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Blepharitis This refers to inflammation of the eyelids.

ids. The most common form occurs in association with acne rosacea or seborrheic dermatitis. The eyelid margins usually are colonized heavily by staphylococci. Inspection, they appear greasy, ulcerated, and crusted with scaling debris that clings to the lashes.

Treatment: Warm compresses, strict eyelid hygiene, bacitracin/polymyxin B ophthalmic ointment. and topical antibiotics such as

An external hordeolum (sty) is caused by staphylococcal infection of the superficial accessory glands of Zeis or Moll located in the eyelid margins. An internal hordeolum occurs after suppurative infection of the oil-secreting meibomian glands within the tarsal plate of the eyelid. Systemic antibiotics, usually tetracyclines or azithromycin, sometimes are necessary for treatment of meibomian gland inflammation (meibomitis) or chronic, severe blepharitis.

Chalazion is a painless, granulomatous inflammation of a meibomian gland that produces a pealike nodule within the eyelid. It can be incised and drained or injected with glucocorticoids. Basal cell, squamous cell, or meibomian gland carcinoma should be suspected with any nonhealing ulcerative lesion of the eyelids.

Thiamine (Vitamin B1) Thiamine was the first B vitamin to be identified and therefore is referred to as vitamin B1. Thiamine functions in the decarboxylation of -ketoacids, such as pyruvate ketoglutarate, and branched-chain amino acids and thus is essential for energy generation. In addition, thiamine pyrophosphate acts as a coenzyme for a transketolase reaction that mediates the conversion of hexose and pentose phosphates. It has been postulated that thiamine plays a role in peripheral nerve conduction, although the exact chemical reactions underlying this function are not known. Food Sources o The median intake of thiamine in the United States from food alone is 2 mg/d. Primary food sources for thiamine include yeast, organ meat, pork, legumes, beef, whole grains, and nuts. Milled rice and grains contain little thiamine, if any. Thiamine deficiency is therefore more common in cultures that rely heavily on a rice-based diet. Tea, coffee (regular and decaffeinated), raw fish, and shellfish contain thiaminases, which can destroy the vitamin. Thus, drinking large amounts of tea or coffee can theoretically lower thiamine body stores.

Deficiency o Most dietary deficiency of thiamine worldwide is the result of poor dietary intake. In Western countries, the primary causes of thiamine deficiency are alcoholism and chronic illnesses such as cancer. Alcohol interferes directly with the absorption of thiamine and with the synthesis of thiamine pyrophosphate. Thiamine should always be replenished when a patient with alcoholism is being refed, as carbohydrate repletion without adequate thiamine can precipitate acute thiamine deficiency with lactic acidosis. Other at-risk populations are women with prolonged hyperemesis gravidarum and anorexia, patients with overall poor nutritional status on parenteral glucose, patients after bariatric bypass surgery, and patients on chronic diuretic therapy due to increased urinary thiamine losses. Maternal thiamine deficiency can lead to infantile beriberi in breast-fed children. Thiamine deficiency should be considered in the setting of motor vehicle accidents associated with head injury. o Thiamine deficiency in its early stage induces anorexia and nonspecific symptoms (e.g., irritability, decrease in short-term memory). Prolonged thiamine deficiency causes beriberi, which is classically categorized as wet or dry, although there is considerable overlap. In either form of beriberi, patients may complain of pain and paresthesia. Wet beriberi presents primarily with cardiovascular symptoms, due to impaired myocardial energy metabolism and dysautonomia, and can occur after 3 months of a thiamine-deficient diet. Patients present with an enlarged heart, tachycardia, high-output congestive heart failure, peripheral edema, and peripheral neuritis. Patients with dry beriberi present with a symmetric peripheral neuropathy of the motor and sensory systems with diminished reflexes. The neuropathy affects the legs most markedly, and these patients have difficulty rising from a squatting position. o Alcoholic patients with chronic thiamine deficiency also may have central nervous system (CNS) manifestations known as Wernicke's encephalopathy, consisting of horizontal nystagmus, ophthalmoplegia (due to weakness of one or more extraocular muscles), cerebellar ataxia, and mental impairment (Chap. 392). When there is an additional loss of memory and a confabulatory psychosis, the syndrome is known as Wernicke-Korsakoff syndrome. Despite the typical clinical picture and history, Wernicke-Korsakoff syndrome is underdiagnosed. o The laboratory diagnosis of thiamine deficiency usually is made by a functional enzymatic assay of transketolase activity measured before and after the addition of thiamine pyrophosphate. A >25% stimulation by the addition of thiamine pyrophosphate (an activity coefficient of 1.25) is interpreted as abnormal. Thiamine or the phosphorylated esters of thiamine in serum or blood also can be measured by high-performance liquid chromatography (HPLC) to detect deficiency. Treatment: Thiamine Deficiency o In acute thiamine deficiency with either cardiovascular or neurologic signs, 100 mg/d of thiamine should be given parenterally for 7 days, followed by 10 mg/d orally until there is complete recovery. Cardiovascular and ophthalmoplegic improvement occurs within 24 h. Other manifestations gradually clear, although

psychosis in Wernicke-Korsakoff syndrome may be permanent or persist for several months. Toxicity o Although anaphylaxis has been reported after high doses of thiamine, no adverse effects have been recorded from either food or supplements at high doses. Thiamine supplements may be bought over the counter in doses of up to 50 mg/d.

Measles (Rubeola) Measles is a highly contagious viral disease that is characterized by a prodromal illness of fever, cough, coryza, and conjunctivitis followed by the appearance of a generalized maculopapular rash. Before the widespread use of measles vaccines, it was estimated that measles caused between 5 million and 8 million deaths worldwide each year.

