im diseases.docx

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Blepharitis

This refers to inflammation of the eyelids. 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, and topical antibiotics such asbacitracin/polymyxin B ophthalmic ointment.

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 fortreatment 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 vitaminB1. 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 thatmediates the conversion of hexose and pentose phosphates. It has been postulated thatthiamine plays a role in peripheral nerve conduction, although the exact chemicalreactions underlying this function are not known.

Food Sourceso

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 arice-based diet. Tea, coffee (regular and decaffeinated), raw fish, and shellfishcontain thiaminases, which can destroy the vitamin. Thus, drinking large amountsof tea or coffee can theoretically lower thiamine body stores.


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Deficiencyo Most dietary deficiency of thiamine worldwide is the result of poor dietary intake.

In Western countries, the primary causes of thiamine deficiency are alcoholismand chronic illnesses such as cancer. Alcohol interferes directly with theabsorption of thiamine and with the synthesis of thiamine pyrophosphate.

Thiamine should always be replenished when a patient with alcoholism is beingrefed, as carbohydrate repletion without adequate thiamine can precipitate acutethiamine deficiency with lactic acidosis. Other at-risk populations are womenwith prolonged hyperemesis gravidarum and anorexia, patients with overall poornutritional status on parenteral glucose, patients after bariatric bypass surgery, andpatients 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 vehicleaccidents 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 isconsiderable overlap. In either form of beriberi, patients may complain of painand paresthesia. Wet beriberi presents primarily with cardiovascular symptoms,due to impaired myocardial energy metabolism and dysautonomia, and can occurafter 3 months of a thiamine-deficient diet. Patients present with an enlargedheart, tachycardia, high-output congestive heart failure, peripheral edema, andperipheral neuritis. Patients with dry beriberipresent with a symmetric peripheralneuropathy of the motor and sensory systems with diminished reflexes. Theneuropathy affects the legs most markedly, and these patients have difficultyrising from a squatting position.

o Alcoholic patients with chronic thiamine deficiency also may have centralnervous system (CNS) manifestations known as Wernicke's encephalopathy,consisting of horizontal nystagmus, ophthalmoplegia (due to weakness of one ormore extraocular muscles), cerebellar ataxia, and mental impairment (Chap. 392).When there is an additional loss of memory and a confabulatory psychosis, thesyndrome is known as Wernicke-Korsakoff syndrome. Despite the typical clinicalpicture and history, Wernicke-Korsakoff syndrome is underdiagnosed.

o The laboratory diagnosis of thiamine deficiency usually is made by a functionalenzymatic assay of transketolase activity measured before and after the additionof thiamine pyrophosphate. A >25% stimulation by the addition of thiaminepyrophosphate (an activity coefficient of 1.25) is interpreted as abnormal.Thiamine or the phosphorylated esters of thiamine in serum or blood also can bemeasured by high-performance liquid chromatography (HPLC) to detectdeficiency.

Treatment: Thiamine Deficiencyo 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/dorally until there is complete recovery. Cardiovascular and ophthalmoplegicimprovement occurs within 24 h. Other manifestations gradually clear, although


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psychosis in Wernicke-Korsakoff syndrome may be permanent or persist forseveral months.

Toxicityo 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 offever, 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 amember 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 longperiods. Airborne transmission appears to be important in certain settings, includingschools, physicians' offices, hospitals, and enclosed public places. The virus can betransmitted by direct contact with infected secretions but does not survive for long onfomites.

The incubation period for measles is 10 days to fever onset and 14 days to rashonset. 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


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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

Definitiono Varicella-zoster virus (VZV) causes two distinct clinical entities: varicella

(chickenpox) and herpes zoster (shingles). Chickenpox, a ubiquitous andextremely contagious infection, is usually a benign illness of childhoodcharacterized by an exanthematous vesicular rash. With reactivation of latentVZV (which is most common after the sixth decade of life), herpes zoster presentsas a dermatomal vesicular rash, usually associated with severe pain.

