Anatomy and Function
The appendix first becomes visible in the eighth week of
embryologic development as a protuberance off the terminal portion of the cecum.
During both antenatal and postnatal development, the growth rate of the cecum
exceeds that of the appendix, so that the appendix is displaced medially toward
the ileocecal valve. The relationship of the base of the appendix to the cecum
remains constant, whereas the tip can be found in a retrocecal, pelvic,
subcecal, preileal, or right pericolic position. These anatomic
considerations have significant clinical importance in the context of acute
appendicitis. The three taeniae coli converge at the junction of the cecum with
the appendix and can be a useful landmark to identify the appendix. The appendix
can vary in length from <1 cm to >30 cm; most appendices are 6 to 9 cm
long. Appendiceal absence, duplication, and diverticula have all been
described.1–4
For many years, the appendix was erroneously viewed as a
vestigial organ with no known function. It is now well recognized that the
appendix is an immunologic organ that actively participates in the secretion of
immunoglobulins, particularly immunoglobulin A. Although there is no clear role
for the appendix in the development of human disease, recent studies demonstrate
a potential correlation between appendectomy and the development of inflammatory
bowel disease. There appears to be a negative age-related association between
prior appendectomy and subsequent development of ulcerative colitis. In
addition, comparative analysis clearly shows that prior appendectomy is
associated with a more benign phenotype in ulcerative colitis and a delay in
onset of disease. The association between Crohn's disease and appendectomy is
less clear. Although earlier studies suggested that appendectomy increases the
risk of developing Crohn's disease, more recent studies that carefully assessed
the timing of appendectomy in relation to the onset of Crohn's disease
demonstrated a negative correlation. These data suggest that appendectomy may
protect against the subsequent development of inflammatory bowel disease;
however, the mechanism is unclear.
Lymphoid tissue first appears in the appendix approximately
2 weeks after birth. The amount of lymphoid tissue increases throughout puberty,
remains steady for the next decade, and then begins a steady decrease with age.
After the age of 60 years, virtually no lymphoid tissue remains within the
appendix, and complete obliteration of the appendiceal lumen is common
Acute Appendicitis
Historical Background
Although ancient texts have scattered descriptions of
surgery being undertaken for ailments sounding like appendicitis, credit for
performing the first appendectomy goes to Claudius Amyand, a surgeon at St.
George's Hospital in London and Sergeant Surgeon to Queen Ann, King George I,
and King George II. In 1736, he operated on an 11-year-old boy with a scrotal
hernia and a fecal fistula. Within the hernial sac, Amyand found the appendix
perforated by a pin. He successfully removed the appendix and repaired the
hernia.5
The appendix was not identified as an organ capable of
causing disease until the nineteenth century. In 1824, Louyer-Villermay
presented a paper before the Royal Academy of Medicine in Paris. He reported on
two autopsy cases of appendicitis and emphasized the importance of the
condition. In 1827, François Melier, a French physician, expounded on
Louyer-Villermay's work. He reported six autopsy cases and was the first to
suggest the antemortem recognition of appendicitis.5 This work was
discounted by many physicians of the era, including Baron Guillaume Dupuytren.
Dupuytren believed that inflammation of the cecum was the main cause of
pathology of the right lower quadrant. The term typhlitis or
perityphlitis was used to describe right lower quadrant inflammation. In
1839, a textbook authored by Bright and Addison entitled Elements of
Practical Medicine described the symptoms of appendicitis and identified the
primary cause of inflammatory processes of the right lower quadrant.6
Reginald Fitz, a professor of pathologic anatomy at Harvard, is credited with
coining the term appendicitis. His landmark paper definitively identified
the appendix as the primary cause of right lower quadrant
inflammation.7
Initial surgical therapy for appendicitis was primarily
designed to drain right lower quadrant abscesses that occurred secondary to
appendiceal perforation. It appears that the first surgical treatment for
appendicitis or perityphlitis without abscess was carried out by Hancock in
1848. He incised the peritoneum and drained the right lower quadrant without
removing the appendix. The first published account of appendectomy for
appendicitis was by Krönlein in 1886. However, this patient died 2 days after
operation. Fergus, in Canada, performed the first elective appendectomy in
1883.5
The greatest contributor to the advancement in the
treatment of appendicitis was Charles McBurney. In 1889, he published his
landmark paper in the New York State Medical Journal describing the
indications for early laparotomy for the treatment of appendicitis. It is in
this paper that he described the McBurney point as follows: "maximum tenderness,
when one examines with the fingertips is, in adults, one half to two inches
inside the right anterior spinous process of the ilium on a line drawn to the
umbilicus."8 McBurney subsequently published a paper in 1894
describing the incision that bears his name.9 However, McBurney later
credited McArthur with first describing this incision. Semm is widely credited
with performing the first successful laparoscopic appendectomy in
1982.10
The surgical treatment of appendicitis is one of the great
public health advances of the last 150 years. Appendectomy for appendicitis is
the most commonly performed emergency operation in the world. Appendicitis is a
disease of the young, with 40% of cases occurring in patients between the ages
of 10 and 29 years.11 In 1886, Fitz reported the associated mortality
rate of appendicitis to be at least 67% without surgical therapy.7
Currently, the mortality rate for acute appendicitis with treatment is reported
to be <1%.
Incidence
The lifetime rate of appendectomy is 12% for men and 25%
for women, with approximately 7% of all people undergoing appendectomy for acute
appendicitis during their lifetime. Over the 10-year period from 1987 to 1997,
the overall appendectomy rate decreased in parallel with a decrease in
incidental appendectomy.11,13 However, the rate of appendectomy for
appendicitis has remained constant at 10 per 10,000 patients per
year.14 Appendicitis is most frequently seen in patients in their
second through fourth decades of life, with a mean age of 31.3 years and a
median age of 22 years. There is a slight male:female predominance (1.2 to
1.3:1).
Despite the increased use of ultrasonography, computed tomography (CT), and
laparoscopy, the rate of misdiagnosis of appendicitis has remained constant
(15.3%), as has the rate of appendiceal rupture. The percentage of misdiagnosed
cases of appendicitis is significantly higher among women than among men (22.2
vs. 9.3%). The negative appendectomy rate for women of reproductive age is
23.2%, with the highest rates in women aged 40 to 49 years. The highest negative
appendectomy rate is reported for women >80 years of age
Etiology and Pathogenesis
Obstruction of the lumen is the dominant etiologic factor
in acute appendicitis. Fecaliths are the most common cause of appendiceal
obstruction. Less common causes are hypertrophy of lymphoid tissue, inspissated
barium from previous x-ray studies, tumors, vegetable and fruit seeds, and
intestinal parasites. The frequency of obstruction rises with the severity of
the inflammatory process. Fecaliths are found in 40% of cases of simple acute
appendicitis, in 65% of cases of gangrenous appendicitis without rupture, and in
nearly 90% of cases of gangrenous appendicitis with rupture.
