1792 PART 5 Infectious Diseases

Studies have demonstrated that clinical criteria may aid in diagnosis in selected cases. In patients from endemic areas who had single

enhancing lesions presenting with seizures, a normal physical examination, and no evidence of systemic disease (e.g., no fever, adenopathy,

or chest radiographic abnormalities), the constellation of rounded CT

lesions 5–20 mm in diameter with no midline shift was almost always

caused by neurocysticercosis.

A definite or probable diagnosis is made in accordance with the

criteria and combinations of criteria listed in the footnote of Table

235-1. Patients may have CSF pleocytosis with a predominance of

lymphocytes, neutrophils, or eosinophils. The protein level in CSF

may be elevated; the glucose concentration is usually normal but may

be depressed.

TREATMENT

Taeniasis Solium and Cysticercosis

Intestinal T. solium infection is treated with a single dose of praziquantel (10 mg/kg). However, praziquantel occasionally evokes an

inflammatory response in the CNS if concomitant cryptic cysticercosis is present. Niclosamide (2 g) is also effective but is not widely

available.

The initial management of neurocysticercosis should focus

on symptom-based treatment of seizures or hydrocephalus. Seizures can usually be controlled with antiepileptic treatment. If

parenchymal lesions resolve without development of calcifications

and patients remain free of seizures, antiepileptic therapy can

usually be discontinued after 2 years; less in patients with a single enhancing lesion. Placebo-controlled trials are clarifying the

clinical advantage of antiparasitic drugs for parenchymal neurocysticercosis. Faster resolution of neuroradiologic abnormalities

has been observed in most studies. The clinical benefits are less

dramatic and consist mainly of shortening the period during which

recurrent seizures occur and decreasing the number of patients who

have many recurrent seizures. For the treatment of patients with

brain parenchymal cysticerci, most authorities favor antiparasitic

drugs, including albendazole (15 mg/kg per day for 8–28 days)

and/or praziquantel (50–100 mg/kg daily in three divided doses for

15–30 days). A combination of albendazole and praziquantel (50

mg/kg per day) is more effective in patients with more than two

cystic lesions. A longer course or combination therapy is needed

in patients with multiple subarachnoid cysticerci. Both agents may

exacerbate the inflammatory response around the dying parasite, thereby exacerbating seizures or hydrocephalus as well. Thus,

patients receiving these drugs should be carefully monitored. Highdose glucocorticoids should be used during treatment. Because

glucocorticoids induce first-pass metabolism of praziquantel and

may decrease its antiparasitic effect, cimetidine should be co-administered to inhibit praziquantel metabolism.

For patients with hydrocephalus, the emergent reduction of intracranial pressure is the mainstay of therapy. In the case of obstructive

FIGURE 235-1 Neurocysticercosis is caused by Taenia solium. Neurologic infection can be classified on the basis of the location and viability of the parasites. Upper

left: Parenchymal viable cysts (FLAIR MRI sequence). Upper center: Parenchymal viable cysts (postcontrast T1 MRI sequence). Upper right: Single enhancing lesion

(postcontrast T1 MRI sequence). Bottom left: Extensive basal subarachnoid neurocysticercosis in the anterior fossa (FLAIR MRI sequence). Bottom center: Viable cyst in

the fourth ventricle (FLAIR MRI sequence). Bottom right: Intraparenchymal brain calcifications (noncontrasted CT scan). Lesions are marked with arrowheads. FLAIR, fluidattenuated inversion recovery. (Modified with permission from A White, H Garcia: Curr Opin Infect Dis 31:377, 2018. Lippincott Williams & Wilkins.)

1793CHAPTER 235 Cestode Infections

hydrocephalus, the preferred approach is removal of the cysticercus

via neurosurgery. This should be performed via neuroendoscopy

when the cysticerci are in the lateral or third ventricles. The fourth

ventricular cysticerci can be approached by microdissection using

an open craniotomy and a posterior approach or, in some cases,

via neuroendoscopy. However, removal of the cysticercus is not

always possible. An alternative approach is initially to perform a

diverting procedure, such as ventriculoperitoneal shunting. Historically, shunts have usually failed, but failure rates may be lowered by administration of antiparasitic drugs and glucocorticoids.

For patients with subarachnoid cysts or giant cysticerci, antiinflammatory medications such as glucocorticoids are needed to

reduce arachnoiditis and accompanying vasculitis. Most authorities recommend prolonged courses of antiparasitic drugs as well

as shunting when hydrocephalus is present. Methotrexate and,

in some cases, tumor necrosis factor inhibitors can be used as

steroid-sparing agents in patients requiring prolonged therapy.

In patients with diffuse cerebral edema and elevated intracranial

pressure due to multiple inflamed lesions, glucocorticoids are the

mainstay of therapy, and antiparasitic drugs should be avoided. For

ocular and spinal medullary lesions, drug-induced inflammation

may cause irreversible damage. Ocular disease should be managed

surgically. Recent data suggest that either medical or surgical therapy can be used for spinal disease.

Prevention Measures for the prevention of intestinal T. solium

infection consist of the application to pork of precautions similar to

those described above for beef with regard to T. saginata infection. The

prevention of cysticercosis involves minimizing the opportunities for

ingestion of fecally derived eggs by means of good personal hygiene,

effective fecal disposal, and treatment and prevention of human intestinal infections. Optimal eradication programs in endemic areas include

mass chemotherapy administered to human and porcine populations

and vaccinations of pigs. A vaccine for porcine infection is licensed in

India and a few other countries.

■ ECHINOCOCCOSIS

Echinococcosis (also termed hydatidosis) is an infection caused in

humans by the larval stage of Echinococcus granulosus sensu lato,

E. multilocularis, or E. vogeli. E. granulosus sensu lato parasites produce

cystic hydatid disease, with unilocular cystic lesions. These infections

are prevalent in most areas where livestock is raised in association

with dogs. Molecular evidence has demonstrated that E. granulosus

strains belong to a range of genotypes and several species. Currently,

human cystic hydatid disease is caused by organisms formerly termed

E. granulosus that are now classified as E. granulosus sensu stricto

(genotypes 1–3), E. canadensis (genotypes 6–8 and 10), and E. ortleppi

(genotype 5). Other species—E. equinus (genotype 4) and E. felidis

(lion strain)—have not been identified in human infections. Some

classify genotypes 6 and 7 as a separate species—E. intermedius.