Etiologyo A clinical association between varicella and herpes zoster has been recognized for

nearly 100 years. Early in the twentieth century, similarities in the histopathologicfeatures of skin lesions resulting from varicella and herpes zoster weredemonstrated. Viral isolates from patients with chickenpox and herpes zosterproduced similar alterations in tissue culturespecifically, the appearance ofeosinophilic intranuclear inclusions and multinucleated giant cells. These resultssuggested that the viruses were biologically similar. Restriction endonucleaseanalyses of viral DNA from a patient with chickenpox who subsequentlydeveloped herpes zoster verified the molecular identity of the two virusesresponsible for these different clinical presentations.

o VZV is a member of the family Herpesviridae, sharing with other members suchstructural characteristics as a lipid envelope surrounding a nucleocapsid with

icosahedral symmetry, a total diameter of 180200 nm, and centrally located

double-stranded DNA that is 125,000 bp in length.

Nephrotic Syndrome

Nephrotic syndrome classically presents with heavy proteinuria, minimal hematuria,hypoalbuminemia, hypercholesterolemia, edema, and hypertension. If left undiagnosed oruntreated, 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


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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 renin-

angiotensin system can lower urinary protein excretion.

Peptic Ulcer Disease

Burning epigastric pain exacerbated by fasting and improved with meals is a symptomcomplex associated with peptic ulcer disease (PUD). An ulceris 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 anestimated 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 declinedsteadily 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 Helicobacterpylori. Before the discovery of H. pylori, the natural history of DUs was typified by frequent

recurrences after initial therapy. Eradication of H. pylorihas greatly reduced these recurrence

rates.

Pathology

Duodenal Ulcers

DUs occur most often in the first portion of the duodenum (>95%), with ~90% located within 3cm of the pylorus. They are usually 1 cm in diameter but can occasionally reach 36 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


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o Pancreatic inflammatory disease may be classified as (1) acute pancreatitis or (2)chronic pancreatitis. The pathologic spectrum of acute pancreatitis varies frominterstitial pancreatitis, which is usually a mild and self-limited disorder, tonecrotizing pancreatitis, in which the extent of pancreatic necrosis may correlatewith 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, anti-HIV medications)

Sphincter of Oddi dysfunction

Etiology and Pathogenesis

There are many causes of acute pancreatitis (Table 313-1), but the mechanisms bywhich these conditions trigger pancreatic inflammation have not been fully

elucidated. Gallstones continue to be the leading cause of acute pancreatitis in mostseries (3060%). The risk of acute pancreatitis in patients with at least one gallstone


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metabolism, probably unrelated to pancreatitis. Such patients are prone to recurrentepisodes of pancreatitis. Any factor (e.g., drugs or alcohol) that causes an abruptincrease in serum triglycerides to levels >11 mmol/L (1000 mg/dL) can precipitate about of acute pancreatitis. Finally, patients with a deficiency of apolipoprotein CIIhave an increased incidence of pancreatitis; apolipoprotein CII activates lipoprotein

lipase, which is important in clearing chylomicrons from the bloodstream. Patientswith diabetes mellitus who have developed ketoacidosis and patients who are oncertain medications such as oral contraceptives may also develop high triglyceridelevels. Approximately 25% of cases of acute pancreatitis are drug related. Drugscause pancreatitis either by a hypersensitivity reaction or by the generation of a toxicmetabolite, although in some cases it is not clear which of these mechanisms isoperative (Table 313-1).

o Autodigestion is a currently accepted pathogenic theory; according to it, pancreatitisresults 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, viralinfections, 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 subsidesspontaneously, usually within three to seven days after treatment is instituted. Conventionalmeasures 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 canusually 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


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Iodine deficiency remains the most common cause of hypothyroidism worldwide. Inareas 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: I treatment, subtotal or total thyroidectomy, external irradiation of neck forlymphoma 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-Rmutation

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 thyroiditisWithdrawal of thyroxine treatment in individuals with an intact thyroid

After I treatment or subtotal thyroidectomy for Graves' disease

Secondary

Hypopituitarism: tumors, pituitary surgery or irradiation, infiltrative disorders, Sheehan'ssyndrome, 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


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delayed bone maturation, and umbilical hernia. Importantly, permanent neurologic damageresults 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 commonin congenital hypothyroidism.