Etiology
Measles virus is a spherical, nonsegmented, single-stranded, negative-sense RNA virus and a member of the Morbillivirus genus in the family of Paramyxoviridae. Measles was originally a zoonotic infection, arising from cross-species transmission from animals to humans by an ancestral morbillivirus 10,000 years ago, when human populations attained sufficient size to sustain virus transmission. Although RNA viruses typically have high mutation rates, measles virus is considered to be an antigenically monotypic virus; i.e., the surface proteins responsible for inducing protective immunity have retained their antigenic structure across time and space. The public health significance of this stability is that measles vaccines developed decades ago from a single strain of measles virus remain protective worldwide. Measles virus is killed by ultraviolet light and heat, and attenuated measles vaccine viruses retain these characteristics, necessitating a cold chain for vaccine transport and storage.

Pathogenesis Measles virus is transmitted primarily by respiratory droplets over short distances and, less commonly, by small-particle aerosols that remain suspended in the air for long periods. Airborne transmission appears to be important in certain settings, including schools, physicians' offices, hospitals, and enclosed public places. The virus can be transmitted by direct contact with infected secretions but does not survive for long on fomites. The incubation period for measles is 10 days to fever onset and 14 days to rash onset. This period may be shorter in infants and longer (up to 3 weeks) in adults. Infection is initiated when measles virus is deposited on epithelial cells in the respiratory tract, oropharynx, or conjunctivae (Fig. 192-1A). During the first 24 days after infection, measles virus proliferates locally in the respiratory mucosa and spreads to draining lymph nodes. Virus then enters the bloodstream in infected leukocytes (primarily monocytes), producing the primary viremia that disseminates infection

throughout the reticuloendothelial system. Further replication results in secondary viremia that begins 57 days after infection and disseminates measles virus throughout the body. Replication of measles virus in these target organs, together with the host's immune response, is responsible for the signs and symptoms of measles that occur 812 days after infection and mark the end of the incubation period. Varicella-Zoster Virus Infections: Introduction Definition o Varicella-zoster virus (VZV) causes two distinct clinical entities: varicella (chickenpox) and herpes zoster (shingles). Chickenpox, a ubiquitous and extremely contagious infection, is usually a benign illness of childhood characterized by an exanthematous vesicular rash. With reactivation of latent VZV (which is most common after the sixth decade of life), herpes zoster presents as a dermatomal vesicular rash, usually associated with severe pain. Etiology o A clinical association between varicella and herpes zoster has been recognized for nearly 100 years. Early in the twentieth century, similarities in the histopathologic features of skin lesions resulting from varicella and herpes zoster were demonstrated. Viral isolates from patients with chickenpox and herpes zoster produced similar alterations in tissue culturespecifically, the appearance of eosinophilic intranuclear inclusions and multinucleated giant cells. These results suggested that the viruses were biologically similar. Restriction endonuclease analyses of viral DNA from a patient with chickenpox who subsequently developed herpes zoster verified the molecular identity of the two viruses responsible for these different clinical presentations. o VZV is a member of the family Herpesviridae, sharing with other members such structural characteristics as a lipid envelope surrounding a nucleocapsid with icosahedral symmetry, a total diameter of double-stranded DNA that is Nephrotic Syndrome Nephrotic syndrome classically presents with heavy proteinuria, minimal hematuria, hypoalbuminemia, hypercholesterolemia, edema, and hypertension. If left undiagnosed or untreated, some of these syndromes will progressively damage enough glomeruli to cause a fall in GFR, producing renal failure. Therapies for various causes of nephrotic syndrome are noted under individual disease headings below. In general, all patients with hypercholesterolemia secondary to nephrotic syndrome should be treated with lipid-lowering agents because they are at increased risk for cardiovascular disease. Edema secondary to salt and water retention can be controlled with the judicious use of diuretics, avoiding intravascular volume depletion. Venous complications secondary to the hypercoagulable state associated with nephrotic syndrome 180200 nm, and centrally located

125,000 bp in length.

can be treated with anticoagulants. The losses of various serum binding proteins, such as thyroid-binding globulin, lead to alterations in functional tests. Lastly, proteinuria itself is hypothesized to be nephrotoxic, and treatment of proteinuria with inhibitors of the reninangiotensin system can lower urinary protein excretion. Peptic Ulcer Disease Burning epigastric pain exacerbated by fasting and improved with meals is a symptom complex associated with peptic ulcer disease (PUD). An ulcer is defined as disruption of the mucosal integrity of the stomach and/or duodenum leading to a local defect or excavation due to active inflammation. Ulcers occur within the stomach and/or duodenum and are often chronic in nature. Acid peptic disorders are very common in the United States, with 4 million individuals (new cases and recurrences) affected per year. Lifetime prevalence of PUD in the United States is ~12% in men and 10% in women. Moreover, an estimated 15,000 deaths per year occur as a consequence of complicated PUD. The financial impact of these common disorders has been substantial, with an estimated burden on direct and indirect health care costs of ~$10 billion per year in the United States.

Epidemiology Duodenal Ulcers


DUs are estimated to occur in 615% of the Western population. The incidence of DUs declined steadily from 1960 to 1980 and has remained stable since then. The death rates, need for surgery, and physician visits have decreased by >50% over the past 30 years. The reason for the reduction in the frequency of DUs is likely related to the decreasing frequency of Helicobacter pylori. Before the discovery of H. pylori, the natural history of DUs was typified by frequent recurrences after initial therapy. Eradication of H. pylori has greatly reduced these recurrence rates.

Pathology Duodenal Ulcers


DUs occur most often in the first portion of the duodenum (>95%), with ~90% located within 3 cm of the pylorus. They are usually 1 cm in diameter but can occasionally reach 3 6 cm (giant ulcer). Ulcers are sharply demarcated, with depth at times reaching the muscularis propria. The base of the ulcer often consists of a zone of eosinophilic necrosis with surrounding fibrosis. Malignant DUs are extremely rare.