Traditionally the belief has been that there is a
predictable sequence of events leading to eventual appendiceal rupture. The
proximal obstruction of the appendiceal lumen produces a closed-loop
obstruction, and continuing normal secretion by the appendiceal mucosa rapidly
produces distention. The luminal capacity of the normal appendix is only 0.1 mL.
Secretion of as little as 0.5 mL of fluid distal to an obstruction raises the
intraluminal pressure to 60 cm H2O. Distention of the appendix
stimulates the nerve endings of visceral afferent stretch fibers, producing
vague, dull, diffuse pain in the midabdomen or lower epigastrium. Peristalsis
also is stimulated by the rather sudden distention, so that some cramping may be
superimposed on the visceral pain early in the course of appendicitis.
Distention increases from continued mucosal secretion and from rapid
multiplication of the resident bacteria of the appendix. Distention of this
magnitude usually causes reflex nausea and vomiting, and the diffuse visceral
pain becomes more severe. As pressure in the organ increases, venous pressure is
exceeded. Capillaries and venules are occluded, but arteriolar inflow continues,
resulting in engorgement and vascular congestion. The inflammatory process soon
involves the serosa of the appendix and in turn parietal peritoneum in the
region, which produces the characteristic shift in pain to the right lower
quadrant.
The mucosa of the GI tract, including the appendix, is
susceptible to impairment of blood supply; thus its integrity is compromised
early in the process, which allows bacterial invasion. As progressive distention
encroaches on first the venous return and subsequently the arteriolar inflow,
the area with the poorest blood supply suffers most: ellipsoidal infarcts
develop in the antimesenteric border. As distention, bacterial invasion,
compromise of vascular supply, and infarction progress, perforation occurs,
usually through one of the infarcted areas on the antimesenteric border.
Perforation generally occurs just beyond the point of obstruction rather than at
the tip because of the effect of diameter on intraluminal tension.
This sequence is not inevitable, however, and some episodes
of acute appendicitis apparently subside spontaneously. Many patients who are
found at operation to have acute appendicitis give a history of previous
similar, but less severe, attacks of right lower quadrant pain. Pathologic
examination of the appendices removed from these patients often reveals
thickening and scarring, suggesting old, healed acute
inflammation. The strong association between delay in
presentation and appendiceal perforation supported the proposition that
appendiceal perforation is the advanced stage of acute appendicitis; however,
recent epidemiologic studies have suggested that nonperforated and perforated
appendicitis may, in fact, be different diseases
Bacteriology
The bacterial population of the normal appendix is similar
to that of the normal colon. The appendiceal flora remains constant throughout
life with the exception of Porphyromonas gingivalis. This bacterium is
seen only in adults.18 The bacteria cultured in cases of appendicitis
are therefore similar to those seen in other colonic infections such as
diverticulitis. The principal organisms seen in the normal appendix, in acute
appendicitis, and in perforated appendicitis are Escherichia coli and
Bacteroides fragilis.18–21 However, a wide variety of both
facultative and anaerobic bacteria and mycobacteria may be present (Table 30-1).
Appendicitis is a polymicrobial infection, with some series reporting the
culture of up to 14 different organisms in patients with
perforation.18
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The routine culture of intraperitoneal samples in patients
with either perforated or nonperforated appendicitis is questionable. As
discussed earlier, the flora is known, and therefore broad-spectrum antibiotics
are indicated. By the time culture results are available, the patient often has
recovered from the illness. In addition, the number of organisms cultured and
the ability of a specific laboratory to culture anaerobic organisms vary
greatly. Peritoneal culture should be reserved for patients who are
immunosuppressed, as a result of either illness or medication, and for patients
who develop an abscess after the treatment of appendicitis.20–22
Antibiotic prophylaxis is effective in the prevention of postoperative wound
infection and intra-abdominal abscess.23 Antibiotic coverage is
limited to 24 to 48 hours in cases of nonperforated appendicitis. For perforated
appendicitis, 7 to 10 days of therapy is recommended. IV antibiotics are usually
given until the white blood cell count is normal and the patient is afebrile for
24 hours. Antibiotic irrigation of the peritoneal cavity and the use of
transperitoneal drainage through the wound are controversial
Clinical Manifestations
Symptoms
Abdominal pain is the prime symptom of acute appendicitis.
Classically, pain is initially diffusely centered in the lower epigastrium or
umbilical area, is moderately severe, and is steady, sometimes with intermittent
cramping superimposed. After a period varying from 1 to 12 hours, but usually
within 4 to 6 hours, the pain localizes to the right lower quadrant. This
classic pain sequence, although usual, is not invariable. In some patients, the
pain of appendicitis begins in the right lower quadrant and remains there.
Variations in the anatomic location of the appendix account for many of the
variations in the principal locus of the somatic phase of the pain. For example,
a long appendix with the inflamed tip in the left lower quadrant causes pain in
that area. A retrocecal appendix may cause principally flank or back pain; a
pelvic appendix, principally suprapubic pain; and a retroileal appendix,
testicular pain, presumably from irritation of the spermatic artery and ureter.
Intestinal malrotation also is responsible for puzzling pain patterns. The
visceral component is in the normal location, but the somatic component is felt
in that part of the abdomen where the cecum has been arrested in rotation.
Anorexia nearly always accompanies appendicitis. It is so
constant that the diagnosis should be questioned if the patient is not
anorectic. Although vomiting occurs in nearly 75% of patients, it is neither
prominent nor prolonged, and most patients vomit only once or twice. Vomiting is
caused by both neural stimulation and the presence of ileus.
Most patients give a history of obstipation beginning
before the onset of abdominal pain, and many feel that defecation would relieve
their abdominal pain. Diarrhea occurs in some patients, however, particularly
children, so that the pattern of bowel function is of little differential
diagnostic value.