Table 341-5 Signs and Symptoms of Hypothyroidism (Descending Order of Frequency)

Symptoms

Tiredness, weakness

Dry skin

Feeling cold

Hair loss

Difficulty concentrating and poor memory

Constipation

Weight gain with poor appetite

Dyspnea

Hoarse voice

Menorrhagia (later oligomenorrhea oramenorrhea)

Paresthesia

Impaired hearing

Signs

Dry coarse skin; cool peripheralextremities

Puffy face, hands, and feet (myxedema)

Diffuse alopecia

Bradycardia

Peripheral edema

Delayed tendon reflex relaxation

Carpal tunnel syndrome

Serous cavity effusions

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, T 4is instituted at a

dose of 1015 g/kg per day, and the dose is adjusted by close monitoring of TSH levels. T4

requirements are relatively great during the first year of life, and a high circulating T 4 level is

usually needed to normalize TSH. Early treatment with T4results 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.


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Chronic Obstructive Pulmonary Disease: Introduction

Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized byairflow limitation that is not fully reversible (http://www.goldcopd.com/). COPD includesemphysema, an anatomically defined condition characterized by destruction and enlargement of

the lung alveoli; chronic bronchitis, a clinically defined condition with chronic cough andphlegm; andsmall airways disease, a condition in which small bronchioles are narrowed. COPDis present only if chronic airflow obstruction occurs; chronic bronchitis withoutchronic airflowobstruction is notincluded 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. Estimatessuggest that COPD will rise from the sixth to the third most common cause of death worldwideby 2020.

Risk Factors

Cigarette Smoking Airway Responsiveness and COPD Respiratory Infections Occupational Exposures Ambient Air Pollution Passive, or Second-Hand, Smoking Exposure Genetic Considerations A1Antitrypsin Deficiency Other Genetic Risk FactorsPathophysiology

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 Obstructiono 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

FEV1and 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.


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Hyperinflation

o Lung volumes are also routinely assessed in pulmonary function testing. In COPD thereis 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 maximumexpiratory 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 otherphysiologic 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

FEV1values 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 FEV1is


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IIA Moderate With or without chroniccough or sputum production

FEV1/FVC


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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.


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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 amystery. 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 adiverse 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) 0

210 large joints 1

13 small joints (MCP, PIP, Thumb IP, MTP, wrists) 2

410 small joints 3

>10 joints (at least 1 small joint) 5

Serology Negative RF and negative ACPA 0

Low-positive RF or low-positive anti-CCP antibodies (3 timesULN)

2

High-positive RF or high-positive anti-CCP antibodies (>3 timesULN)

3

Acute-phasereactants Normal CRP and normal ESR 0

Abnormal CRP or abnormal ESR 1

Duration ofsymptoms


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Treatment: Rheumatoid Arthritis

The amount of clinical disease activity in patients with RA reflects the overall burden ofinflammation and is the variable most influencing treatment decisions. Joint inflammation is themain 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 diseaseactivity. The ACR 20, 50, and 70 improvement criteria [which corresponds to a 20%, 50%, and70% 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 disabilityusing a self-administered patient questionnaire] are a composite index with a dichotomousresponse variable. The ACR improvement criteria are commonly used in clinical trials as anendpoint for comparing the proportion of responders between treatment groups. In contrast, theDisease Activity Score (DAS), Simplified Disease Activity Index (SDAI), and the ClinicalDisease Activity Index (CDAI) are continuous measures of disease activity. These scales areincreasingly used in clinical practice for tracking disease status, and in particular, fordocumenting 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 morethan half the cause is AD. It is estimated that the annual total cost of caring for a single ADpatient in an advanced stage of the disease is >$50,000. The disease also exacts a heavyemotional toll on family members and caregivers. AD can occur in any decade of adulthood, butit is the most common cause of dementia in the elderly. AD most often presents with an insidiousonset 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 andmedial parietal lobes and lateral frontal cortex. Microscopically, there are neuritic plaques

containing A , neurofibrillary tangles (NFTs) composed of hyperphosphorylated taufilaments, and accumulation of amyloid in blood vessel walls in cortex and leptomeninges (see