Acute Pancreatitis General Considerations

o Pancreatic inflammatory disease may be classified as (1) acute pancreatitis or (2) chronic pancreatitis. The pathologic spectrum of acute pancreatitis varies from interstitial pancreatitis, which is usually a mild and self-limited disorder, to necrotizing pancreatitis, in which the extent of pancreatic necrosis may correlate with the severity of the attack and its systemic manifestations. The incidence of pancreatitis varies in different countries and depends on cause [e.g., alcohol, gallstones, metabolic factors, and drugs (Table 313-1)]. The estimated incidence in the United States is increasing and is now estimated to be 70 hospitalizations/100,000 persons annually, thus resulting in >200,000 new cases of acute pancreatitis per year.

Common Causes Gallstones (including microlithiasis) Alcohol (acute and chronic alcoholism) Hypertriglyceridemia Endoscopic retrograde cholangiopancreatography (ERCP), especially after biliary manometry Trauma (especially blunt abdominal trauma) Postoperative (abdominal and nonabdominal operations) Drugs (azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline, valproic acid, antiHIV medications) Sphincter of Oddi dysfunction Etiology and Pathogenesis There are many causes of acute pancreatitis (Table 313-1), but the mechanisms by which these conditions trigger pancreatic inflammation have not been fully elucidated. Gallstones continue to be the leading cause of acute pancreatitis in most series (3060%). The risk of acute pancreatitis in patients with at least one gallstone <5 mm in diameter is fourfold greater than that in patients with larger stones. Alcohol is the second most common cause, responsible for 1530% of cases in the United States. The incidence of pancreatitis in alcoholics is surprisingly low (5/100,000), indicating that in addition to the amount of alcohol ingested unknown factors affect a person's susceptibility to pancreatic injury. The mechanism of injury is incompletely understood. Acute pancreatitis occurs in 520% of patients following endoscopic retrograde cholangiopancreatography (ERCP). Despite extensive research into the medical and endoscopic prevention of post-ERCP pancreatitis, there has been little decline in incidence. Use of prophylactic pancreatic duct stent after retrograde pancreatogram or pancreatic sphincterotomy has shown promise in reducing pancreatitis but requires further prospective evaluation. Risk factors for post-ERCP pancreatitis include minor papilla sphincterotomy, sphincter of Oddi dysfunction, prior history of post-ERCP pancreatitis, age <60 years, >2 contrast injections into the pancreatic duct, and endoscopic trainee involvement. Hypertriglyceridemia is the cause of acute pancreatitis in 1.33.8% of cases; serum triglyceride levels are usually >11.3 mmol/L (>1000 mg/dL). Most patients with hypertriglyceridemia, when subsequently examined, show evidence of an underlying derangement in lipid

metabolism, probably unrelated to pancreatitis. Such patients are prone to recurrent episodes of pancreatitis. Any factor (e.g., drugs or alcohol) that causes an abrupt increase in serum triglycerides to levels >11 mmol/L (1000 mg/dL) can precipitate a bout of acute pancreatitis. Finally, patients with a deficiency of apolipoprotein CII have an increased incidence of pancreatitis; apolipoprotein CII activates lipoprotein lipase, which is important in clearing chylomicrons from the bloodstream. Patients with diabetes mellitus who have developed ketoacidosis and patients who are on certain medications such as oral contraceptives may also develop high triglyceride levels. Approximately 25% of cases of acute pancreatitis are drug related. Drugs cause pancreatitis either by a hypersensitivity reaction or by the generation of a toxic metabolite, although in some cases it is not clear which of these mechanisms is operative (Table 313-1). o Autodigestion is a currently accepted pathogenic theory; according to it, pancreatitis
results when proteolytic enzymes (e.g., trypsinogen, chymotrypsinogen, proelastase, and lipolytic enzymes such as phospholipase A2) are activated in the pancreas rather than in the intestinal lumen. A number of factors (e.g., endotoxins, exotoxins, viral infections, ischemia, anoxia, lysosomal calcium, and direct trauma) are believed to facilitate activation of trypsin. Activated proteolytic enzymes, especially trypsin, not only digest pancreatic and peripancreatic tissues but also can activate other enzymes, such as elastase and phospholipase A2. Spontaneous activation of trypsin also can occur.

Treatment: Acute Pancreatitis In most patients (8590%) with acute pancreatitis, the disease is self-limited and subsides spontaneously, usually within three to seven days after treatment is instituted. Conventional measures include (1) analgesics for pain, (2) IV fluids and colloids to maintain normal intravascular volume, and (3) no oral alimentation.
Once it is clear that a patient will not be able to tolerate oral feeding (a determination that can usually be made within 4872 hours), enteral nutrition should be considered [rather than total parenteral nutrition (TPN)] since it maintains gut barrier integrity, thereby preventing bacterial translocation, is less expensive, and has fewer complications than TPN. The route through which enteral feeding is administered is under debate. Nasogastric access is easier to establish and may be as safe as nasojejunal enteral nutrition. However, enteral nutrition that bypasses the stomach and duodenum stimulates pancreatic secretions less and this rationale theoretically supports the use of the nasojejunal route. It has not been demonstrated whether either route is superior in altering morbidity and mortality. When patients with necrotizing pancreatitis begin oral intake of food, consideration should also be given to the addition of pancreatic enzyme supplementation and proton pump inhibitor therapy to assist with fat digestion and reduce gastric acid.