The sequence of symptom appearance has great significance
for the differential diagnosis. In >95% of patients with acute appendicitis,
anorexia is the first symptom, followed by abdominal pain, which is followed, in
turn, by vomiting (if vomiting occurs). If vomiting precedes the onset of pain,
the diagnosis of appendicitis should be questioned.
Signs
Physical findings are determined principally by what the
anatomic position of the inflamed appendix is, as well as by whether the organ
has already ruptured when the patient is first examined.
Vital signs are minimally changed by uncomplicated
appendicitis. Temperature elevation is rarely >1°C (1.8°F) and the pulse rate
is normal or slightly elevated. Changes of greater magnitude usually indicate
that a complication has occurred or that another diagnosis should be
considered.25
Patients with appendicitis usually prefer to lie supine,
with the thighs, particularly the right thigh, drawn up, because any motion
increases pain. If asked to move, they do so slowly and with caution.
The classic right lower quadrant physical signs are present
when the inflamed appendix lies in the anterior position. Tenderness often is
maximal at or near the McBurney point.8 Direct rebound tenderness
usually is present. In addition, referred or indirect rebound tenderness is
present. This referred tenderness is felt maximally in the right lower quadrant,
which indicates localized peritoneal irritation.25 The Rovsing
sign—pain in the right lower quadrant when palpatory pressure is exerted in the
left lower quadrant—also indicates the site of peritoneal irritation. Cutaneous
hyperesthesia in the area supplied by the spinal nerves on the right at T10,
T11, and T12 frequently accompanies acute appendicitis. In patients with obvious
appendicitis, this sign is superfluous, but in some early cases, it may be the
first positive sign. Hyperesthesia is elicited either by needle prick or by
gently picking up the skin between the forefinger and thumb.
Muscular resistance to palpation of the abdominal wall
roughly parallels the severity of the inflammatory process. Early in the
disease, resistance, if present, consists mainly of voluntary guarding. As
peritoneal irritation progresses, muscle spasm increases and becomes largely
involuntary, that is, true reflex rigidity due to contraction of muscles
directly beneath the inflamed parietal peritoneum.
Anatomic variations in the position of the inflamed
appendix lead to deviations in the usual physical findings. With a retrocecal
appendix, the anterior abdominal findings are less striking, and tenderness may
be most marked in the flank. When the inflamed appendix hangs into the pelvis,
abdominal findings may be entirely absent, and the diagnosis may be missed
unless the rectum is examined. As the examining finger exerts pressure on the
peritoneum of Douglas' cul-de-sac, pain is felt in the suprapubic area as well
as locally within the rectum. Signs of localized muscle irritation also may be
present. The psoas sign indicates an irritative focus in proximity to that
muscle. The test is performed by having the patient lie on the left side as the
examiner slowly extends the patient's right thigh, thus stretching the iliopsoas
muscle. The test result is positive if extension produces pain. Similarly, a
positive obturator sign of hypogastric pain on stretching the obturator internus
indicates irritation in the pelvis. The test is performed by passive internal
rotation of the flexed right thigh with the patient supine.
Laboratory Findings
Mild leukocytosis, ranging from 10,000 to 18,000
cells/mm3, usually is present in patients with acute, uncomplicated
appendicitis and often is accompanied by a moderate polymorphonuclear
predominance. White blood cell counts are variable, however. It is unusual for
the white blood cell count to be >18,000 cells/mm3 in
uncomplicated appendicitis. White blood cell counts above this level raise the
possibility of a perforated appendix with or without an abscess. Urinalysis can
be useful to rule out the urinary tract as the source of infection. Although
several white or red blood cells can be present from ureteral or bladder
irritation as a result of an inflamed appendix, bacteriuria in a urine specimen
obtained via catheter generally is not seen in acute appendicitis
Imaging Studies
Plain films of the abdomen, although frequently obtained as
part of the general evaluation of a patient with an acute abdomen, rarely are
helpful in diagnosing acute appendicitis. However, plain radiographs can be of
significant benefit in ruling out other pathology. In patients with acute
appendicitis, one often sees an abnormal bowel gas pattern, which is a
nonspecific finding. The presence of a fecalith is rarely noted on plain films
but, if present, is highly suggestive of the diagnosis. A chest radiograph is
sometimes indicated to rule out referred pain from a right lower lobe pneumonic
process.
Additional radiographic studies include barium enema
examination and radioactively labeled leukocyte scans. If the appendix fills on
barium enema, appendicitis is excluded. On the other hand, if the appendix does
not fill, no determination can be made.27 To date, there has not been
enough experience with radionuclide scans to assess their utility.
Graded compression sonography has been suggested as an
accurate way to establish the diagnosis of appendicitis. The technique is
inexpensive, can be performed rapidly, does not require a contrast medium, and
can be used even in pregnant patients. Sonographically, the appendix is
identified as a blind-ending, nonperistaltic bowel loop originating from the
cecum. With maximal compression, the diameter of the appendix is measured in the
anteroposterior dimension. Scan results are considered positive if a
noncompressible appendix ≥6 mm in the anteroposterior direction is demonstrated
(Fig. 30-3). The presence of an appendicolith establishes the diagnosis.
Thickening of the appendiceal wall and the presence of periappendiceal fluid is
highly suggestive. Sonographic demonstration of a normal appendix, which is an
easily compressible, blind-ending tubular structure measuring ≤5 mm in diameter,
excludes the diagnosis of acute appendicitis. The study results are considered
inconclusive if the appendix is not visualized and there is no pericecal fluid
or mass. When the diagnosis of acute appendicitis is excluded by sonography, a
brief survey of the remainder of the abdominal cavity should be performed to
establish an alternative diagnosis. In females of childbearing age, the pelvic
organs must be adequately visualized either by transabdominal or endovaginal
ultrasonography to exclude gynecologic pathology as a cause of acute abdominal
pain. The sonographic diagnosis of acute appendicitis has a reported sensitivity
of 55 to 96% and a specificity of 85 to 98%.28–30 Sonography is
similarly effective in children and pregnant women, although its application is
somewhat limited in late pregnancy.
The rational approach is the selective use of CT scanning.