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"Pathogenesis," below). The identification of four different susceptibility genes for AD hasprovided 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 memoryimpairment and spreading to language and visuospatial deficits. Yet, approximately 20% ofpatients with AD present with nonmemory complaints such as word-finding, organizational, ornavigational difficulty. In the early stages of the disease, the memory loss may go unrecognizedor be ascribed to benign forgetfulness. Once the memory loss becomes noticeable to the patientand spouse and falls 1.5 standard deviations below normal on standardized memory tests, theterm MCI is applied. This construct provides useful prognostic information, becauseapproximately 50% of patients with MCI (roughly 12% per year) will progress to AD over 4years. Slowly the cognitive problems begin to interfere with daily activities, such as keepingtrack of finances, following instructions on the job, driving, shopping, and housekeeping. Somepatients 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, thepatient is unable to work, is easily lost and confused, and requires daily supervision. Socialgraces, routine behavior, and superficial conversation may be surprisingly intact. Languagebecomes impairedfirst naming, then comprehension, and finally fluency. In some patients,aphasiais an early and prominent feature. Word-finding difficulties and circumlocution may bea problem even when formal testing demonstrates intact naming and fluency.Apraxiaemerges,and patients have trouble performing learned sequential motor tasks. Visuospatial deficits beginto interfere with dressing, eating, or even walking, and patients fail to solve simple puzzles orcopy 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 ofjudgment and reasoning is inevitable. Delusions are common and usually simple, with commonthemes of theft, infidelity, or misidentification. Approximately 10% of AD patients developCapgras' syndrome, believing that a caregiver has been replaced by an impostor. In contrast toDLB, where Capgras' syndrome is an early feature, in AD this syndrome emerges later. Loss ofinhibitions and aggression may occur and alternate with passivity and withdrawal. Sleep-wakepatterns are disrupted, and nighttime wandering becomes disturbing to the household. Somepatients develop a shuffling gait with generalized muscle rigidity associated with slowness andawkwardness of movement. Patients often look parkinsonian (Chap. 372) but rarely have a high-amplitude, rhythmic, resting tremor. In end-stage AD, patients become rigid, mute, incontinent,and bedridden. Help is needed with eating, dressing, and toileting. Hyperactive tendon reflexesand myoclonic jerks (sudden brief contractions of various muscles or the whole body) may occurspontaneously or in response to physical or auditory stimulation. Generalized seizures may alsooccur. Often death results from malnutrition, secondary infections, pulmonary emboli, heartdisease, or, most commonly, aspiration. The typical duration of AD is 810 years, but the coursecan range from 1 to 25 years. For unknown reasons, some AD patients show a steady decline infunction, while others have prolonged plateaus without major deterioration.


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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 benormal 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 medialtemporal memory structures (Fig. 371-2A, B). The main purpose of imaging is to exclude otherdisorders, such as primary and secondary neoplasms, vascular dementia, diffuse white matterdisease, and NPH; it also helps to distinguish AD from other degenerative disorders withdistinctive imaging patterns such as FTD or CJD. Functional imaging studies in AD revealhypoperfusion or hypometabolism in the posterior temporal-parietal cortex (Fig. 371-2C,D). TheEEG in AD is normal or shows nonspecific slowing. Routine spinal fluid examination is also

normal. CSF A 42levels are reduced, whereas levels of hyperphosphorylated tau protein areelevated, but the considerable overlap of these levels with those of the normal aged populationlimits the usefulness of these measurements in diagnosis. The use of blood ApoE genotyping isdiscussed 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 clinicaldiagnosis 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 describedlater 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, visualhallucinations, 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


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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 oligomersmay 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 robustpharmacologic treatment. The primary focus is on long-term amelioration of associatedbehavioral and neurologic problems, as well as providing caregiver support.