E. granulosus sensu lato parasites are found on all continents, with areas

of high prevalence in western China, central Asia, the Middle East, the

Mediterranean region, eastern Africa, and parts of South America.

E. multilocularis, which causes multilocular alveolar lesions that are

locally invasive, is found in Alpine, sub-Arctic, or Arctic regions,

including central and northern Europe; western China and central

Asia; and isolated areas in North America. E. vogeli and E. oligarthrus

cause neotropical echinococcosis (formerly termed polycystic hydatid

disease) and are found only in South America.

Like other cestodes, echinococcal species have both intermediate

and definitive hosts. The definitive hosts are canines that pass eggs in

their feces. After the ingestion of eggs, cysts develop in the intermediate hosts—sheep, cattle, humans, goats, camels, and horses for the E.

granulosus complex and mice and other rodents for E. multilocularis.

When a dog (E. granulosus) or fox (E. multilocularis) ingests infected

meat containing cysts, the life cycle is completed. Humans are an incidental dead-end host and not part of the transmission life cycle.

Etiology The small (5-mm-long) adult E. granulosus sensu lato

worms live for 5–20 months in the jejunum of dogs. They have three

proglottids: one immature, one mature, and one gravid. The gravid segments are shed to release eggs that are morphologically similar to Taenia

eggs and are extremely hardy. After humans ingest the eggs, embryos

escape from the eggs, penetrate the intestinal mucosa, enter the portal

circulation, and are carried to various organs, most commonly the liver

and lungs. Larvae of E. granulosus sensu lato develop into fluid-filled

unilocular hydatid cysts that consist of an external membrane and an

inner germinal layer. Daughter cysts develop from the inner aspect of

the germinal layer, as do germinating cystic structures called brood capsules. New larvae, called protoscolices, develop in large numbers within

the brood capsule. The cysts expand slowly over a period of years.

The life cycle of E. multilocularis is similar except that wild canines, such

as foxes or wolves, serve as the main definitive hosts, and small rodents

serve as the intermediate hosts. The larval form of E. multilocularis, however, is quite different in that it remains in the proliferative phase, the

parasite is always multilocular, and vesicles without brood capsules or

protoscolices progressively invade the host tissue by peripheral extension of processes from the germinal layer.

Clinical Manifestations Slowly enlarging echinococcal cysts

generally remain asymptomatic until their expanding size or their

space-occupying effect in an involved organ elicits symptoms. The

liver and the lungs are the most common sites of these cysts. The liver

is involved in about two-thirds of E. granulosus infections and in nearly

all E. multilocularis infections. Because a period of years elapses before

cysts enlarge sufficiently to cause symptoms, they may be discovered

incidentally on a routine x-ray or ultrasound study.

TABLE 235-1 Revised Diagnostic Criteria for Neurocysticercosisa

1. Absolute criteria

a. Histologic demonstration of the parasite from biopsy of a brain or spinal

cord lesion

b. Visualization of subretinal cysticercus

c. Conclusive demonstration of a scolex within a cystic lesion on

neuroimaging studies

2. Neuroimaging criteria

a. Major neuroimaging criteria

Cystic lesions without a discernible scolex, typical small enhancing

lesions, multilobulated cystic lesions in the subarachnoid space, typical

parenchymal brain calcifications

b. Confirmative neuroimaging criteria

Resolution of cystic lesions spontaneously or after cysticidal drug therapy

Migration of ventricular cysts documented on sequential neuroimaging

studies

c. Minor neuroimaging criteria

Obstructive hydrocephalus or abnormal enhancement of basal

leptomeninges

3. Clinical/exposure criteria

a. Major clinical/exposure criteria

Detection of specific anticysticercal antibodies (e.g., by enzyme-linked

immunoelectrotransfer blot [EITB]) or cysticercal antigens by wellstandardized immunodiagnostic tests

Cysticercosis outside the central nervous system

Evidence of a household contact with T. solium infection

b. Minor clinical/exposure criteria

Clinical manifestations suggestive of neurocysticercosis

Individuals coming from or living in an area where cysticercosis is

endemic

a

Diagnosis is confirmed by one absolute criterion, by two major criteria or one

major and one confirmatory neuroimaging criteria plus any clinical/exposure

criterion, or by one major neuroimaging criterion plus two clinical/exposure

criteria (including at least one major clinical/exposure criterion), together with the

exclusion of other pathologies producing similar neuroimaging findings. A probable

diagnosis is supported by one major neuroimaging criterion plus any two clinical/

exposure criteria or by one minor neuroimaging criterion plus at least one major

clinical/exposure criterion.

Source: Reproduced with permission from OH Del Brutto et al: Revised diagnostic

criteria for neurocysticercosis. J Neurol Sci 372:202, 2017.

1794 PART 5 Infectious Diseases

Patients with hepatic echinococcosis who are symptomatic most

often present with abdominal pain or a palpable mass in the right

upper quadrant. Compression of a bile duct or leakage of cyst fluid

into the biliary tree may mimic recurrent cholelithiasis, and biliary

obstruction can result in jaundice. Rupture of or episodic leakage from

a hydatid cyst may produce fever, pruritus, urticaria, eosinophilia, or

anaphylaxis. Pulmonary hydatid cysts may rupture into the bronchial

tree or pleural cavity and produce cough, salty phlegm, dyspnea,

chest pain, or hemoptysis. Rupture of hydatid cysts, which can occur

spontaneously or at surgery, may lead to multifocal dissemination of

protoscolices, which can form additional cysts. Other presentations are

due to the involvement of bone (invasion of the medullary cavity with

slow bone erosion producing pathologic fractures), the CNS (spaceoccupying lesions), the heart (conduction defects, pericarditis), and the

pelvis (pelvic mass).

The larval forms of E. multilocularis characteristically present as a

slowly growing hepatic tumor, with progressive destruction of the liver

and extension into vital structures. Clinical symptoms develop decades

after initial infection. Patients commonly report upper-quadrant and

epigastric pain. Liver enlargement and obstructive jaundice may be

apparent. The lesions may infiltrate adjoining organs (e.g., diaphragm,

kidneys, or lungs) or may metastasize to the spleen, lungs, or brain.