This has been documented by several studies in which imaging was performed based
on an algorithm or protocol.48 The likelihood of appendicitis can be
ascertained using the Alvarado scale (Table 30-2).49 This scoring
system was designed to improve the diagnosis of appendicitis and was devised by
giving relative weight to specific clinical manifestation. Table 30-2 lists the
eight specific indicators identified. Patients with scores of 9 or 10 are almost
certain to have appendicitis; there is little advantage in further work-up, and
they should go to the operating room. Patients with scores of 7 or 8 have a high
likelihood of appendicitis, whereas scores of 5 or 6 are compatible with, but
not diagnostic of, appendicitis. CT scanning is certainly appropriate for
patients with Alvarado scores of 5 and 6, and a case can be built for imaging
for those with scores of 7 and 8. On the other hand, it is difficult to justify
the expense, radiation exposure, and possible complications of CT scanning in
patients whose scores of 0 to 4 make it extremely unlikely (but not impossible)
that they have appendicitis.
Selective CT scanning based on the likelihood of
appendicitis takes advantage of the clinical skill of the experienced surgeon
and, when indicated, adds the expertise of the radiologist and his or her
imaging study. Figure 30-5 proposes a treatment algorithm addressing the
rational use of diagnostic testing
Laparoscopy can serve as both a diagnostic and therapeutic
maneuver for patients with acute abdominal pain and suspected acute
appendicitis. Laparoscopy is probably most useful in the evaluation of females
with lower abdominal complaints, because appendectomy is performed on a normal
appendix in as many as 30 to 40% of these patients. Differentiating acute
gynecologic pathology from acute appendicitis can be effectively accomplished
using the laparoscope.
Appendiceal Rupture
Immediate appendectomy has long been the recommended
treatment for acute appendicitis because of the presumed risk of progression to
rupture. The overall rate of perforated appendicitis is 25.8%. Children <5
years of age and patients >65 years of age have the highest rates of
perforation (45 and 51%, respectively) (Fig. 30-6).14,15,51 It has
been suggested that delays in presentation are responsible for the majority of
perforated appendices. There is no accurate way of determining when and if an
appendix will rupture before resolution of the inflammatory process. Recent
studies suggest that, in selected patients, observation and antibiotic therapy
alone may be an appropriate treatment for acute appendicitis
Appendiceal rupture occurs most frequently distal to the
point of luminal obstruction along the antimesenteric border of the appendix.
Rupture should be suspected in the presence of fever with a temperature of
>39°C (102°F) and a white blood cell count of >18,000
cells/mm3. In the majority of cases, rupture is contained and
patients display localized rebound tenderness. Generalized peritonitis will be
present if the walling-off process is ineffective in containing the
rupture.
In 2 to 6% of cases, an ill-defined mass is detected on
physical examination. This could represent a phlegmon, which consists of matted
loops of bowel adherent to the adjacent inflamed appendix, or a periappendiceal
abscess. Patients who present with a mass have experienced symptoms for a longer
duration, usually at least 5 to 7 days. Distinguishing acute, uncomplicated
appendicitis from acute appendicitis with perforation on the basis of clinical
findings is often difficult, but it is important to make the distinction because
their treatment differs. CT scan may be beneficial in guiding therapy. Phlegmons
and small abscesses can be treated conservatively with IV antibiotics;
well-localized abscesses can be managed with percutaneous drainage; complex
abscesses should be considered for surgical drainage. If operative drainage is
required, it should be performed using an extraperitoneal approach, with
appendectomy reserved for cases in which the appendix is easily accessible.
Interval appendectomy performed at least 6 weeks after the acute event has
classically been recommended for all patients treated either nonoperatively or
with simple drainage of an abscess.53,54
Differential Diagnosis
The differential diagnosis of acute appendicitis is
essentially the diagnosis of the acute abdomen (see Chap. 35). This is because
clinical manifestations are not specific for a given disease but are specific
for disturbance of a given physiologic function or functions. Thus, an
essentially identical clinical picture can result from a wide variety of acute
processes within the peritoneal cavity that produce the same alterations of
function as does acute appendicitis.
The accuracy of preoperative diagnosis should be
approximately 85%. If it is consistently less, it is likely that some
unnecessary operations are being performed, and a more rigorous preoperative
differential diagnosis is in order. A diagnostic accuracy rate that is
consistently >90% should also cause concern, because this may mean that some
patients with atypical, but bona fide, cases of acute appendicitis are being
"observed" when they should receive prompt surgical intervention. The Haller
group, however, has shown that this is not invariably true.55 Before
that group's study, the perforation rate at the hospital at which the study took
place was 26.7%, and acute appendicitis was found in 80% of the patients
undergoing operation. By implementing a policy of intensive inhospital
observation when the diagnosis of appendicitis was unclear, the group raised the
rate of acute appendicitis found at operation to 94%, but the perforation rate
remained unchanged at 27.5%.55 The rate of false-negative
appendectomies is highest in young adult females. A normal appendix is found in
32 to 45% of appendectomies performed in women 15 to 45 years of
age.14
A common error is to make a preoperative diagnosis of acute
appendicitis only to find some other condition (or nothing) at operation. Much
less frequently, acute appendicitis is found after a preoperative diagnosis of
another condition. The most common erroneous preoperative diagnoses—together
accounting for >75% of cases—are, in descending order of frequency, acute
mesenteric lymphadenitis, no organic pathologic condition, acute pelvic
inflammatory disease, twisted ovarian cyst or ruptured graafian follicle, and
acute gastroenteritis.
The differential diagnosis of acute appendicitis depends on
four major factors: the anatomic location of the inflamed appendix; the stage of
the process (i.e., simple or ruptured); the patient's age; and the patient's
sex.56–60
Acute Mesenteric Adenitis
Acute mesenteric adenitis is the disease most often
confused with acute appendicitis in children. Almost invariably, an upper
respiratory tract infection is present or has recently subsided. The pain
usually is diffuse, and tenderness is not as sharply localized as in
appendicitis. Voluntary guarding is sometimes present, but true rigidity is
rare. Generalized lymphadenopathy may be noted. Laboratory procedures are of
little help in arriving at the correct diagnosis, although a relative
lymphocytosis, when present, suggests mesenteric adenitis. Observation for
several hours is in order if the diagnosis of mesenteric adenitis seems likely,
because it is a self-limited disease. However, if the differentiation remains in
doubt, immediate exploration is the safest course of action.
Human infection with Yersinia enterocolitica or
Yersinia pseudotuberculosis, transmitted through food contaminated by
feces or urine, causes mesenteric adenitis as well as ileitis, colitis, and
acute appendicitis. Many of the infections are mild and self limited, but they
may lead to systemic disease with a high fatality rate if untreated. The
organisms are usually sensitive to tetracyclines, streptomycin, ampicillin, and
kanamycin. A preoperative suspicion of the diagnosis should not delay operative
intervention, because appendicitis caused by Yersinia cannot be
clinically distinguished from appendicitis due to other causes. Approximately 6%
of cases of mesenteric adenitis are caused by Yersinia infection.