Hypothyroidism

Iodine deficiency remains the most common cause of hypothyroidism worldwide. In areas of iodine sufficiency, autoimmune disease (Hashimoto's thyroiditis) and iatrogenic causes (treatment of hyperthyroidism) are most common

Table 341-4 Causes of Hypothyroidism

Primary Autoimmune hypothyroidism: Hashimoto's thyroiditis, atrophic thyroiditis Iatrogenic: 131I treatment, subtotal or total thyroidectomy, external irradiation of neck for lymphoma or cancer Drugs: iodine excess (including iodine-containing contrast media and amiodarone), lithium, antithyroid drugs, p-aminosalicylic acid, interferon- and other cytokines, aminoglutethimide, sunitinib Congenital hypothyroidism: absent or ectopic thyroid gland, dyshormonogenesis, TSH-R mutation Iodine deficiency Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis, scleroderma, cystinosis, Riedel's thyroiditis Overexpression of type 3 deoiodinase in infantile hemangioma Transient Silent thyroiditis, including postpartum thyroiditis Subacute thyroiditis Withdrawal of thyroxine treatment in individuals with an intact thyroid After 131I treatment or subtotal thyroidectomy for Graves' disease Secondary Hypopituitarism: tumors, pituitary surgery or irradiation, infiltrative disorders, Sheehan's syndrome, trauma, genetic forms of combined pituitary hormone deficiencies Isolated TSH deficiency or inactivity Bexarotene treatment Hypothalamic disease: tumors, trauma, infiltrative disorders, idiopathic

Clinical Manifestations The majority of infants appear normal at birth, and <10% are diagnosed based on clinical features, which include prolonged jaundice, feeding problems, hypotonia, enlarged tongue,

delayed bone maturation, and umbilical hernia. Importantly, permanent neurologic damage results if treatment is delayed. Typical features of adult hypothyroidism may also be present (Table 341-5). Other congenital malformations, especially cardiac, are four times more common in congenital hypothyroidism. Table 341-5 Signs and Symptoms of Hypothyroidism (Descending Order of Frequency)

Symptoms Tiredness, weakness Dry skin

Signs Dry coarse skin; cool peripheral extremities Puffy face, hands, and feet (myxedema)

Feeling cold Diffuse alopecia Hair loss Bradycardia Difficulty concentrating and poor memory Peripheral edema Constipation Delayed tendon reflex relaxation Weight gain with poor appetite Carpal tunnel syndrome Dyspnea Serous cavity effusions Hoarse voice Menorrhagia (later oligomenorrhea or amenorrhea) Paresthesia Impaired hearing Diagnosis and Treatment Because of the severe neurologic consequences of untreated congenital hypothyroidism, neonatal screening programs have been established. These are generally based on measurement of TSH or T4 levels in heel-prick blood specimens. When the diagnosis is confirmed, T4 is instituted at a dose of 1015 g/kg per day, and the dose is adjusted by close monitoring of TSH levels. T 4 requirements are relatively great during the first year of life, and a high circulating T4 level is usually needed to normalize TSH. Early treatment with T4 results in normal IQ levels, but subtle neurodevelopmental abnormalities may occur in those with the most severe hypothyroidism at diagnosis or when treatment is delayed or suboptimal.

Chronic Obstructive Pulmonary Disease: Introduction Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by airflow limitation that is not fully reversible (http://www.goldcopd.com/). COPD includes emphysema, an anatomically defined condition characterized by destruction and enlargement of the lung alveoli; chronic bronchitis, a clinically defined condition with chronic cough and phlegm; and small airways disease, a condition in which small bronchioles are narrowed. COPD is present only if chronic airflow obstruction occurs; chronic bronchitis without chronic airflow obstruction is not included within COPD. COPD is the fourth leading cause of death and affects >10 million persons in the United States. COPD is also a disease of increasing public health importance around the world. Estimates suggest that COPD will rise from the sixth to the third most common cause of death worldwide by 2020. Risk Factors Cigarette Smoking
Airway Responsiveness and COPD Respiratory Infections Occupational Exposures Ambient Air Pollution Passive, or Second-Hand, Smoking Exposure Genetic Considerations A1 Antitrypsin Deficiency Other Genetic Risk Factors

Pathophysiology Persistent reduction in forced expiratory flow rates is the most typical finding in COPD. Increases in the residual volume and the residual volume/total lung capacity ratio, nonuniform distribution of ventilation, and ventilation-perfusion mismatching also occur. Airflow Obstruction o Airflow limitation, also known as airflow obstruction, is typically determined by spirometry, which involves forced expiratory maneuvers after the subject has inhaled to total lung capacity. Key parameters obtained from spirometry include FEV1 and the total volume of air exhaled during the entire spirometric maneuver [forced vital capacity (FVC)]. Patients with airflow obstruction related to COPD have a chronically reduced ratio of FEV1/FVC. In contrast to asthma, the reduced FEV1 in COPD seldom shows large responses to inhaled bronchodilators, although improvements up to 15% are common. Asthma patients can also develop chronic (not fully reversible) airflow obstruction.

Hyperinflation o Lung volumes are also routinely assessed in pulmonary function testing. In COPD there
is often "air trapping" (increased residual volume and increased ratio of residual volume to total lung capacity) and progressive hyperinflation (increased total lung capacity) late in the disease. Hyperinflation of the thorax during tidal breathing preserves maximum expiratory airflow, because as lung volume increases, elastic recoil pressure increases, and airways enlarge so that airway resistance decreases.

