ある内科臨床医の夢

An Unusual Cause of Lower Abdominal Pain in a 28-Year-Old Man

Background

A 28-year-old man with a medical history significant for asthma presents
to the emergency department (ED) with a 2-week history of intermittent lower abdominal pain,
loose stools, myalgia, and low-grade fevers.
His symptoms began following an episode of diarrhea and vomiting,
which had also affected his wife and children at the same time.
Although his family's symptoms resolved shortly after their onset, his symptoms have progressed.
He has been generally active, playing soccer at least twice per week,
but he has recently felt too ill to participate in any physical activity.
His only medication is a salbutamol inhaler, which he uses intermittently for asthma exacerbation.
He is employed as a groundskeeper, which involves the occasional handling of raw animal manure.
Because of his occupation and manure exposure,
his family health care provider had considered leptospirosis
as a potential diagnosis accounting for his symptoms;
however, laboratory examination of the patient's blood and urine for leptospirosis is negative.

On physical examination, the patient appears mildly dehydrated,
with sunken eyes and decreased skin turgor.
Vital signs demonstrate an oral temperature of 100.6oF (38.1oC), pulse of 90 bpm,
blood pressure of 121/65 mm Hg, respirations of 20 breaths/minute,
and an oxygen saturation of 98% while breathing room air.
The abdomen is soft and nondistended, with active bowel sounds present.
Significant tenderness to palpation is noted in the lower abdomen,
and it is most prominent in the left iliac fossa and suprapubic regions,
where localized rebound and guarding are present.
No organomegaly or hernias are noted.
The remainder of the physical examination, including the cardiac, respiratory,
and neurologic examinations, is normal.

A peripheral intravenous line is placed, and blood is drawn and sent for laboratory testing.
Abdominal and upright chest radiographs are obtained.
Laboratory tests are significant for a leukocyte count of 15.0 × 103/μL (15.0 × 109/L;
normal range, 3.5-12.5 × 103/μL ) and a C-reactive protein of 212 mg/L (normal range, 0.08-3.1 mg/L).
The rest of his laboratory tests are within normal limits,
and both the abdominal and chest radiographic examinations are normal.
Urine dipstick testing does not demonstrate any blood or leukocyte esterase.
A computed tomography (CT) scan of the abdomen and pelvis is performed,
which demonstrates an area of inflammation deep to the pubic symphysis.
Magnetic resonance imaging (MRI) of the pelvis is obtained,
which reveals the characteristic signs of this uncommon condition (see Figure 1).
At this time, blood cultures obtained on admission return positive for Staphylococcus aureus.

Discussion

The MRI scan (Figure 1) revealed abnormal marrow signal in the pubis,
with periosteal elevation and marked soft-tissue reaction.
These features demonstrated a significant inflammatory condition of the pubic symphysis.
These MRI findings, along with the proven bacteremia and elevated inflammatory markers,
were consistent with a final diagnosis of osteomyelitis pubis.

Inflammation of the fibrocartilaginous pubic symphysis joint is rare and occurs in 2 forms,
termed infective and noninfective.
The noninfective variant, osteitis pubis, was first described by Beer[1] in 1924;
it is a self-limiting inflammatory condition of the joint and its surroundings.
In contrast, osteomyelitis pubis involves infective inflammation of bone,
and it accounts for 2% of all reported cases of hematogenous osteomyelitis.[2]
Both conditions share a very similar clinical presentation and delineating between them can be difficult.