Diagnosis Radiographic and related imaging studies are important in detecting and evaluating echinococcal cysts. Plain x-rays will

define pulmonary cysts of E. granulosus—usually as rounded masses

of uniform density—but may miss cysts in other organs unless there is

cyst wall calcification (as occurs in the liver). MRI, CT, and ultrasound

reveal well-defined cysts with thick or thin walls. Imaging methods

may reveal a fluid layer of different density, termed hydatid sand, that

contains protoscolices. However, the most pathognomonic finding,

if demonstrable, is that of daughter cysts within the larger cyst. This

finding, like eggshell or mural calcification on CT, is indicative of E.

granulosus infection and helps to distinguish the cyst from carcinomas,

bacterial or amebic liver abscesses, or hemangiomas. In contrast, ultrasound or CT of alveolar hydatid cysts reveals indistinct solid masses

with central necrosis and plaquelike calcifications.

A specific diagnosis of cystic hydatid disease can be made by the

examination of aspirated fluids for protoscolices or hooklets, but diagnostic aspiration is not usually recommended because of the potential

risk of fluid leakage resulting in either dissemination of infection or

anaphylactic reactions. Serodiagnostic assays can be useful, although a

negative test does not exclude the diagnosis of echinococcosis. Cysts in

the liver elicit positive antibody responses in ~90% of cases, whereas up

to 50% of individuals with cysts in the lungs are seronegative. Detection of antibody to specific echinococcal antigens by immunoblotting

has the highest degree of specificity.

TREATMENT

Echinococcosis

Therapy for cystic echinococcosis is based on considerations of the

size, location, and manifestations of cysts and the overall health

of the patient. Surgery has traditionally been the principal definitive method of treatment. Currently, ultrasound staging is recommended for cystic echinococcosis (Fig. 235-2). Small CL, CE1,

and CE3 lesions may respond to chemotherapy with albendazole.

For CE1 lesions and uncomplicated CE3 lesions, PAIR (percutaneous aspiration, infusion of scolicidal agents, and reaspiration)

is now recommended instead of surgery. PAIR is contraindicated

for superficially located cysts (because of the risk of rupture) and

for cysts communicating with the biliary tree. For prophylaxis of

secondary peritoneal echinococcosis due to inadvertent spillage of

fluid during PAIR, the administration of albendazole (15 mg/kg daily

in two divided doses) should be initiated at least 2 days before the

procedure and continued for at least 4 weeks afterward. Ultrasoundor CT-guided aspiration allows confirmation of the diagnosis by

demonstration of protoscolices or hooks in the aspirate. After

aspiration, contrast material should be injected to detect occult

communications with the biliary tract. Alternatively, the fluid

should be checked for bile staining visually and by dipstick. If

no bile is found and no communication is visualized, the contrast material is reaspirated, with subsequent infusion of scolicidal

agents (usually 95% ethanol; alternatively, hypertonic saline). This

approach, when implemented by a skilled practitioner, yields rates

of cure and relapse equivalent to those following surgery, with less

perioperative morbidity and shorter hospitalization. In experienced

hands, some CE2 lesions can be treated by modified catheter

drainage. Daughter cysts within the primary cyst may need to be

punctured separately.

Surgery remains the treatment of choice for complicated cystic

echinococcosis (e.g., cysts communicating with the biliary tract),

for most thoracic and intracranial cysts, and for areas where PAIR

is not possible. For liver cysts, the preferred surgical approach is

total cystectomy, in which the entire cyst and the surrounding

fibrous tissue are removed. Recent studies demonstrate that many

cysts can be safely removed by laparoscopic or robotic surgery.

The risks posed by leakage of fluid during surgery or PAIR include

anaphylaxis and dissemination of infectious protoscolices. The latter complication has been minimized by careful attention to the

prevention of spillage of the cyst. Infusion of scolicidal agents is

no longer recommended because of problems with hypernatremia,

intoxication, or sclerosing cholangitis. Albendazole, which is active

against Echinococcus, should be administered adjunctively, beginning several days before resection of the liver and continuing for

several weeks for E. granulosus. Praziquantel (50 mg/kg daily for

2 weeks or weekly throughout the duration of albendazole) may

hasten the death of the protoscolices. Medical therapy with albendazole alone for 12 weeks to 6 months results in cure in ~30% of

cases and in improvement in another 50%. In many instances of

treatment failure, E. granulosus infections are subsequently treated

successfully with PAIR or additional courses of medical therapy.

Response to treatment is best assessed by serial imaging studies,

with attention to cyst size and consistency. Some cysts may not

demonstrate complete radiologic resolution even though no viable

protoscolices are present. Some of these cysts with partial radiologic

resolution (e.g., CE4 or CE5) can be managed with observation only.

Surgical resection remains the treatment of choice for E. multilocularis

infection. Complete removal of the parasite continues to offer the

best chance for cure. Ongoing therapy with albendazole for at least

2 years after presumptively curative surgery is recommended. Positron emission tomography can be used to follow disease activity.

Most cases are diagnosed at a stage at which complete resection

is not possible; in these cases, albendazole treatment should be

continued indefinitely, with careful monitoring. In some cases, liver

transplantation has been used because of the size of the necessary

liver resection. However, continuous immunosuppression favors

the proliferation of E. multilocularis larvae and reinfection of the

transplant. Thus, indefinite treatment with albendazole is required.

Prevention In endemic areas, echinococcosis can be prevented by

administering praziquantel to infected dogs, by denying dogs access to

viscera from infected animals, or by vaccinating sheep. Limiting the

number of stray dogs is helpful in reducing the prevalence of infection

among humans. In Europe, E. multilocularis infection has been associated with gardening; gloves should be used when working with soil.

Praziquantel-impregnated bait has also been used to treat tapeworms

in wild canines.

■ HYMENOLEPIASIS NANA

Infection with H. nana, the dwarf tapeworm, is the most common

of all the cestode infections. H. nana is endemic in both temperate

and tropical regions of the world. Infection is spread by fecal/oral

contamination.