Gas Exchange
Although there is considerable variability in the relationships between the FEV1 and other physiologic abnormalities in COPD, certain generalizations may be made. The PaO2 usually remains near normal until the FEV1 is decreased to ~50% of predicted, and even much lower FEV1 values can be associated with a normal PaO2, at least at rest. An elevation of arterial level of carbon dioxide (PaCO2) is not expected until the FEV1 is <25% of predicted and even then may not occur. Pulmonary hypertension severe enough to cause cor pulmonale and right ventricular failure due to COPD typically occurs in individuals who have marked decreases in FEV1 (<25% of predicted) and chronic hypoxemia (PaO2 <55 mmHg); however, recent evidence suggests that some patients will develop significant pulmonary hypertension independent of COPD severity

Pathogenesis Airflow limitation, the major physiologic change in COPD, can result from both small airway obstruction and emphysema, as discussed above. Pathologic findings that can contribute to small airway obstruction are described above, but their relative importance is unknown. Fibrosis surrounding the small airways appears to be a significant contributor. Mechanisms leading to collagen accumulation around the airways in the face of increased collagenase activity remain an enigma. Although seemingly counterintuitive, there are several potential mechanisms whereby a proteinase can predispose to fibrosis, including proteolytic activation of transforming growth factor (TGF-). Largely due to greater similarity of animal air spaces than airways to humans, we know much more about mechanisms involved in emphysema than small airway obstruction.

Table 260-1 Gold Criteria for COPD Severity

GOLD Stage 0 I

Severity At Risk Mild

Symptoms Chronic cough, sputum production With or without chronic cough or sputum production

Spirometry Normal FEV1/FVC <0.7 and FEV1 80% predicted

IIA

Moderate With or without chronic cough or sputum production Severe With or without chronic cough or sputum production With or without chronic cough or sputum production

FEV1/FVC <0.7 and 50% FEV1 <80% predicted FEV1/FVC <0.7 and 30% FEV1 <50% predicted FEV1/FVC <0.7 and FEV1 <30% predicted or FEV1 <50% predicted with respiratory failure or signs of right heart failure

III

IV

Very Severe

Treatment: Chronic Obstructive Pulmonary Disease Stable Phase COPD Only three interventionssmoking cessation, oxygen therapy in chronically hypoxemic patients, and lung volume reduction surgery in selected patients with emphysemahave been demonstrated to influence the natural history of patients with COPD. There is currently suggestive, but not definitive, evidence that the use of inhaled glucocorticoids may alter mortality rate (but not lung function). All other current therapies are directed at improving symptoms and decreasing the frequency and severity of exacerbations. The institution of these therapies should involve an assessment of symptoms, potential risks, costs, and benefits of therapy. This should be followed by an assessment of response to therapy, and a decision should be made whether or not to continue treatment. Pharmacotherapy

Smoking Cessation
Bronchodilators Anticholinergic Agents Beta Agonists Inhaled Glucocorticoids Oral Glucocorticoids Theophylline

Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology marked by a symmetric, peripheral polyarthritis. It is the most common form of chronic inflammatory arthritis and

often results in joint damage and physical disability. Because it is a systemic disease, RA may result in a variety of extraarticular manifestations, including fatigue, subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities.

Clinical Features The incidence of RA increases between 25 and 55 years of age, after which it plateaus until the age of 75 and then decreases. The presenting symptoms of RA typically result from inflammation of the joints, tendons, and bursae. Patients often complain of early morning joint stiffness lasting more than 1 hour and easing with physical activity. The earliest involved joints are typically the small joints of the hands and feet. The initial pattern of joint involvement may be monoarticular, oligoarticular (4 joints), or polyarticular (>5 joints), usually in a symmetric distribution. Some patients with an inflammatory arthritis will present with too few affected joints and other characteristic features to be classified as having RAso-called undifferentiated inflammatory arthritis. Those with an undifferentiated arthritis, who are most likely to be diagnosed later with RA, have a higher number of tender and swollen joints, test positive for serum rheumatoid factor (RF) or anti-CCP antibodies, and have higher scores for physical disability.

Pathogenesis The pathogenic mechanisms of synovial inflammation are likely to result from a complex interplay of genetic, environmental, and immunologic factors that produces dysregulation of the immune system and a breakdown in self-tolerance (Fig. 321-4). Precisely what triggers these initiating events and what genetic and environmental factors disrupt the immune system remain a mystery. However, a detailed molecular picture is emerging of the mechanisms underlying the chronic inflammatory response and the destruction of the articular cartilage and bone.
In RA, the earliest detectable preclinical stage is a breakdown in self-tolerance. This idea is supported by the finding that autoantibodies, such as RF and anti-CCP antibodies, may be found in sera from patients long before clinical disease. However, the antigenic targets of anti-CCP antibodies and RF are not restricted to the joint, and their role in disease pathogenesis remains speculative. Anti-CCP antibodies are directed against deiminated peptides, which result from posttranslational modification by the enzyme PADI4. They recognize citrulline-containing regions of several different matrix proteins, including filaggrin, keratin, fibrinogen, and vimentin. Other autoantibodies have been found in a minority of patients with RA, but they also occur in the setting of other types of arthritis. They bind to a diverse array of autoantigens, including type II collagen, human cartilage gp-39, aggrecan, calpastatin, BiP (immunoglobulin binding protein), and glucose-6-phosphate isomerase.