Salmonella typhimurium infection causes mesenteric
adenitis and paralytic ileus with symptoms similar to those of appendicitis. The
diagnosis can be established by serologic testing. Campylobacter jejuni
causes diarrhea and pain that mimics that of appendicitis. The organism can be
cultured from stool.
Gynecologic Disorders
Diseases of the female internal reproductive organs that
may erroneously be diagnosed as appendicitis are, in approximate descending
order of frequency, pelvic inflammatory disease, ruptured graafian follicle,
twisted ovarian cyst or tumor, endometriosis, and ruptured ectopic
pregnancy.
Pelvic Inflammatory Disease
In pelvic inflammatory disease the infection usually is
bilateral but, if confined to the right tube, may mimic acute appendicitis.
Nausea and vomiting are present in patients with appendicitis, but in only
approximately 50% of those with pelvic inflammatory disease. Pain and tenderness
are usually lower, and motion of the cervix is exquisitely painful.
Intracellular diplococci may be demonstrable on smear of the purulent vaginal
discharge. The ratio of cases of appendicitis to cases of pelvic inflammatory
disease is low in females in the early phase of the menstrual cycle and high
during the luteal phase. The careful clinical use of these features has reduced
the incidence of negative findings on laparoscopy in young women to 15%.
Ruptured Graafian Follicle
Ovulation commonly results in the spillage of sufficient
amounts of blood and follicular fluid to produce brief, mild lower abdominal
pain. If the amount of fluid is unusually copious and is from the right ovary,
appendicitis may be simulated. Pain and tenderness are rather diffuse.
Leukocytosis and fever are minimal or absent. Because this pain occurs at the
midpoint of the menstrual cycle, it is often called mittelschmerz.
Twisted Ovarian Cyst
Serous cysts of the ovary are common and generally remain
asymptomatic. When right-sided cysts rupture or undergo torsion, the
manifestations are similar to those of appendicitis. Patients develop right
lower quadrant pain, tenderness, rebound, fever, and leukocytosis. If the mass
is palpable on physical examination, the diagnosis can be made easily. Both
transvaginal ultrasonography and CT scanning can be diagnostic if a mass is not
palpable.
Torsion requires emergent operative treatment. If the
torsion is complete or longstanding, the pedicle undergoes thrombosis, and the
ovary and tube become gangrenous and require resection. Leakage of ovarian cysts
resolves spontaneously, however, and is best treated
nonoperatively.24,56–61
Ruptured Ectopic Pregnancy
Blastocysts may implant in the fallopian tube (usually the
ampullary portion) and in the ovary. Rupture of right tubal or ovarian
pregnancies can mimic appendicitis. Patients may give a history of abnormal
menses, either missing one or two periods or noting only slight vaginal
bleeding. Unfortunately, patients do not always realize they are pregnant. The
development of right lower quadrant or pelvic pain may be the first symptom. The
diagnosis of ruptured ectopic pregnancy should be relatively easy. The presence
of a pelvic mass and elevated levels of chorionic gonadotropin are
characteristic. Although the leukocyte count rises slightly (to approximately
14,000 cells/mm3), the hematocrit level falls as a consequence of the
intra-abdominal hemorrhage. Vaginal examination reveals cervical motion and
adnexal tenderness, and a more definitive diagnosis can be established by
culdocentesis. The presence of blood and particularly decidual tissue is
pathognomonic. The treatment of ruptured ectopic pregnancy is emergency
surgery.
Acute Gastroenteritis
Acute gastroenteritis is common but usually can be easily
distinguished from acute appendicitis. Gastroenteritis is characterized by
profuse diarrhea, nausea, and vomiting. Hyperperistaltic abdominal cramps
precede the watery stools. The abdomen is relaxed between cramps, and there are
no localizing signs. Laboratory values vary with the specific cause.
Other Intestinal Disorders
Meckel's Diverticulitis
Meckel's diverticulitis gives rise to a clinical picture
similar to that of acute appendicitis. Meckel's diverticulum is located within
the distal 2 ft of the ileum. Meckel's diverticulitis is associated with the
same complications as appendicitis and requires the same treatment—prompt
surgical intervention. Resection of the segment of ileum bearing the
diverticulum with end-to-end anastomosis can nearly always be done through a
McBurney incision, extended if necessary, or laparoscopically.
Crohn's Enteritis
The manifestations of acute regional enteritis—fever, right
lower quadrant pain and tenderness, and leukocytosis—often simulate acute
appendicitis. The presence of diarrhea and the absence of anorexia, nausea, and
vomiting favor a diagnosis of enteritis, but this is not sufficient to exclude
acute appendicitis. In an appreciable percentage of patients with chronic
regional enteritis, the diagnosis is first made at the time of operation for
presumed acute appendicitis. In cases of an acutely inflamed distal ileum with
no cecal involvement and a normal appendix, appendectomy is indicated.
Progression to chronic Crohn's ileitis is uncommon.
Colonic Lesions
Diverticulitis or perforating carcinoma of the cecum, or of
that portion of the sigmoid that lies in the right side, may be impossible to
distinguish from appendicitis. These entities should be considered in older
patients. CT scanning is often helpful in making a diagnosis in older patients
with right lower quadrant pain and atypical clinical presentations.
Epiploic appendagitis probably results from infarction of
the colonic appendage(s) secondary to torsion. Symptoms may be minimal, or there
may be continuous abdominal pain in an area corresponding to the contour of the
colon, lasting several days. Pain shift is unusual, and there is no diagnostic
sequence of symptoms. The patient does not look ill, nausea and vomiting are
unusual, and appetite generally is unaffected. Localized tenderness over the
site is usual and often is associated with rebound without rigidity. In 25% of
reported cases, pain persists or recurs until the infarcted epiploic appendage
is removed.