The etiology of both osteitis pubis and osteomyelitis pubis is not fully understood;
similar causative factors have been cited for both conditions.
These factors include athletic overexertion, pregnancy and childbirth,
urologic or gynecologic manipulation, intravenous drug abuse, and surgery.[3,4]
Although the mechanisms by which surgery, childbirth,
or intravenous injection result in osteomyelitis pubis can be readily explained
by hematogenous dissemination or extension of local infection,
athletic exertion as an etiology is less straightforward.
Certain sports are known to predispose athletes to injury of the groin and pubic symphysis,
particularly those that involve repetitive twisting or turning motions at the pelvis,
such as soccer, hockey, rugby, and tennis.[4]
One theory is that some form of low-grade localized trauma occurs in the region
(which may even go unnoticed by the patient),
followed by a transient bacteremia opportunistically seeding the damaged area.[5]
This transient bacteremia may arise from any number of innocuous causes,
ranging from minor skin trauma to dental extraction.[6,7]
The most common pathogen found in patients with osteomyelitis pubis is Staphylococcus aureus,
although in intravenous drug users it is more commonly Pseudomonas aeruginosa.
In postsurgical cases, mixed Gram-negative bacteria are often the causative agents.[7-9]
Individual cases have also been reported with a wide range of other organisms,
such as Streptococcus viridans, Staphylococcus epidermidis, and Salmonella species.[6-8]

In both osteomyelitis pubis and osteitis pubis, patients usually present
with vague unilateral or bilateral pelvic, groin, or lower abdominal pain.
The pain generally worsens with exercise, and patients may report difficulty ambulating.
When standing or walking patients tend to lean forward secondary to adductor or rectus muscle spasm.
On examination,
abduction of the hip results in significant pain, and the patient's range of movement
may be diminished as well.
The insidious onset and nonspecific nature of these symptoms coupled
with the unfamiliarity of clinicians with these conditions leads to a high rate of delayed diagnosis.
These entities are often misdiagnosed as subclinical inguinal hernias, coxarthrosis,
and adductor muscle spasms.[3]
One review of 18 cases of osteomyelitis pubis reported an average delay of 13 days
from the onset of symptoms to diagnosis (range, 1-30 days).[7]

In cases of osteomyelitis pubis, symptoms tend to progressively worsen,
whereas osteitis pubis is largely self-limiting.
The key differentiating factor between these conditions is the establishment of (or absence of) infection,
which is implicated by signs of systemic infection
(such as fever, tachycardia, vomiting, and elevated inflammatory markers)
but is only confirmed by verification of the presence of organisms
either in blood cultures (in severe cases) or by aspiration or biopsy of the pubic symphysis region.
Plain radiographs are of limited value in the initial stages of both conditions
because there is a delay of some weeks before radiographic changes occur.
MRI, in the early stages, is much more sensitive;
both conditions will produce some edema of the bone marrow,
but the presence of fluid and extensive soft-tissue reaction raises suspicion for osteomyelitis.[4]
Three-phase bone scintigraphy normally shows increased uptake in all 3 phases in osteomyelitis pubis,
but uptake is only increased in the mineralization (or delayed) phase in the case of osteitis pubis.[3] Finally,
it is important to note that the symptoms and signs of established osteomyelitis pubis
(lower abdominal pain, fever, vomiting, tachycardia, and elevated inflammatory markers)
closely mimic more common lower abdominal pathologies, such as appendicitis or diverticulitis,
and as such, the negative laparotomy and laparoscopy rates in these patients are fairly high.[4,6,8]

The treatment of osteitis pubis is largely symptomatic
because most cases resolve spontaneously with physical therapy and anti-inflammatory medications.
Some physicians advocate more invasive measures,
such as injection of steroids and/or local anesthetics into the joint,
or even the use of dextrose prolotherapy
(the act of injecting an otherwise nonpharmacologic irritant solution into the region of tendons
or ligaments in an attempt to strengthen weakened connective tissue
and thus alleviate musculoskeletal pain).
There have been no randomized controlled trials of any of these practices,
however, and a recent systematic review found only level 4 evidence for all of these therapies.[10]
The mainstay of treatment of osteomyelitis pubis is a prolonged course of antibiotic therapy
(initially intravenous) targeted at the causative agent.
Up to 50% of patients will not fully resolve on antibiotic therapy alone
and may require formal surgical debridement of the area.[9]
This debridement involves curettage and jet lavage; some surgeons
will also implant antibiotic-impregnated beads into the affected area.[3]
Whether or not surgery is performed, targeted antibiotic therapy is recommended
until the erythrocyte sedimentation rate has normalized,
which generally requires at least 6 weeks of antibiotic therapy.[4]

In the patient in this case,
the antibiotic therapy was changed to full-dose intravenous flucloxacillin
on the basis of the microbiologic sensitivities of the organisms recovered from the blood cultures.
He was given nonsteroidal anti-inflammatory medication for pain control.
Within 36 hours of this targeted antibiotic therapy, his pain improved and he remained afebrile.
Following daily physical therapy, he was discharged to home on hospital day 9,
ambulating with crutches, and he was instructed to continue oral flucloxacillin for 8 weeks postdischarge. Following completion of his antibiotic course, his symptoms had entirely resolved;
he had no residual disability and was back to playing soccer.