Table 321-1 Classification Criteria for Rheumatoid Arthritis

Score Joint involvement 1 large joint (shoulder, elbow, hip, knee, ankle) 210 large joints 13 small joints (MCP, PIP, Thumb IP, MTP, wrists) 410 small joints >10 joints (at least 1 small joint) Serology Negative RF and negative ACPA Low-positive RF or low-positive anti-CCP antibodies (3 times ULN) High-positive RF or high-positive anti-CCP antibodies (>3 times ULN) Acute-phase reactants Duration of symptoms Normal CRP and normal ESR Abnormal CRP or abnormal ESR <6 weeks 6 weeks 0 1 2 3 5 0 2 3 0 1 0 1

Treatment: Rheumatoid Arthritis The amount of clinical disease activity in patients with RA reflects the overall burden of inflammation and is the variable most influencing treatment decisions. Joint inflammation is the main driver of joint damage and is the most important cause of functional disability in the early stages of disease. Several composite indices have been developed to assess clinical disease activity. The ACR 20, 50, and 70 improvement criteria [which corresponds to a 20%, 50%, and 70% improvement in joint counts, physician/patient assessment of disease severity, pain scale, serum levels of acute-phase reactants (ESR or CRP), and a functional assessment of disability using a self-administered patient questionnaire] are a composite index with a dichotomous response variable. The ACR improvement criteria are commonly used in clinical trials as an endpoint for comparing the proportion of responders between treatment groups. In contrast, the Disease Activity Score (DAS), Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI) are continuous measures of disease activity. These scales are increasingly used in clinical practice for tracking disease status, and in particular, for documenting treatment response. Several developments during the past two decades have changed the therapeutic landscape in RA. They include: (1) the emergence of methotrexate as the disease-modifying antirheumatic drug (DMARD) of first choice for the treatment of early RA; (2) the development of novel highly efficacious biologicals that can be used alone or in combination with methotrexate; and (3) the proven superiority of combination DMARD regimens over methotrexate alone. The medications used for the treatment of RA may be divided into broad categories: nonsteroidal anti-inflammatory drugs (NSAIDs); glucocorticoids, such as prednisone and methylprednisolone; conventional disease-modifying anti-rheumatic drugs (DMARDs); and biologic DMARDs (Table 321-2). While disease for some patients with RA is managed adequately with a single DMARD, such as methotrexate, the situation entails in most cases the use of a combination DMARD regimen that may vary in its components over the treatment course depending on fluctuations in disease activity and emergence of drug-related toxicities and comorbidities. Alzheimer's Disease Approximately 10% of all persons over the age of 70 have significant memory loss, and in more than half the cause is AD. It is estimated that the annual total cost of caring for a single AD patient in an advanced stage of the disease is >$50,000. The disease also exacts a heavy emotional toll on family members and caregivers. AD can occur in any decade of adulthood, but it is the most common cause of dementia in the elderly. AD most often presents with an insidious onset of memory loss followed by a slowly progressive dementia over several years. Pathologically, atrophy is distributed throughout the medial temporal lobes, as well as lateral and medial parietal lobes and lateral frontal cortex. Microscopically, there are neuritic plaques containing A , neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau filaments, and accumulation of amyloid in blood vessel walls in cortex and leptomeninges (see

"Pathogenesis," below). The identification of four different susceptibility genes for AD has provided a foundation for rapid progress in understanding the biologic basis of the disorder. Clinical Manifestations The cognitive changes of AD tend to follow a characteristic pattern, beginning with memory impairment and spreading to language and visuospatial deficits. Yet, approximately 20% of patients with AD present with nonmemory complaints such as word-finding, organizational, or navigational difficulty. In the early stages of the disease, the memory loss may go unrecognized or be ascribed to benign forgetfulness. Once the memory loss becomes noticeable to the patient and spouse and falls 1.5 standard deviations below normal on standardized memory tests, the term MCI is applied. This construct provides useful prognostic information, because approximately 50% of patients with MCI (roughly 12% per year) will progress to AD over 4 years. Slowly the cognitive problems begin to interfere with daily activities, such as keeping track of finances, following instructions on the job, driving, shopping, and housekeeping. Some patients are unaware of these difficulties (anosognosia), while others remain acutely attuned to their deficits. Changes in environment (such as vacations or hospital stays) may be disorienting, and the patient may become lost on walks or while driving. In the middle stages of AD, the patient is unable to work, is easily lost and confused, and requires daily supervision. Social graces, routine behavior, and superficial conversation may be surprisingly intact. Language becomes impairedfirst naming, then comprehension, and finally fluency. In some patients, aphasia is an early and prominent feature. Word-finding difficulties and circumlocution may be a problem even when formal testing demonstrates intact naming and fluency. Apraxia emerges, and patients have trouble performing learned sequential motor tasks. Visuospatial deficits begin to interfere with dressing, eating, or even walking, and patients fail to solve simple puzzles or copy geometric figures. Simple calculations and clock reading become difficult in parallel. In the late stages of the disease, some persons remain ambulatory but wander aimlessly. Loss of judgment and reasoning is inevitable. Delusions are common and usually simple, with common themes of theft, infidelity, or misidentification. Approximately 10% of AD patients develop Capgras' syndrome, believing that a caregiver has been replaced by an impostor. In contrast to DLB, where Capgras' syndrome is an early feature, in AD this syndrome emerges later. Loss of inhibitions and aggression may occur and alternate with passivity and withdrawal. Sleep-wake patterns are disrupted, and nighttime wandering becomes disturbing to the household. Some patients develop a shuffling gait with generalized muscle rigidity associated with slowness and awkwardness of movement. Patients often look parkinsonian (Chap. 372) but rarely have a highamplitude, rhythmic, resting tremor. In end-stage AD, patients become rigid, mute, incontinent, and bedridden. Help is needed with eating, dressing, and toileting. Hyperactive tendon reflexes and myoclonic jerks (sudden brief contractions of various muscles or the whole body) may occur spontaneously or in response to physical or auditory stimulation. Generalized seizures may also occur. Often death results from malnutrition, secondary infections, pulmonary emboli, heart disease, or, most commonly, aspiration. The typical duration of AD is 810 years, but the course can range from 1 to 25 years. For unknown reasons, some AD patients show a steady decline in function, while others have prolonged plateaus without major deterioration.