Etiology and Pathogenesis H. nana is the only cestode of

humans that does not require an intermediate host. Both the larval

1795CHAPTER 235 Cestode Infections

Imaging of cystic echinococcosis

CE 1

Ultrasound CT scan MRI

CE 2

CE 3a

CE 3b

CE 4

CE 5

a

FIGURE 235-2 Management of cystic hydatid disease caused by Echinococcus granulosus should be based on viability of the parasite, which can be estimated from

radiographic appearance. Staging is done by imaging studies including ultrasound, CT, or MRI and includes lesions classified as active, transitional, and inactive. Active

cysts include types CL (with a cystic lesion and no visible cyst wall), CE1 (with a visible cyst wall and internal echoes [snowflake sign]), and CE2 (with a visible cyst

wall and internal septation). Transitional cysts may have detached laminar membranes (CE3a) or may be partially collapsed (CE3b). Inactive cysts include types CE4 (a

nonhomogeneous mass) and CE5 (a cyst with a thick calcified wall).

and adult phases of the life cycle take place in the same person. The

adult—the smallest tapeworm parasitizing humans—is ~2 cm long and

dwells in the proximal ileum. Proglottids, which are small and rarely

seen in the stool, release spherical eggs 30–44 μm in diameter, each of

which contains an oncosphere with six hooklets. The eggs are immediately infective and are unable to survive for >10 days in the external

environment. When the egg is ingested by a new host, the oncosphere

is freed and penetrates the intestinal villi, becoming a cysticercoid

larva. Larvae migrate back into the intestinal lumen, attach to the

mucosa, and mature into adult worms over 10–12 days. Eggs may also

hatch before passing into the stool, causing internal autoinfection with

increasing numbers of intestinal worms. Although the life span of adult

H. nana worms is only ~4–10 weeks, the autoinfection cycle perpetuates the infection.

Clinical Manifestations H. nana infection, even with many intestinal worms, is usually asymptomatic. Heavy infection may be associated with diarrhea, abdominal pain, and weight loss.

Diagnosis Infection is diagnosed by the finding of eggs in the stool.

TREATMENT

Hymenolepiasis Nana

Praziquantel (25 mg/kg once) is the treatment of choice because

it acts against both the adult worms and the cysticercoids in the

intestinal villi. Nitazoxanide (500 mg bid for 3 days) may be used

as an alternative.

Prevention Good personal hygiene and improved sanitation can

eradicate the disease. Epidemics have been controlled by mass chemotherapy coupled with improved hygiene.

■ HYMENOLEPIASIS DIMINUTA

Hymenolepis diminuta, a cestode of rodents, occasionally infects small

children, who ingest the larvae in uncooked cereal foods contaminated

by fleas and other insects in which larvae develop. Infection is usually

asymptomatic and is diagnosed by the detection of eggs in the stool.

Treatment with praziquantel results in cure in most cases.

1796 PART 5 Infectious Diseases

■ DIPHYLLOBOTHRIASIS

Dibothriocephalus latus (formerly Diphyllobothrium latum) and other

diphyllobothriid species (including Adenocephlus pacificus and Dibothriocephalus nihonkaiensis) are found in the lakes, rivers, and deltas of

the Northern Hemisphere, central Africa, and South America.

Etiology and Pathogenesis The adult worm—the longest tapeworm (up to 25 m)—attaches to the ileal and occasionally to the jejunal

mucosa by its suckers, which are located on its elongated scolex. The

adult worm has 3000–4000 proglottids, which release ~1 million eggs

daily into the feces. If an egg reaches water, it hatches and releases a

free-swimming embryo that can be eaten by small freshwater crustaceans (Cyclops or Diaptomus species). After an infected crustacean

containing a developed procercoid is swallowed by a fish, the larva

migrates into the fish’s flesh and grows into a sparganum, or plerocercoid larva. Humans acquire the infection by ingesting infected raw or

smoked fish. Within 3–5 weeks, the tapeworm matures into an adult in

the human intestine.

Clinical Manifestations Most Diphyllobothrium infections are

asymptomatic, although manifestations may include transient abdominal discomfort, diarrhea, vomiting, weakness, and weight loss. Occasionally, infection can cause acute abdominal pain and intestinal

obstruction; in rare cases, cholangitis or cholecystitis may be produced

by migrating proglottids.

Because the D. latum tapeworm absorbs large quantities of

vitamin B12 and interferes with ileal B12 absorption, vitamin B12 deficiency can develop that uncommonly causes a megaloblastic anemia

resembling pernicious anemia and may result in neurologic sequelae.

Diagnosis The diagnosis is made readily by the detection of the

characteristic eggs in the stool. The eggs possess a single shell with

an operculum at one end and a knob at the other. Mild to moderate

eosinophilia may be detected.

TREATMENT

Diphyllobothriasis

Praziquantel (5–10 mg/kg once) is highly effective. Parenteral

vitamin B12 should be given if B12 deficiency is manifest.

Prevention Infection can be prevented by heating fish to 54°C for

5 min or by freezing it at –18°C for 24 h. Placing fish in brine with a

high salt concentration for long periods kills the eggs.

■ DIPYLIDIASIS

Dipylidium caninum, a common tapeworm of dogs and cats, may

accidentally infect humans. Dogs, cats, and occasionally humans

become infected by ingesting fleas harboring cysticercoids. Children

are more likely to become infected than adults. Most infections are

asymptomatic, but passage of segments in the stool or vague abdominal symptoms may occur. The diagnosis is made by the detection of

proglottids or ova in the stool. As in D. latus infection, therapy consists

of praziquantel. Prevention requires anthelminthic treatment and flea

control for pet dogs or cats.

■ SPARGANOSIS

Humans can be infected by the sparganum, or plerocercoid larva, of a

diphyllobothriid tapeworm of the genus Spirometra. Infection can be

acquired by the consumption of water containing infected Cyclops; by

the ingestion of infected snakes, birds, or mammals; or by the application of infected flesh as poultices. The worm migrates slowly in tissues,

and infection commonly presents as a subcutaneous swelling. Periorbital tissues can be involved, and ocular sparganosis may destroy the

eye. Surgical excision is used to treat localized sparganosis.

■ COENUROSIS

This rare infection of humans by the larval stage (coenurus) of the

dog tapeworm Taenia multiceps or T. serialis results in a spaceoccupying cystic lesion. As in cysticercosis, involvement of the CNS

and subcutaneous tissue is most common. Both definitive diagnosis

and treatment require surgical excision of the lesion. Chemotherapeutic agents generally are not effective.

■ FURTHER READING

Brunetti E et al: Expert consensus for the diagnosis and treatment of

cystic and alveolar echinococcosis in humans. Acta Trop 114:1, 2010.

Del Brutto OH et al: Revised diagnostic criteria for neurocysticercosis. J Neurol Sci 372:202, 2017.

