly in the feet, and often occurs in diabetics. Trauma, especially when it involves open fracture, with its attendant disruption of the bony architecture and vascular supply, is a major risk factor for development of osteomyelitis and septic arthritis. This is particularly true when an open fracture (such as from a fall or a motor vehicle accident), is heavily contaminated with soil or other environmental materials. The presence of such internal fixation devices provides a nidus for bacteria and other microorganisms, including fungi, to elude the immune system and incubate. Chronic osteomyelitis is a possible complication of such injuries and is often a result of multiple or unusual organisms. Infection typically involves the pelvis, sacrum, and lower spine, corresponding to areas of unrelieved pressure and resulting pressure sores. The former is typically hematogenous and associated with signs of inflammation in the overlying soft tissue, with onset occurring over the course of days to 1 week. Chronic osteomyelitis is typically more indolent, with onset over the course of months. It is more likely to show bony destruction on plain radiographs at the time of presentation and is often associated with a draining sinus tract. Sequestra (areas of dead bone) and involucra (new bone formed around sequestra) may also be seen on radiographs. Whereas with acute osteomyelitis, a 6-week course of antibiotics may effect a cure, chronic osteomyelitis more typically requires surgical intervention and a prolonged (3 months) course of antibiotic therapy. Although bone is generally resistant to infection, the vasculature of the metaphysis contains capillary loops composed of a single layer of discontinuous endothelial cells, which may allow bacteria to enter the extracellular matrix. Finally, many bacteria can elaborate biofilms that allow them to elude clearance by the immune system. Prosthetic material, such as that used in joint replacements and other grafts, can serve as a platform for the formation of such biofilms. In the case of septic arthritis, there is usually some underlying joint abnormality. It is hypothesized that relatively trivial injuries, which may even go unnoticed or unremembered by the patient, can cause minor bleeding into the joint, providing a hospitable environment for bacteria to incubate. The overlying soft tissue may have signs of inflammation or tissue destruction; the latter is often seen in diabetics with soft tissue ulceration. Historically, the diagnosis of osteomyelitis relied on the presence of lucency on plain radiographs of the affected area. The diagnosis could be confirmed histologically by bone biopsy with culture to identify the pathogenic organism. Isolated species include Escherichia coli, Haemophilus influenzae, and Haemophilus parainfluenzae. Infections with Serratia marcescens and Pseudomonas spp are associated with exposure to water and are usually nosocomial or related to intravenous drug use. Fungi such as Candida, Aspergillus, and Zygomycetes may cause bone and joint infections particularly in immune-compromised patients, diabetics, and those who have suffered trauma. Propionibacterium acnes is often isolated from shoulder infections, especially those involving prosthetic joints. The variety of potential pathogens underscores the need to obtain appropriate specimens for culture before administration of antibiotics. Infection with Borrelia burgdorferi, the causative agent of Lyme disease, can lead to a multifocal or monoarticular septic arthritis. Fluid analysis is consistent with bacterial septic arthritis but is negative for typical organisms on culture. Associated findings of erythema migrans, diffuse myalgias and arthralgias, cranial nerve palsies, fever, and aseptic meningitis may also be present. Diagnosis relies on serology and associated findings in patients who reside in endemic areas. Later-stage disease may manifest with a less inflammatory-appearing effusion, often without any other symptoms. Neisseria gonorrhoeae can cause a solitary or multifocal septic arthritis often associated with tenosynovitis and skin lesions. Culture of the joint fluid may be negative, but testing of specimens from the pharynx, urethra, or rectum is usually positive by nucleic acid amplification.

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