Hypoglycemia A Diagnostic Challenge

The differential diagnosis in patients who present with syncope
is typically quite broad. Laboratory and other clinical tests,
while often extensive, usually don’t identify the cause.
In low-risk patients without a concerning presentation of syncope,
minimal testing is acceptable and appropriate;
however, given this patient’s unusual presentation and underlying medical conditions,
an extensive workup including evaluation of cardiac, metabolic,
and neurologic causes of syncope was initiated.

A possible hematoma in the chest wall as suggested by interpretation of the chest CT scan
was initially entertained
because this would have explained the patient’s anemia and
possible cardiopulmonary effects (because of the location); however,
this still did not explain the presence of hypoglycemia.
The patient’s anemia was more likely the result of a chronic gastrointestinal (GI) bleed
complicated by anticoagulation.
On cardiac evaluation,
his cardiac enzymes, ECG, and echocardiogram did not reveal
any acute processes or conduction abnormalities.
Whipple's triad (hypoglycemic symptoms, low plasma glucose,
and relief of symptoms with the administration of dextrose) was noted.
During the hospital course, his hemoglobulin and hematocrit remained relatively stable,
without any signs of active bleeding after warfarin was withdrawn.

On review of the patient’s endocrine data,
the presence of a low insulin level was incompatible with a diagnosis of insulinoma.
The plasma insulin and C-peptide levels were appropriately suppressed
in response to the low fasting blood glucose.
His pituitary function was evaluated and revealed a mildly elevated follicle-stimulating hormone,
but normal thyroid hormones, prolactin, and cortisol levels were noted.
Adrenal insufficiency was also excluded given the combination of a normal morning cortisol level
and normal adrenocorticotropin stimulation test.
It was also important to exclude the possibility of hepatic and renal dysfunction,
which can both lead to recurrent hypoglycemia.
Factitious hypoglycemia was not suspected in this patient
as it was excluded by the low levels of insulin and C-peptide.
Additionally, he was not taking any medications
which could have been a source of iatrogenically-induced hypoglycemia.

The most likely diagnosis was determined to be a non-islet cell tumor (NICT) producing hypoglycemia.
The patient presented with hypoglycemic symptoms and an abnormal chest examination,
which correlated with a chest mass on CT scanning.
Surgical consultation was obtained for a biopsy of the left-sided chest mass.
A CT scan of the abdomen and pelvis was also obtained to rule out metastatic disease;
the result of the scan was negative.
Biopsy of the left chest mass (see Figure 4) showed bland spindle cells
with a lacy or reticulated appearance (see Figure 5)
which led to the diagnosis of a solitary fibrous tumor of mesenchymal origin.
The tumor was noted to be 6.8 × 5.2 × 3.9 in (17.2 × 13.2 × 9.9 cm) in size.
This large mesenchymal tumor accounted for all of the patient’s symptoms,
including his recurrent hypoglycemia.[1,2]