Kern P et al: The echinococcoses: Diagnosis, clinical management and

burden of disease. Adv Parasitol 96:259, 2017.

Nash TE et al: Natural history of treated subarachnoid neurocysticercosis. Am J Trop Med Hyg 102:78, 2020.

Scholz T et al: Update on the human broad tapeworm (genus Diphyllobothrium), including clinical relevance. Clin Microbiol Rev 22:146,

2009.

Wen H et al: Echinococcosis: Advances in the 21st century. Clin

Microbiol Rev 32:e00075, 2019.

White AC Jr et al: Diagnosis and treatment of neurocysticercosis:

2017 clinical practice guidelines by the Infectious Diseases Society of

America (IDSA) and the American Society of Tropical Medicine and

Hygiene (ASTMH). Clin Infect Dis 66:1159, 2018.

Section 1 Introduction to Cardiovascular

Disorders

Disorders of the Cardiovascular System PART 6

236 Approach to the

Patient with Possible

Cardiovascular Disease

Joseph Loscalzo

■ THE MAGNITUDE OF THE PROBLEM

Cardiovascular diseases comprise the most prevalent serious disorders in industrialized nations and are a rapidly growing problem in

developing nations (Chap. 238). Age-adjusted death rates for coronary

heart disease have declined by two-thirds in the past four decades in

the United States, reflecting the identification and reduction of risk

factors as well as improved treatments and interventions for the management of coronary artery disease, arrhythmias, and heart failure.

Nonetheless, cardiovascular diseases remain the most common causes of

death, responsible for one-third of all deaths, >800,000 deaths each year.

Approximately one-fourth of these deaths are sudden. In addition, cardiovascular diseases are highly prevalent, diagnosed in nearly half of the

adult population. The growing prevalence of obesity (Chap. 402), type 2

diabetes mellitus (Chap. 403), and metabolic syndrome (Chap. 408),

which are important risk factors for atherosclerosis, now threatens to

reverse the progress that has been made in the age-adjusted reduction

in the mortality rate of coronary heart disease.

For many years, cardiovascular disease was considered to be more

common in men than in women. In fact, cardiovascular disease is the

leading cause of all deaths among women and men (Chap. 398). In

addition, although the absolute number of deaths secondary to cardiovascular disease has declined over the past decades in men, this number has actually risen in women. Inflammation, obesity, type 2 diabetes

mellitus, and the metabolic syndrome appear to play more prominent

roles in the development of coronary atherosclerosis in women than

in men. Coronary artery disease (CAD) is more frequently associated

with dysfunction of the coronary microcirculation in women than in

men. Exercise electrocardiography has a lower diagnostic accuracy in

the prediction of epicardial obstruction in women than in men.

■ NATURAL HISTORY

Cardiovascular disorders often present acutely, as in a previously asymptomatic person who develops an acute myocardial infarction (Chap. 275),

or a previously asymptomatic patient with hypertrophic cardiomyopathy

(Chap. 259) or with a prolonged QT interval (Chap. 252) whose first

clinical manifestation is syncope or even sudden death. However, the

alert physician may recognize the patient at risk for these complications

long before they occur and often can take measures to prevent their

occurrence. For example, a patient with acute myocardial infarction

will often have had risk factors for atherosclerosis for many years.

Had these risk factors been recognized, their elimination or reduction might have delayed or even prevented the infarction. Similarly,

a patient with hypertrophic cardiomyopathy may have had a heart

murmur for years and a family history of this disorder. These findings

could have led to an echocardiographic examination, recognition of

the condition, and appropriate therapy long before the occurrence of a

serious acute manifestation.

Patients with valvular heart disease or idiopathic dilated cardiomyopathy, by contrast, may have a prolonged course of gradually increasing

dyspnea and other manifestations of chronic heart failure that is punctuated by episodes of acute deterioration only late in the course of the

disease. Understanding the natural history of various cardiac disorders

is essential for applying appropriate diagnostic and therapeutic measures to each stage of the condition, as well as for providing the patient

and family with the likely prognosis.

■ CARDIAC SYMPTOMS

The symptoms caused by heart disease result most commonly from

myocardial ischemia, disturbance of the contraction and/or relaxation

of the myocardium, obstruction to blood flow, or an abnormal cardiac

rhythm or rate. Ischemia, which is caused by an imbalance between

the heart’s oxygen supply and demand, is manifest most frequently

as chest discomfort (Chap. 14), whereas reduction of the pumping

ability of the heart commonly leads to fatigue and elevated intravascular pressure upstream of the failing ventricle. The latter results in

abnormal fluid accumulation, with peripheral edema (Chap. 41) or

pulmonary congestion and dyspnea (Chap. 37). Obstruction to blood

flow, as occurs in valvular stenosis, can cause symptoms resembling

those of myocardial failure (Chap. 257). Cardiac arrhythmias often

develop suddenly, and the resulting symptoms and signs—palpitations

(Chap. 43), dyspnea, hypotension, and syncope (Chap. 21)—generally

occur abruptly and may disappear as rapidly as they develop.

Although dyspnea, chest discomfort, edema, and syncope are cardinal manifestations of cardiac disease, they occur in other conditions as

well. Thus, dyspnea is observed in disorders as diverse as pulmonary

disease, marked obesity, and anxiety (Chap. 37). Similarly, chest discomfort may result from a variety of noncardiac and cardiac causes

other than myocardial ischemia (Chap. 14). Edema, an important

finding in untreated or inadequately treated heart failure, also may

occur with primary renal disease and in hepatic cirrhosis (Chap. 41).

Syncope occurs not only with serious cardiac arrhythmias but in a

number of neurologic conditions as well (Chap. 21). Whether heart

disease is responsible for these symptoms frequently can be determined

by carrying out a careful clinical examination (Chap. 239), supplemented by noninvasive testing using electrocardiography at rest and

during exercise (Chap. 240), echocardiography, roentgenography, and

other forms of myocardial imaging (Chap. 241).

Myocardial or coronary function that may be adequate at rest may

be insufficient during exertion. Thus, dyspnea and/or chest discomfort that appear during activity are characteristic of patients with

heart disease, whereas the opposite pattern, that is, the appearance of

these symptoms at rest and their remission during exertion, is rarely

observed in such patients. It is important, therefore, to question the

patient carefully about the relation of symptoms to exertion.