Differential Diagnosis Early in the disease course, other etiologies of dementia should be excluded (Table 371-1). Neuroimaging studies (CT and MRI) do not show a single specific pattern with AD and may be normal early in the course of the disease. As AD progresses, more distributed but usually posterior-predominant cortical atrophy becomes apparent, along with atrophy of the medial temporal memory structures (Fig. 371-2A, B). The main purpose of imaging is to exclude other disorders, such as primary and secondary neoplasms, vascular dementia, diffuse white matter disease, and NPH; it also helps to distinguish AD from other degenerative disorders with distinctive imaging patterns such as FTD or CJD. Functional imaging studies in AD reveal hypoperfusion or hypometabolism in the posterior temporal-parietal cortex (Fig. 371-2C,D). The EEG in AD is normal or shows nonspecific slowing. Routine spinal fluid examination is also normal. CSF A 42 levels are reduced, whereas levels of hyperphosphorylated tau protein are elevated, but the considerable overlap of these levels with those of the normal aged population limits the usefulness of these measurements in diagnosis. The use of blood ApoE genotyping is discussed under "Pathology," below. Slowly progressive decline in memory and orientation, normal results on laboratory tests, and an MRI or CT scan showing only distributed or posteriorly predominant cortical and hippocampal atrophy is highly suggestive of AD. A clinical diagnosis of AD reached after careful evaluation is confirmed at autopsy about 90% of the time, with misdiagnosed cases usually representing one of the other dementing disorders described later in this chapter, a mixture of AD with vascular pathology, or DLB. Simple clinical clues are useful in the differential diagnosis. Early prominent gait disturbance with only mild memory loss suggests vascular dementia or, rarely, NPH (see below). Resting tremor with stooped posture, bradykinesia, and masked facies suggest PD (Chap. 372). When dementia occurs after a well-established diagnosis of PD, PDD is usually the correct diagnosis. The early appearance of parkinsonian features in association with fluctuating alertness, visual hallucinations, or delusional misidentification suggests DLB. Chronic alcoholism should prompt the search for vitamin deficiency. Loss of sensibility to position and vibration stimuli accompanied by Babinski responses suggests vitamin B12 deficiency (Chap. 377). Early onset of a focal seizure suggests a metastatic or primary brain neoplasm (Chap. 379). Previous or ongoing depression raises suspicion for depression-related cognitive impairment, although AD can feature a depressive prodrome. A history of treatment for insomnia, anxiety, psychiatric disturbance, or epilepsy suggests chronic drug intoxication. Rapid progression over a few weeks or months associated with rigidity and myoclonus suggests CJD (Chap. 383). Prominent behavioral changes with intact navigation and focal anterior-predominant atrophy on brain imaging are typical of FTD. A positive family history of dementia suggests either one of the familial forms of AD or one of the other genetic disorders associated with dementia, such as HD (see below), FTD (see below), prion disease (Chap. 383), or rare hereditary ataxias (Chap. 373). Pathology At autopsy, the earliest and most severe degeneration is usually found in the medial temporal lobe (entorhinal/perirhinal cortex and hippocampus), lateral temporal cortex, and nucleus basalis

of Meynert. The characteristic microscopic findings are neuritic plaques and NFTs. These lesions accumulate in small numbers during normal brain aging but dominate the picture in AD. Increasing evidence suggests that soluble amyloid species called oligomers may cause cellular dysfunction and represent the early toxic molecule in AD. Eventually, further amyloid polymerization and fibril formation lead to neuritic plaques (Fig. 371-3), which contain a central amyloid core, proteoglycans, Apo 4, -antichymotrypsin, and other proteins. A is a protein of 3942 amino acids that is derived proteolytically from a larger transmembrane protein, amyloid precursor protein (APP), when APP is cleaved by and secretases. The normal

function of A is unknown. APP has neurotrophic and neuroprotective properties. The plaque core is surrounded by a halo, which contains dystrophic, tau-immunoreactive neurites and activated microglia. The accumulation of A in cerebral arterioles is termed amyloid angiopathy. NFTs are composed of silver-staining neuronal cytoplasmic fibrils composed of abnormally phosphorylated tau ( ) protein; they appear as paired helical filaments by electron microscopy. Tau binds to and stabilizes microtubules, supporting axonal transport of organelles, glycoproteins, neurotransmitters, and other important cargoes throughout the neuron. Once hyperphosphorylated, tau can no longer bind properly to microtubules and its functions are disrupted. Finally, patients with AD often show comorbid DLB and vascular pathology.

Treatment: Alzheimer's Disease The management of AD is challenging and gratifying, despite the absence of a cure or a robust pharmacologic treatment. The primary focus is on long-term amelioration of associated behavioral and neurologic problems, as well as providing caregiver support. Building rapport with the patient, family members, and other caregivers is essential to successful management. In the early stages of AD, memory aids such as notebooks and posted daily reminders can be helpful. Family members should emphasize activities that are pleasant and curtail those that are unpleasant. In other words, practicing skills that have become difficult, such as through memory games and puzzles, will often frustrate and depress the patient without proven benefits. Kitchens, bathrooms, stairways, and bedrooms need to be made safe, and eventually patients must stop driving. Loss of independence and change of environment may worsen confusion, agitation, and anger. Communication and repeated calm reassurance are necessary. Caregiver "burnout" is common, often resulting in nursing home placement of the patient or new health problems for the caregiver, and respite breaks for the caregiver help to maintain a successful long-term therapeutic milieu. Use of adult day care centers can be helpful. Local and national support groups, such as the Alzheimer's Association and the Family Caregiver Alliance, are valuable resources. Internet access to these resources has become available to clinicians and families in recent years.