Treatment
Despite the advent of more sophisticated diagnostic
modalities, the importance of early operative intervention should not be
minimized. Once the decision to operate for presumed acute appendicitis has been
made, the patient should be prepared for the operating room. Adequate hydration
should be ensured, electrolyte abnormalities should be corrected, and
pre-existing cardiac, pulmonary, and renal conditions should be addressed. A
large meta-analysis has demonstrated the efficacy of preoperative antibiotics in
lowering the infectious complications in appendicitis. Most
surgeons routinely administer antibiotics to all patients with suspected
appendicitis. If simple acute appendicitis is encountered, there is no benefit
in extending antibiotic coverage beyond 24 hours. If perforated or gangrenous
appendicitis is found, antibiotics are continued until the patient is afebrile
and has a normal white blood cell count. For intra-abdominal infections of GI
tract origin that are of mild to moderate severity, the Surgical Infection
Society has recommended single-agent therapy with cefoxitin, cefotetan, or
ticarcillin-clavulanic acid. For more severe infections, single-agent therapy
with carbapenems or combination therapy with a third-generation cephalosporin,
monobactam, or aminoglycoside plus anaerobic coverage with clindamycin or
metronidazole is indicated. The recommendations are similar for
children.
Open Appendectomy
For open appendectomy most surgeons use either a McBurney
(oblique) or Rocky-Davis (transverse) right lower quadrant muscle-splitting
incision in patients with suspected appendicitis. The incision should be
centered over either the point of maximal tenderness or a palpable mass. If an
abscess is suspected, a laterally placed incision is imperative to allow
retroperitoneal drainage and to avoid generalized contamination of the
peritoneal cavity. If the diagnosis is in doubt, a lower midline incision is
recommended to allow a more extensive examination of the peritoneal cavity. This
is especially relevant in older patients with possible malignancy or
diverticulitis.
Several techniques can be used to locate the appendix.
Because the cecum usually is visible within the incision, the convergence of the
taeniae can be followed to the base of the appendix. A sweeping lateral to
medial motion can aid in delivering the appendiceal tip into the operative
field. Occasionally, limited mobilization of the cecum is needed to aid in
adequate visualization. Once identified, the appendix is mobilized by dividing
the mesoappendix, with care taken to ligate the appendiceal artery
securely.
The appendiceal stump can be managed by simple ligation or
by ligation and inversion with either a purse-string or Z stitch. As long as the
stump is clearly viable and the base of the cecum is not involved with the
inflammatory process, the stump can be safely ligated with a nonabsorbable
suture. The mucosa is frequently obliterated to avoid the development of
mucocele. The peritoneal cavity is irrigated and the wound closed in layers. If
perforation or gangrene is found in adults, the skin and subcutaneous tissue
should be left open and allowed to heal by secondary intent or closed in 4 to 5
days as a delayed primary closure. In children, who generally have little
subcutaneous fat, primary wound closure has not led to an increased incidence of
wound infection.
If appendicitis is not found, a methodical search must be
made for an alternative diagnosis. The cecum and mesentery should first be
inspected. Next, the small bowel should be examined in a retrograde fashion
beginning at the ileocecal valve and extending at least 2 ft. In females,
special attention should be paid to the pelvic organs. An attempt also should be
made to examine the upper abdominal contents. Peritoneal fluid should be sent
for Gram's staining and culture. If purulent fluid is encountered, it is
imperative that the source be identified. A medial extension of the incision
(Fowler-Weir), with division of the anterior and posterior rectus sheath, is
acceptable if further evaluation of the lower abdomen is indicated. If upper
abdominal pathology is encountered, the right lower quadrant incision is closed
and an appropriate upper midline incision is made
Laparoscopic Appendectomy
Semm first reported successful laparoscopic appendectomy
several years before the first laparoscopic cholecystectomy.10
However, the laparoscopic approach to appendectomy did not come into widespread
use until after the success of laparoscopic cholecystectomy. This may be due to
the fact that appendectomy, by virtue of its small incision, is already a form
of minimal-access surgery.
Laparoscopic appendectomy is performed under general
anesthesia. A nasogastric tube and a urinary catheter are placed before
obtaining a pneumoperitoneum. Laparoscopic appendectomy usually requires the use
of three ports. Four ports may occasionally be necessary to mobilize a
retrocecal appendix. The surgeon usually stands to the patient's left. One
assistant is required to operate the camera. One trocar is placed in the
umbilicus (10 mm), and a second trocar is placed in the suprapubic position.
Some surgeons place this second port in the left lower quadrant. The suprapubic
trocar is either 10 or 12 mm, depending on whether or not a linear stapler will
be used. The placement of the third trocar (5 mm) is variable and usually is
either in the left lower quadrant, epigastrium, or right upper quadrant.
Placement is based on location of the appendix and surgeon preference.
Initially, the abdomen is thoroughly explored to exclude other pathology. The
appendix is identified by following the anterior taeniae to its base. Dissection
at the base of the appendix enables the surgeon to create a window between the
mesentery and the base of the appendix. The mesentery and base of
the appendix are then secured and divided separately. When the mesoappendix is
involved with the inflammatory process, it is often best to divide the appendix
first with a linear stapler and then to divide the mesoappendix immediately
adjacent to the appendix with clips, electrocautery, Harmonic Scalpel, or
staples. The base of the appendix is not inverted. The
appendix is removed from the abdominal cavity through a trocar site or within a
retrieval bag. The base of the appendix and the mesoappendix should be evaluated
for hemostasis. The right lower quadrant should be irrigated. Trocars are
removed under direct vision.
The utility of laparoscopic appendectomy in the management
of acute appendicitis remains controversial. Surgeons may be hesitant to
implement a new technique because the conventional open approach already has
proved to be simple and effective. A number of articles in peer-reviewed
journals have compared laparoscopic and open appendectomy, including >20
randomized, controlled trials and 6 meta-analyses.The
overall quality of these randomized, controlled trials has been limited by the
failure to blind patients and providers as to the treatment modality used.
Furthermore, investigators have failed to perform prestudy sample size analysis
for the outcomes studied. The largest meta-analysis comparing open
to laparoscopic appendectomy included 47 studies, 39 of which were studies of
adult patients. This analysis demonstrated that the duration of surgery and
costs of operation were higher for laparoscopic appendectomy than for open
appendectomy. Wound infections were approximately half as likely after
laparoscopic appendectomy as after open appendectomy. However, the rate of
intra-abdominal abscess was three times higher after laparoscopic appendectomy
than after open appendectomy.
A principal proposed benefit of laparoscopic appendectomy
has been decreased postoperative pain. Patient-reported pain on the first
postoperative day is significantly less after laparoscopic appendectomy.