Many patients with cardiovascular disease may be asymptomatic

both at rest and during exertion but may present with an abnormal

physical finding such as a heart murmur, elevated arterial pressure,

or an abnormality of the electrocardiogram (ECG) or imaging test. It

is important to assess the global risk of CAD in asymptomatic individuals, using a combination of clinical assessment and measurement

of cholesterol and its fractions, as well as other biomarkers, such as

C-reactive protein, in some patients. Since the first clinical manifestation of CAD may be catastrophic—sudden cardiac death, acute

myocardial infarction, or stroke in previous asymptomatic persons—it

is mandatory to identify those at high risk of such events and institute

further testing and preventive measures.

■ DIAGNOSIS

As outlined by the New York Heart Association (NYHA), the elements

of a complete cardiac diagnosis include the systematic consideration

of the following:

1. The underlying etiology. Is the disease congenital, hypertensive,

ischemic, or inflammatory in origin?

2. The anatomic abnormalities. Which chambers are involved? Are

they hypertrophied, dilated, or both? Which valves are affected? Are

they regurgitant and/or stenotic? Is there pericardial involvement?

Has there been a myocardial infarction?

1798 PART 6 Disorders of the Cardiovascular System

3. The physiologic disturbances. Is an arrhythmia present? Is there evidence of congestive heart failure or myocardial ischemia?

4. Functional disability. How strenuous is the physical activity required

to elicit symptoms? The classification provided by the NYHA has been

found to be useful in describing functional disability (Table 236-1).

One example may serve to illustrate the importance of establishing

a complete diagnosis. In a patient who presents with exertional chest

discomfort, the identification of myocardial ischemia as the etiology

is of great clinical importance. However, the simple recognition of

ischemia is insufficient to formulate a therapeutic strategy or prognosis until the underlying anatomic abnormalities responsible for the

myocardial ischemia, for example, coronary atherosclerosis or aortic

stenosis, are identified and a judgment is made about whether other

physiologic disturbances that cause an imbalance between myocardial

oxygen supply and demand, such as severe anemia, thyrotoxicosis,

or supraventricular tachycardia, play contributory roles. Finally, the

severity of the disability should govern the extent and tempo of the

workup and strongly influence the therapeutic strategy that is selected.

The establishment of a correct and complete cardiac diagnosis usually

commences with the history and physical examination (Chap. 239).

Indeed, the clinical examination remains the basis for the diagnosis of a

wide variety of disorders. The clinical examination may then be supplemented by five types of laboratory tests: (1) ECG (Chap. 240); (2) noninvasive imaging examinations (chest roentgenogram, echocardiogram,

radionuclide imaging, computed tomographic imaging, positron emission tomography, and magnetic resonance imaging) (Chap. 241); (3)

blood tests to assess risk (e.g., lipid determinations, C-reactive protein)

or cardiac function (e.g., brain natriuretic peptide [BNP] [Chap. 257]);

(4) occasionally, specialized invasive examinations (i.e., cardiac catheterization and coronary arteriography [Chap. 242]); and (5) genetic tests to

identify monogenic cardiac diseases (e.g., hypertrophic cardiomyopathy

[Chap. 259], Marfan’s syndrome [Chap. 413], and abnormalities of cardiac ion channels that lead to prolongation of the QT interval and an

increase in the risk of sudden death [Chap. 246]). These genetic tests

are becoming more widely available.

■ FAMILY HISTORY

In eliciting the history of a patient with known or suspected cardiovascular disease, particular attention should be directed to the family history.

Familial clustering is common in many forms of heart disease. Mendelian

transmission of single-gene defects may occur, as in hypertrophic cardiomyopathy (Chap. 259), Marfan’s syndrome (Chap. 413), and sudden

death associated with a prolonged QT syndrome (Chap. 252). Premature

coronary disease and essential hypertension, type 2 diabetes mellitus,

and hyperlipidemia (the most important risk factors for CAD) are

usually polygenic disorders. Although familial transmission may be

less obvious than in the monogenic disorders, it is helpful in assessing

risk and prognosis in polygenic disorders, as well. Familial clustering of

cardiovascular diseases not only may occur on a genetic basis but also

may be related to familial dietary or behavior patterns, such as excessive ingestion of salt or calories and cigarette smoking.

■ ASSESSMENT OF FUNCTIONAL IMPAIRMENT

When an attempt is made to determine the severity of functional

impairment in a patient with heart disease, it is helpful to ascertain the

level of activity and the rate at which it is performed before symptoms

develop. Thus, it is not sufficient to state that the patient complains

of dyspnea. The breathlessness that occurs after running up two long

flights of stairs denotes far less functional impairment than do similar symptoms that occur after taking a few steps on level ground. In

addition, the degree of customary physical activity at work and during recreation should be considered. The development of two-flight

dyspnea in a well-conditioned marathon runner may be far more

significant than the development of one-flight dyspnea in a previously

sedentary person. The history should include a detailed consideration

of the patient’s therapeutic regimen. For example, the persistence or

development of edema, breathlessness, and other manifestations of

heart failure in a patient who is receiving optimal doses of diuretics and

other therapies for heart failure (Chap. 257) is far graver than are similar manifestations in the absence of treatment. Similarly, the presence

of angina pectoris despite treatment with optimal doses of multiple

antianginal drugs (Chap. 273) is more serious than it is in a patient on

no therapy. In an effort to determine the progression of symptoms, and

thus the severity of the underlying illness, it may be useful to ascertain

what, if any, specific tasks the patient could have carried out 6 months

or 1 year earlier that he or she cannot perform at present.

■ ELECTROCARDIOGRAM

(See also Chap. 240) Although an ECG usually should be recorded in

patients with known or suspected heart disease, with the exception of

the identification of arrhythmias, conduction abnormalities, ventricular hypertrophy, and acute myocardial infarction, it generally does

not establish a specific diagnosis. The range of normal electrocardiographic findings is wide, and the tracing can be affected significantly

by many noncardiac factors, such as age, body habitus, and serum

electrolyte concentrations. In general, electrocardiographic changes

should be interpreted in the context of other abnormal cardiovascular

findings.