Non-islet cell tumors (NICTs) are a rare but well described etiology of chronic fasting hypoglycemia.[3]
These extrapancreatic tumors are generally of mesenchymal or epithelial origin.
Mesenchymal tumors represent 50% of all cases of NICT.
They include mesotheliomas, fibrosarcomas, rhabdomyosarcomas,
leiomyosarcomas, and hemangiopericytomas.
Carcinomas represent another 25% of NICTs and include hepatomas,
adrenocortical carcinomas, and carcinoid tumors.
The remaining 25% of NICTs associated with hypoglycemia include,
but are not limited to, hypernephromas, Wilms tumors, prostate carcinomas,
cervical carcinomas, breast carcinomas, leukemia, lymphomas, and myelomas.[4]
NICTs are characteristically large in size, weighing an average of 4.4-8.8 lb (2-4 kilograms).
Over one-third are retroperitoneal in location, approximately one-third are intra-abdominal,
and the remaining one-third are intrathoracic.[4]
Neuroglycopenic symptoms are the most common clinical features associated with NICT-induced hypoglycemia. These symptoms include obtundation, confusion, and behavioral aberrations.[4]
The diagnostic study of choice is CT scanning of the suspected tumor location,
followed by a tissue biopsy for identification.

In this patient, the large mesenchymal tumor identified in the intrathoracic area
resulted in the neuroglycopenic symptom of obtundation.
His obtundation was only abated by continuous glucose administration preoperatively,
and by surgical removal of the NICT.

It has been proposed that NICTs mediate their effects through insulin-like growth factor (IGF)?II.
In normal circumstances, IGF-II is produced by the liver as a 7.5-kilodalton (kD) molecule.
Most IGFs subsequently form a 150-kD tertiary complex with IGF-binding protein (IGFBP)?3
and acid-labile glycoprotein.
This large complex is retained in circulation and delivers IGF to tissues,
where it interacts with specific IGF receptors for local growth promotion.
Normally, the circulating IGF-II tertiary complex does not interact with insulin receptors and,
therefore, is not associated with hypoglycemia.[3-6]

In contrast to normal physiology, NICTs produce a partially processed,
high molecular weight (MW) IGF-II (also known as “big” IGF-II).
Its MW has been demonstrated to be 11-18 kD.
It constitutes up to 50-75% of circulating IGF-II in patients with NICTs.[6]
Big IGF-II does not form a tertiary complex,
but instead forms a binary complex with less restrictive IGFBPs, such as IGFBP-2.
This smaller, 50-kD binary complex allows for capillary crossing
and delivery of big IGF-II to insulin receptors, primarily in skeletal muscle,
where increased bioavailability leads to increased glucose utilization and,
therefore, hypoglycemia.
Big IGF-II also binds to insulin receptors in the liver,
where it suppresses gluconeogenesis and glycogenolysis, thereby enhancing the hypoglycemic response.[4]
The increase in bioavailable IGF-II also leads to the suppression of insulin and growth hormone,
as well as a decrease in the production of IGF-I, IGFBP-3,
and acid labile subunit, while increasing production of IGFBP-2.

The treatment of hypoglycemia for patients with NICTs is symptomatic support
until resection of the tumor is performed.
During this patient’s hospital course, he required continuous infusion
of dextrose along with frequent monitoring of his blood glucose.
Complete resolution of his hypoglycemic symptoms after tumor resection
supported the diagnosis of NICT-induced hypoglycemia.
Low levels of growth hormone, IGF-I, and IGFBP-3 also supported the hypothesis
that altered IGF-II was the mediator of hypoglycemia.
Although an elevated IGF-II level was not identified,
it is well known that IGF-II levels may be normal or elevated.[7]
In NICT-associated hypoglycemia,
IGF-II can cause hypoglycemia at normal total serum levels
as a result of altered processing and increased bioavailability of IGF-II.[4]
The patient was fortunate to have a benign tumor
which did not require further chemotherapy or radiation.

It should also be noted that this patient’s presentation of hypoglycemia
differs substantially from classic hypoglycemic episodes.
Hypoglycemic symptoms typically include hyperadrenergic and neuroglycopenic-type symptoms;
however, this patient did not describe symptoms such as these prior to syncope.
Patients with tumor-related hypoglycemia usually have gradual slow falls in their blood glucose.
This slow fall does not trigger the hyperadrenergic response,
and neuroglycopenia can progress from confusion to coma and possible seizures
without being recognizable to the patient.
Additionally, it is highly unusual for a patient with hypoglycemia to spontaneously
wake from an altered or comatose state.
Unlike in the setting of hypoglycemia secondary to diabetes medications,
it is likely that in cases of tumor-related hypoglycemia the body's counter-regulatory mechanisms
are able to provide a sufficient response to bring the serum glucose to a reasonable level
and result in recovery of alertness without pharmacologic intervention.