Building rapport with the patient, family members, and other caregivers is essential to successfulmanagement. In the early stages of AD, memory aids such as notebooks and posted dailyreminders can be helpful. Family members should emphasize activities that are pleasant andcurtail those that are unpleasant. In other words, practicing skills that have become difficult, suchas through memory games and puzzles, will often frustrate and depress the patient withoutproven benefits. Kitchens, bathrooms, stairways, and bedrooms need to be made safe, andeventually patients must stop driving. Loss of independence and change of environment may

worsen confusion, agitation, and anger. Communication and repeated calm reassurance arenecessary. Caregiver "burnout" is common, often resulting in nursing home placement of thepatient or new health problems for the caregiver, and respite breaks for the caregiver help tomaintain 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 FamilyCaregiver Alliance, are valuable resources. Internet access to these resources has becomeavailable to clinicians and families in recent years.


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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 thecholinesterases, primarily acetylcholinesterase, with a resulting increase in cerebral acetylcholine

levels. Memantine appears to act by blocking overexcitedN-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 byLewy body and Lewy neurite pathology that ascends from the low brainstem up through thesubstantia nigra, limbic system, and cortex. The DLB clinical syndrome is characterized byvisual hallucinations, parkinsonism, fluctuating alertness, falls, and often RBD. Dementia can

precede or follow the appearance of parkinsonism. Hence, one pathway occurs in patients withlong-standing PD without cognitive impairment, who slowly develop a dementia that isassociated with visual hallucinations and fluctuating alertness. When this occurs after anestablished diagnosis of PD, many use the termParkinson's disease dementia(PDD). In others,the dementia and neuropsychiatric syndrome precede the parkinsonism, and this constellation isreferred to as DLB. Both PDD and DLB may be accompanied or preceded by symptomsreferable 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 forparkinsonian symptoms attributed to PD may likewise provide the initial clue to a PDDdiagnosis. Conversely, patients with mild cognitive deficits and hallucinations may receivetypical or atypical antipsychotic medications, which induce profound parkinsonism at low dosesdue to a subclinical DLB-related nigral dopaminergic neuron loss. Even without an underlyingprecipitant, fluctuations can be marked in DLB, with episodic confusion or even stupor admixedwith lucid intervals. However, despite the fluctuating pattern, the clinical features persist over along period, unlike delirium, which resolves following correction of the inciting factor.Cognitively, DLB features relative preservation of memory but more severe visuospatial andexecutive deficits than patients with early AD.

The key neuropathologic feature in DLB is the presence of Lewy bodies and Lewy neuritesthroughout specific brainstem nuclei, substantia nigra, amygdala, cingulate gyrus, and,ultimately, the neocortex. Lewy bodies are intraneuronal cytoplasmic inclusions that stain withperiodic acidSchiff (PAS) and ubiquitin but are now identified with antibodies to the

presynaptic protein, -synuclein. They are composed of straight neurofilaments 720 nmlong with surrounding amorphous material and contain epitopes recognized by antibodies against


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phosphorylated and nonphosphorylated neurofilament proteins, ubiquitin, and -synuclein.Lewy bodies are typically found in the substantia nigra of patients with idiopathic PD, wherethey 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 visualhallucinations. In patients without other pathologic features, the condition is sometimes referredto as diffuse Lewy body disease. In patients whose brains also contain a substantial burden ofamyloid plaques and NFTs, the condition is sometimes called theLewy body variant ofAlzheimer'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 todopaminergic 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 agingbut 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 theperiphery 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 copperexcretion, 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.


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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 adeeper plane and only through the pupil.

Pterygium.

A triangular thickening of the bulbar conjunctiva that grows slowly across the outer surface ofthe cornea, usually from the nasal side. Reddening may occur. May interfere with vision as itencroaches 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 grayopacity is surrounded by a black rim.

Peripheral cataract.

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

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