■ ASSESSMENT OF THE PATIENT WITH A HEART

MURMUR

(Fig. 236-1) The cause of a heart murmur can often be readily elucidated from a systematic evaluation of its major attributes: timing,

duration, intensity, quality, frequency, configuration, location, and

radiation when considered in the light of the history, general physical examination, and other features of the cardiac examination, as

described in Chap. 239.

PRESENCE OF CARDIAC MURMUR

Systolic Murmur Diastolic or

Continuous Murmur

Grade I + II

and midsystolic

Grade III or >,

holosystolic,

or late systolic

Other signs or

symptoms of

cardiac disease

No further

workup

Normal ECG and

chest X-ray

Abnormal ECG

or chest X-ray

Asymptomatic and

no associated findings

Echocardiography

Cardiac consult

if appropriate

FIGURE 236-1 Approach to the evaluation of a heart murmur. ECG,

electrocardiogram. (Reproduced with permission from E Braunwald, L Goldman

(eds): Primary Cardiology, 2nd ed. Philadelphia, Saunders, 2003.)

TABLE 236-1 New York Heart Association Functional Classification

Class I Class III

No limitation of physical activity Marked limitation of physical activity

 No symptoms with ordinary

exertion

 Less than ordinary activity causes

symptoms

Class II Asymptomatic at rest

Slight limitation of physical activity Class IV

Ordinary activity causes symptoms Inability to carry out any physical

activity without discomfort

Symptoms at rest

Source: Data from The Criteria Committee of the New York Heart Association.

Basic Biology of the Cardiovascular System

1799CHAPTER 237

The majority of heart murmurs are midsystolic and soft (grades I–

II/VI). When such a murmur occurs in an asymptomatic child or young

adult without other evidence of heart disease on clinical examination,

it is usually benign and echocardiography generally is not required. By

contrast, two-dimensional and Doppler echocardiography (Chap. 241)

are indicated in patients with loud systolic murmurs (grades ≥III/

VI), especially those that are holosystolic or late systolic, and in most

patients with diastolic or continuous murmurs.

■ PITFALLS IN CARDIOVASCULAR MEDICINE

Increasing subspecialization in internal medicine and the perfection

of advanced diagnostic techniques in cardiology can lead to several

undesirable consequences. Examples include the following:

1. Failure by the noncardiologist to recognize important cardiac manifestations of systemic illnesses. For example, the presence of mitral

stenosis, patent foramen ovale, and/or transient atrial arrhythmia

should be considered in a patient with stroke, or the presence of

pulmonary hypertension and cor pulmonale should be considered

in a patient with scleroderma or Raynaud’s syndrome. A cardiovascular examination should be carried out to identify and estimate the

severity of the cardiovascular involvement that accompanies many

noncardiac disorders.

2. Failure by the cardiologist to recognize underlying systemic disorders in patients with heart disease. For example, hyperthyroidism

should be considered in an elderly patient with atrial fibrillation and

unexplained heart failure, and Lyme disease should be considered

in a patient with unexplained fluctuating atrioventricular block. A

cardiovascular abnormality may provide the clue critical to the recognition of some systemic disorders. For example, an unexplained

pericardial effusion may provide an early clue to the diagnosis of

tuberculosis or a neoplasm.

3. Overreliance on and overutilization of laboratory tests, particularly invasive techniques, for the evaluation of the cardiovascular system. Cardiac catheterization and coronary arteriography

(Chap. 242) provide precise diagnostic information that may be

crucial in developing a therapeutic plan in patients with known or

suspected CAD. Although a great deal of attention has been directed

to these examinations, it is important to recognize that they serve

to supplement, not supplant, a careful examination carried out

with clinical and noninvasive techniques. A coronary arteriogram

should not be performed in lieu of a careful history in patients with

chest pain suspected of having ischemic heart disease. Although

coronary arteriography may establish whether the coronary arteries

are obstructed and to what extent, the results of the procedure by

themselves often do not provide a definitive answer to the question

of whether a patient’s complaint of chest discomfort is attributable

to coronary atherosclerosis and whether or not revascularization is

indicated.

Despite the value of invasive tests in certain circumstances, they

entail some small risk to the patient, involve discomfort and substantial

cost, and place a strain on medical facilities. Therefore, they should be

carried out only if the results can be expected to modify the patient’s

management.

■ DISEASE PREVENTION AND MANAGEMENT

The prevention of heart disease, especially of CAD, is one of the most

important tasks of primary health care givers as well as cardiologists.

Prevention begins with risk assessment, followed by attention to lifestyle,

such as achieving optimal weight, physical activity, and smoking cessation, and then aggressive treatment of all abnormal risk factors, such as

hypertension, hyperlipidemia, and diabetes mellitus (Chap. 403).

After a complete diagnosis has been established in patients with

known heart disease, a number of management options are usually

available. Several examples may be used to demonstrate some of the

principles of cardiovascular therapeutics:

1. In the absence of evidence of heart disease, the patient should be

clearly informed of this assessment and not be asked to return at

intervals for repeated examinations. If there is no evidence of disease, such continued attention may lead to the patient’s developing

inappropriate concern about the possibility of heart disease.

2. If there is no evidence of cardiovascular disease but the patient has

one or more risk factors for the development of ischemic heart disease (Chap. 273), a plan for their reduction should be developed and

the patient should be retested at intervals to assess compliance and

efficacy in risk reduction.

3. Asymptomatic or mildly symptomatic patients with valvular heart

disease that is anatomically severe should be evaluated periodically,

every 6–12 months, by clinical and noninvasive examinations. Early

signs of deterioration of ventricular function may signify the need

for surgical treatment before the development of disabling symptoms, irreversible myocardial damage, and excessive risk of surgical

treatment (Chap. 261).

4. In patients with CAD (Chap. 273), available practice guidelines

should be considered in the decision on the form of treatment (medical, percutaneous coronary intervention, or surgical revascularization). Mechanical revascularization may be employed too frequently

in the United States and too infrequently in Eastern Europe and

developing nations. The mere presence of angina pectoris and/or the

demonstration of critical coronary arterial narrowing at angiography

should not reflexively evoke a decision to treat the patient by revascularization. Instead, these interventions should be limited to patients

with CAD whose angina has not responded adequately to medical

treatment or in whom revascularization has been shown to improve

the natural history (e.g., acute coronary syndrome or multivessel

CAD with left ventricular dysfunction).

■ FURTHER READING

Benjamin EJ et al: Heart disease and stroke statistics – 2019 update:

A report from the American Heart Association. Circulation 139:e56,

2019.