However, the difference has been calculated to be only 8 points on a 100-point
visual analogue scale. This difference is below the level of pain that an
average patient is able to perceive. Hospital length of stay also
is statistically significantly less after laparoscopic appendectomy. However, in
most studies this difference is <1 day. It appears that a
more important determinant of length of stay after appendectomy is the pathology
found at operation—specifically, whether a patient has perforated or
nonperforated appendicitis. In nearly all studies, laparoscopic appendectomy is
associated with a shorter period before return to normal activity, return to
work, and return to sports. However, treatment and subject
bias may have a significant impact on the data. Although the majority of studies
have been performed in adults, similar data have been obtained in
children.
There appears to be little benefit to laparoscopic
appendectomy over open appendectomy in thin males between the ages of 15 and 45
years. In these patients, the diagnosis usually is straightforward. Open
appendectomy has been associated with outstanding results for several decades.
Laparoscopic appendectomy should be considered an option in these patients,
based on surgeon and patient preference. Laparoscopic appendectomy may be
beneficial in obese patients, in whom it may be difficult to gain adequate
access through a small right lower quadrant incision. In a retrospective study
of 116 patients with a mean body mass index of 35, postoperative length of stay
was significantly shorter in the group undergoing laparoscopic appendectomy, and
there were fewer open wounds. In all obese patients in whom the procedure was
completed laparoscopically the incisions closed primarily, whereas the wounds
closed primarily in only 58% of obese patients who underwent open appendectomy.
There was no difference in rates of wound infection; intra-abdominal abscess
rates were not reported.
Diagnostic laparoscopy has been advocated as a potential
tool to decrease the number of negative appendectomies performed. However, the
morbidity associated with laparoscopy and general anesthesia is acceptable only
if pathology requiring surgical treatment is present and is amenable to
treatment using laparoscopic techniques. The question of leaving a normal
appendix in situ is a controversial one. Seventeen to 26% of appendices that
appear normal at exploration are found to have pathologic features on histologic
analysis. The availability of diagnostic laparoscopy may actually
lower the threshold for exploration and thus adversely impact the negative
appendectomy rate. Fertile women with presumed appendicitis
constitute the group of patients most likely to benefit from diagnostic
laparoscopy. Up to one third of these patients do not have appendicitis at
exploration. In most of the patients without appendicitis, gynecologic pathology
is identified. A large meta-analysis demonstrated that in fertile
women in whom appendectomy was deemed necessary, diagnostic laparoscopy reduced
the number of unnecessary appendectomies. In addition, the number
of women without a final diagnosis was smaller. It appears that leaving a
normal-appearing appendix in fertile women with identifiable gynecologic
pathology is safe.
In summary, it has not been resolved whether laparoscopic
appendectomy is more effective in treating acute appendicitis than the
time-proven method of open appendectomy. It does appear that laparoscopic
appendectomy is effective in the management of acute appendicitis. Laparoscopic
appendectomy should be considered part of the surgical armamentarium available
to treat acute appendicitis. The decision on how to treat a specific patient
with appendicitis should be based on surgical skill, patient characteristics,
clinical scenario, and patient preference. Additional well-controlled,
prospective, blinded studies are needed to determine which subsets of patients
may benefit from any given approach to the treatment of appendicitis.
Natural Orifice Transluminal Endoscopic Surgery
Natural orifice transluminal endoscopic surgery (NOTES) is
a new surgical procedure using flexible endoscopes in the abdominal cavity. In
this procedure, access is gained by way of organs that are reached through a
natural, already-existing external orifice. The hoped-for advantages associated
with this method include the reduction of postoperative wound pain, shorter
convalescence, avoidance of wound infection and abdominal-wall hernias, and the
absence of scars. The first case of transvaginal removal of a normal appendix
has recently been reported. Much work remains to determine if NOTES
provides any additional advantages over the laparoscopic approach to
appendectomy.
Antibiotics as Definitive Therapy
Traditional management of acute appendicitis has emphasized
emergent surgical management. This approach has been based on the theory that,
over time, simple appendicitis will progress to perforation, with resulting
increases in morbidity and mortality. As a result, a relatively high negative
appendectomy rate has been accepted to avoid the possibility of progression to
perforation. Recent data suggest that acute appendicitis and acute appendicitis
with perforation may be separate disease entities with distinct pathophysiology.
A time series analysis performed on a 25-year data set did not find a
significant negative relationship between the rates of negative appendectomy and
perforation.17 A study analyzing time to surgery and perforation
demonstrated that risk of rupture is minimal within 36 hours of symptom onset.
Beyond this point, there is about a 5% risk of rupture in each ensuing 12-hour
period. However, in many patients the disease will have an indolent course. In
one study 10 of the 18 patients who did not undergo operation for ≥6 days after
their symptoms began did not experience rupture.89
Many acute abdominal conditions such as acute
diverticulitis and acute cholecystitis are managed with urgent but not emergent
surgery. Moreover, evidence from submarine personnel who develop appendicitis
suggests that nonoperative management of appendicitis may be a viable treatment
option. Sailors who develop appendicitis while stationed on submarines do not
have access to prompt surgical care. They are successfully treated with
antibiotics and fluids days to weeks after the initial attack until the ship can
surface and they can be transferred to a hospital for care.90
A randomized study comparing antibiotic treatment with
immediate appendectomy has been completed. Two hundred and fifty-two men 18 to
50 years of age with the presumptive diagnosis of appendicitis were enrolled in
the study between March 1996 and June 1999. For patients randomly assigned to
antibiotic therapy, if symptoms did not improve within the first 24 hours, an
appendectomy was performed. Participants were evaluated after 1 week, 6 weeks,
and 1 year. Acute appendicitis was found in 97% of the 124 patients randomly
assigned to surgery. Six patients (5%) had perforated appendices. The
complication rate in the surgery group was 14% (17 of 124). Of the 128 patients
enrolled in the antibiotic group, 15 patients (12%) underwent operation within
the first 24 hours due to lack of improvement in symptoms and apparent local
peritonitis. At operation seven patients (5%) had perforation. The rate of
recurrence within 1 year was 15% (16 patients) in the group treated with
antibiotics. In five of these patients a perforated appendix was found at
operation.52 Although it initially appears from these data that the
use of antibiotics alone may be reasonable therapy for acute appendicitis, there
are several issues to take into account. First, this study included only men
between the ages of 18 and 50 and may not have broad applicability to all
patients with appendicitis, especially those populations known to have higher
perforation rates. Second, the incidence of perforation was 9% in the antibiotic
group when patients requiring operation in both the acute and delayed settings
are considered. This compares unfavorably with the perforation rate of 5% for
those patients operated on immediately. In addition, the study follow-up was
only 1 year, which suggests that patients receiving only antibiotic therapy may
still be at risk for the development of appendicitis. Finally, when patients are
treated with antibiotics alone it is possible that diagnoses of significant
pathology such as carcinoid or carcinoma may be delayed. Because no
laboratory test or clinical investigation can reliably distinguish patients
whose appendicitis is potentially amenable to conservative treatment, surgery
still remains the gold standard of care for patients with acute
appendicitis.