Donepezil (target dose, 10 mg daily), rivastigmine (target dose, 6 mg twice daily or 9.5-mg patch daily), galantamine (target dose 24 mg daily, extended-release), memantine (target dose, 10 mg twice daily), and tacrine are the drugs presently approved by the Food and Drug Administration (FDA) for treatment of AD. Due to hepatotoxicity, tacrine is no longer used. Dose escalations for each of these medications must be carried out over 46 weeks to minimize side effects. The pharmacologic action of donepezil, rivastigmine, and galantamine is inhibition of the cholinesterases, primarily acetylcholinesterase, with a resulting increase in cerebral acetylcholine levels. Memantine appears to act by blocking overexcited N-methyl-d-aspartate (NMDA) glutamate receptors. Parkinson's Disease Dementia and Dementia with Lewy Bodies The parkinsonian dementia syndromes are under increasing study, with many cases unified by Lewy body and Lewy neurite pathology that ascends from the low brainstem up through the substantia nigra, limbic system, and cortex. The DLB clinical syndrome is characterized by visual hallucinations, parkinsonism, fluctuating alertness, falls, and often RBD. Dementia can precede or follow the appearance of parkinsonism. Hence, one pathway occurs in patients with long-standing PD without cognitive impairment, who slowly develop a dementia that is associated with visual hallucinations and fluctuating alertness. When this occurs after an established diagnosis of PD, many use the term Parkinson's disease dementia (PDD). In others, the dementia and neuropsychiatric syndrome precede the parkinsonism, and this constellation is referred to as DLB. Both PDD and DLB may be accompanied or preceded by symptoms referable to brainstem pathology below the substantia nigra, and many researchers conceptualize these disorders as points on a spectrum of -synuclein pathology.

Patients with PDD and DLB are highly sensitive to metabolic perturbations, and in some patients the first manifestation of illness is a delirium, often precipitated by an infection, new medicine, or other systemic disturbance. A hallucinatory delirium induced by l-dopa, prescribed for parkinsonian symptoms attributed to PD may likewise provide the initial clue to a PDD diagnosis. Conversely, patients with mild cognitive deficits and hallucinations may receive typical or atypical antipsychotic medications, which induce profound parkinsonism at low doses due to a subclinical DLB-related nigral dopaminergic neuron loss. Even without an underlying precipitant, fluctuations can be marked in DLB, with episodic confusion or even stupor admixed with lucid intervals. However, despite the fluctuating pattern, the clinical features persist over a long period, unlike delirium, which resolves following correction of the inciting factor. Cognitively, DLB features relative preservation of memory but more severe visuospatial and executive deficits than patients with early AD. The key neuropathologic feature in DLB is the presence of Lewy bodies and Lewy neurites throughout specific brainstem nuclei, substantia nigra, amygdala, cingulate gyrus, and, ultimately, the neocortex. Lewy bodies are intraneuronal cytoplasmic inclusions that stain with periodic acidSchiff (PAS) and ubiquitin but are now identified with antibodies to the presynaptic protein, -synuclein. They are composed of straight neurofilaments 720 nm long with surrounding amorphous material and contain epitopes recognized by antibodies against

phosphorylated and nonphosphorylated neurofilament proteins, ubiquitin, and -synuclein. Lewy bodies are typically found in the substantia nigra of patients with idiopathic PD, where they can be readily seen with hematoxylin-and-eosin staining. A profound cholinergic deficit, owing to basal forebrain and pedunculopontine nucleus involvement, is present in many patients with DLB and may be a factor responsible for the fluctuations, inattention, and visual hallucinations. In patients without other pathologic features, the condition is sometimes referred to as diffuse Lewy body disease. In patients whose brains also contain a substantial burden of amyloid plaques and NFTs, the condition is sometimes called the Lewy body variant of Alzheimer's disease. Due to the overlap with AD and the cholinergic deficit in DLB, cholinesterase inhibitors often provide significant benefit, reducing hallucinosis, stabilizing delusional symptoms, and even helping with RBD in some patients. Exercise programs maximize motor function and protect against fall-related injury. Antidepressants are often necessary. Atypical antipsychotics may be required for psychosis but can worsen extrapyramidal syndromes, even at low doses, and increase risk of death. As noted above, patients with DLB are extremely sensitive to dopaminergic medications, which must be carefully titrated; tolerability may be improved by concomitant use of a cholinesterase inhibitor.

Opacities of the Cornea and Lens


Corneal Arcus.
A thin grayish white arc or circle not quite at the edge of the cornea. Accompanies normal aging but also seen in younger people, especially African Americans. In young people, suggests possible hyperlipoproteinemia. Usually benign.

Kayser-Fleischer Ring.
A golden to red brown ring, sometimes shading to green or blue, from copper deposition in the periphery of the cornea found in Wilsons disease. Due to a rare autosomal recessive mutation of the ATO7B gene on chromosome 13 causing abnormal copper transport, reduced biliary copper excretion, and abnormal accumulation of copper in the liver and tissues throughout the body. Patients present with liver disease, renal failure, and neurologic symptoms of tremor, dystonia, and psychiatric disorders ranging from behavior changes to depression and schizophrenia.65, 66

Corneal Scar.

A superficial grayish white opacity in the cornea, secondary to an old injury or to inflammation. Size and shape are variable. Do not confuse with the opaque lens of a cataract, visible on a deeper plane and only through the pupil.

Pterygium.
A triangular thickening of the bulbar conjunctiva that grows slowly across the outer surface of the cornea, usually from the nasal side. Reddening may occur. May interfere with vision as it encroaches on the pupil.

Cataracts.
Opacities of the lenses visible through the pupil. Risk factors are older age, smoking, diabetes, corticosteroid use. Nuclear cataract. A nuclear cataract looks gray when seen by a flashlight. If the pupil is widely dilated, the gray opacity is surrounded by a black rim.

Peripheral cataract. Produces spokelike shadows that pointgray against black, as seen with a flashlight, or black against red with an ophthalmoscope. A dilated pupil, as shown here, facilitates this observation.

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