DEVELOPMENTAL BIOLOGY OF THE

CARDIOVASCULAR SYSTEM

The heart forms early during embryogenesis (Fig. 237-1), circulating

blood, nutrients, molecular signals, and oxygen to the other developing

organs while continuing to grow and undergo complex morphogenetic

changes. Early cardiac progenitors arise within crescent-shaped fields

of lateral splanchnic mesoderm under the influence of multiple cues

and migrate to the midline to form the linear heart tube: a single layer

of endocardium and a single layer of primitive beating cardiomyocytes.

The linear heart tube undergoes chamber specification and asymmetric looping, coordinated with linear and concentric growth of different regions of the heart tube, to produce the presumptive atria and

ventricles. Cells continue to migrate into the heart at both ends from

later, or second, heart fields in adjacent pharyngeal mesoderm as looping and growth occur. These cells exhibit distinctive gene expression

(e.g., Islet-1) and distinctive physiology (e.g., calcium handling), contributing to discrete areas of the adult heart, including the right atrium

and the right ventricle. Different embryonic origins of cells within the

right and left ventricles help explain why some forms of congenital and

adult heart diseases affect discrete regions of the heart.

237 Basic Biology of the

Cardiovascular System

Joseph Loscalzo, John F. Keaney, Jr.,

Calum A. MacRae

1800 PART 6 Disorders of the Cardiovascular System

and folic acid, and congenital heart disease involving abnormal remodeling of

the aortic arch arteries is observed with

maternal deficiencies of these vitamins.

The shared embryonic origins of different cardiovascular cell types lead to

syndromic associations between various

congenital heart diseases and a range of

extracardiac abnormalities.

Coronary artery formation requires

the addition of yet another cell population to the embryonic heart. Epicardial

cells arise in the proepicardial organ, a

derivative of the septum transversum,

which also contributes to the fibrous

portion of the diaphragm and to the liver.

Proepicardial cells contribute smooth

muscle to the coronary arteries and are

required for proper coronary patterning. Other cell types within the heart

(e.g., fibroblasts) also can arise from the

proepicardium.

The cardiac conduction system,

which generates and propagates electrical impulses, differentiates from cardiomyocyte precursors. The conduction

system is composed of slow-conducting

(proximal) components, such as the

sinoatrial (SA) and atrioventricular (AV)

nodes, as well as fast-conducting (distal)

components, including the His bundle,

bundle branches, and Purkinje fibers.

Precursors within the sinus venosus

give rise to the SA node, whereas those

within the AV canal mature into heterogeneous cell types that compose the AV

node. So-called decremental conduction

through the AV node delays the electrical

impulses between atria and ventricles,

whereas the distal conduction system

rapidly delivers the impulse throughout

the ventricles. Each compartment within

the conduction system expresses distinct

gap junction proteins and ion channels

that characterize the discrete cell fates

and electrical properties. Developmental

defects in the conduction system can lead to clinical electrophysiologic

disorders, such as congenital heart block or pre-excitation (WolffParkinson-White syndrome) (Chap. 246).

■ ORIGIN OF VASCULAR CELLS

Smooth-muscle cells are of varied origin. Some upper-body arterial

smooth-muscle cells derive from the neural crest, whereas lower-body

arteries develop smooth-muscle cells from neighboring mesodermal

structures. Bone marrow–derived endothelial progenitors may aid

repair of damaged or aging arteries. With the latter, bone marrow clonality, increasingly prevalent in aging, may impart significant clonality

into endothelial cell populations. Vascular stem cells resident in vessel

walls may give rise to some smooth-muscle cells in injured or atheromatous arteries (Chaps. 96 and 484).

THE BLOOD VESSEL

■ VASCULAR ULTRASTRUCTURE

Blood vessels participate in physiologic function as well as disease

biology in virtually every organ system. The smallest blood vessels—

capillaries—consist of a monolayer of endothelial cells on a basement

membrane, adjacent to a discontinuous layer of smooth-muscle-like

Early heart-forming Neural folds

regions

Second heart field

RA

RV

RV

LV LV

LA

First heart field

Pericardial

coelom

Foregut Forming heart

A B

C D E

F

FIGURE 237-1 A. Schematic depiction of a transverse section through an early embryo depicts the bilateral regions

where early heart tubes form. B. The bilateral heart tubes subsequently migrate to the midline and fuse to form the

linear heart tube. C. At the early cardiac crescent stage of embryonic development, cardiac precursors include

a primary heart field fated to form the linear heart tube and a second heart field fated to add myocardium to the

inflow and outflow poles of the heart. D. Second heart field cells populate the pharyngeal region before subsequently

migrating to the maturing heart. E. Large portions of the right ventricle and outflow tract and some cells within the atria

derive from the second heart field. F. The aortic arch arteries form as symmetric sets of vessels that then remodel

under the influence of the neural crest to form the asymmetric mature vasculature. LA, left atrium; LV, left ventricle; RA,

right atrium; RV, right ventricle.

After looping and chamber formation, a series of morphogenetic

events divide the left and right sides of the heart, separate the atria

from the ventricles, and fashion the aorta and pulmonary artery from

the truncus arteriosus. Cardiac valves form between the atria and the

ventricles and between the ventricles and the outflow vessels. Early

in development, myocardial cells secrete an extracellular matrix rich

in hyaluronic acid, or “cardiac jelly,” which accumulates within the

endocardial cushions, precursors of the cardiac valves. Signals from

overlying myocardial cells trigger migration, invasion, and phenotypic

changes in underlying endocardial cells, which undergo an epithelialmesenchymal transformation to invade and populate the endocardial

cushion matrix with cells. Mesenchymal cells then proliferate and form

the mature valve leaflets.

The great vessels form as a series of bilaterally symmetric aortic

arch arteries that remodel asymmetrically to define the mature central

vasculature. Migrating neural crest cells from the dorsal neural tube

orchestrate this process and are necessary for aortic arch remodeling

and the septation of the truncus arteriosus. The smooth-muscle cells

within the tunica media of the aortic arch, the ductus arteriosus, and

the carotid arteries all derive from neural crest. By contrast, smoothmuscle within the descending aorta arises from lateral plate mesoderm,

and smooth-muscle of the proximal outflow tract arises from the

second heart field. Neural crest cells are sensitive to both vitamin A