Interval Appendectomy
The accepted approach for the treatment of appendicitis
associated with a palpable or radiographically documented mass (abscess or
phlegmon) is conservative therapy with interval appendectomy 6 to 10 weeks
later. This technique has been quite successful and produces much lower
morbidity and mortality rates than immediate appendectomy. Unfortunately, this
treatment is associated with greater expense and longer hospitalization time (8
to 13 days vs. 3 to 5 days).
The initial treatment consists of IV antibiotics and bowel
rest. Although this therapy is generally effective, there is a 9 to 15% failure
rate, with operative intervention required at 3 to 5 days after presentation.
Percutaneous or operative drainage of abscesses is not considered a failure of
conservative therapy.
Although the second stage of this treatment plan, interval
appendectomy, has usually been carried out, the need for subsequent operation
has been questioned. The major argument against interval appendectomy is that
approximately 50% of patients treated conservatively never develop
manifestations of appendicitis, and those who do generally can be treated
nonoperatively. In addition, pathologic examination of the resected appendix
shows normal findings in 20 to 50% of cases.
On the other hand, the data clearly support the need for
interval appendectomy. In a prospective series, 19 of 48 patients (40%) who were
successfully treated conservatively needed appendectomy at an earlier time (mean
of 4.3 weeks) than the 10 weeks planned because of bouts of
appendicitis.91 Overall, the rate of late failure as a consequence of
acute disease averages 20%. An additional 14% of patients either continue to
have, or redevelop, right lower quadrant pain. Although the appendix may
occasionally be pathologically normal, persistent periappendiceal abscesses and
adhesions are found in 80% of patients. In addition, almost 50% have histologic
evidence of inflammation in the organ itself. Several neoplasms also have been
detected in the resected appendices, even in those of
children.
The timing of interval appendectomy is somewhat
controversial. Appendectomy may be required as early as 3 weeks after
conservative therapy. Two thirds of the cases of recurrent appendicitis occur
within 2 years, and this is the outside limit. Interval appendectomy is
associated with a morbidity rate of ≤3% and a hospitalization time of 1 to 3
days. The laparoscopic approach has been used and has been successful in 68% of
procedures. In a more recent study in children, interval
appendectomy was performed successfully using the laparoscopic approach in all
35 patients.
Prognosis
The mortality from appendicitis in the United States has
steadily decreased from a rate of 9.9 per 100,000 in 1939 to 0.2 per 100,000
today. Among the factors responsible are advances in anesthesia, antibiotics, IV
fluids, and blood products. Principal factors influencing mortality are whether
rupture occurs before surgical treatment and the age of the patient. The overall
mortality rate in acute appendicitis with rupture is approximately 1%. The
mortality rate of appendicitis with rupture in the elderly is approximately 5%—a
fivefold increase from the overall rate. Death is usually attributable to
uncontrolled sepsis—peritonitis, intra-abdominal abscesses, or gram-negative
septicemia. Pulmonary embolism continues to account for some deaths.
Morbidity rates parallel mortality rates and are
significantly increased by rupture of the appendix and, to a lesser extent, by
old age. In one report, complications occurred in 3% of patients with
nonperforated appendicitis and in 47% of patients with perforations. Most of the
serious early complications are septic and include abscess and wound infection.
Wound infection is common but is nearly always confined to the subcutaneous
tissues and responds promptly to wound drainage, which is accomplished by
reopening the skin incision. Wound infection predisposes the patient to wound
dehiscence. The type of incision is relevant; complete dehiscence rarely occurs
in a McBurney incision.
The incidence of intra-abdominal abscess secondary to
peritoneal contamination from gangrenous or perforated appendicitis has
decreased markedly since the introduction of potent antibiotics. The sites of
predilection for abscesses are the appendiceal fossa, pouch of Douglas, the
subhepatic space, and between loops of intestine. In the latter site abscesses
are usually multiple. Transrectal drainage is preferred for an abscess that
bulges into the rectum.
Fecal fistula is an annoying, but not particularly
dangerous, complication of appendectomy that may be caused by sloughing of the
portion of the cecum inside a constricting purse-string suture; by slipping of
the ligature off a tied, but not inverted, appendiceal stump; or by necrosis
from an abscess encroaching on the cecum.
Intestinal obstruction, initially paralytic but sometimes
progressing to mechanical obstruction, may occur with slowly resolving
peritonitis with loculated abscesses and exuberant adhesion formation. Late
complications are quite uncommon. Adhesive band intestinal obstruction after
appendectomy does occur, but much less frequently than after pelvic surgical
therapy. The incidence of inguinal hernia is three times higher in patients who
have had an appendectomy. Incisional hernia is like wound dehiscence in that
infection predisposes to it, it rarely occurs in a McBurney incision, and it is
not uncommon in a lower right paramedian
incision.
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Chronic Appendicitis
Whether chronic appendicitis is a true clinical entity has
been questioned for many years. However, clinical data document the existence of
this uncommon disease. Histologic criteria have been established.
Characteristically, the pain lasts longer and is less intense than that of acute
appendicitis but is in the same location. There is a much lower incidence of
vomiting, but anorexia and occasionally nausea, pain with motion, and malaise
are characteristic. Leukocyte counts are predictably normal and CT scans are
generally nondiagnostic.
At operation, surgeons can establish the diagnosis with 94%
specificity and 78% sensitivity. There is an excellent correlation between
clinical symptomatology, intraoperative findings, and histologic abnormalities.
Laparoscopy can be used effectively in the management of this clinical entity.
Appendectomy is curative. Symptoms resolve postoperatively in 82 to 93% of
patients. Many of those whose symptoms are not cured or recur are ultimately
diagnosed with Crohn's disease.
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