A 77-Year-Old Man With Suddenly Worsened Abdominal Pain

Background

　A 77-year-old man presents to the emergency department (ED) in the early morning
　with a 4-hour history of severe, generalized abdominal pain.
　He describes some “cramp-like” abdominal pain and bilious vomiting yesterday,
　but states he simply “got on with things”.
　His condition had worsened considerably by late evening.
　He describes the sudden onset of generalized, constant,
　intense abdominal pain necessitating an ambulance call.
　On presentation to the ED, he has no current vomiting.
　He complains of episodic “indigestion” that has occurred off and on for the past few months.
　On further questioning,
　the patient reports experiencing infrequent but quite painful episodes of upper abdominal pain
　after meals which sometimes feel as if it is ”going to his right upper back”
　and is associated with intermittent vomiting.
　This lasts for minutes to hours after the intake of meals.
　He states that antacid preparations do little good in controlling these symptoms,
　but he takes them anyway.
　His past medical history includes hypertension, ischemic heart disease,
　chronic obstructive pulmonary disease (COPD), and gout.
　He has no significant past surgical history and
　his currently prescribed medications include aspirin, atenolol,
　furosemide, a glyceryl trinitrate spray,
　and 2 inhalers for his COPD (the names of which the patient does not know).

　On examination, the patient is lying quite still.
　He does not appear cachectic, but does seem clinically dehydrated.
　His heart rate is 80 bpm, his blood pressure is 102/65 mm Hg,
　his capillary refill time is prolonged, and cool extremities are noted. He is afebrile.
　His lungs are clear to auscultation and his heart sounds are normal, with no added sounds.
　His abdomen is mildly distended, without visible scars, and there is no discoloration of the skin.
　When asked to cough, the patient winces in pain.
　No hernias are appreciated on examination.
　Palpation of the abdomen reveals generalized, diffuse tenderness and board-like rigidity.
　The abdomen is tender to percussion throughout all 4 quadrants,
　with a tympanitic note that is associated with loss of liver dullness.
　A rectal examination reveals a small amount of normal stool.
　Both femoral pulses are palpable and equal.
　The neurologic examination reveals no abnormalities.
　The peripheral examination is normal except for cool extremities.

　A fluid challenge of 500 mL 0.9% saline is given along with analgesia, and his vital signs improve.
　Laboratory investigations yield the following information:
　a white blood cell (WBC) count of 15.8 × 103/μL (15.8 × 109/L),
　C-reactive protein is 247 mg/L, sodium is 148 mEq/L (148 mmol/L),
　potassium is 3.1 mEq/L (3.1 mmol/L), urea is 28.6 mg/dL (10.2 mmol/L),
　creatinine is 1.5 mg/dL (131μmol L). Blood gas analysis reveals
　a pH of 7.31, HCO3 of 20 mEq/L (20 mmol/L), PCO2 4.1 kPa, and lactate of 23.4 mg/dL (2.6 mmol/L).
　Erect chest and supine abdominal radiographs are obtained (see Figures 1 and 2).
　A nasogastric tube is inserted and instructions are given for the patient to remain ‘nil by mouth’.
　He is catheterized and the urinary output is monitored along with the vitals.
　A further 1000 mL of 0.9% is initiated.
　Cefuroxime and metronidazole are started intravenously,
　and after urgent surgical consultation the patient is taken to the operating room
　for an emergency laparotomy.

Discussion

　This patient was suffering from mechanical small-bowel obstruction
　complicated by perforation and subsequent peritonitis.
　The patient’s history and examination findings were consistent with this sequence of events.
　Further support for this was found on the erect chest and supine abdominal radiographs;
　the presence of a large amount of free intraperitoneal air and dilated loops of small bowel were noted.
Regardless of the underlying etiology,
　the initial treatment for intra-abdominal free air with peritonitis is emergency laparotomy.

　After resuscitation,
　the patient was transferred to the operating room for an exploratory laparotomy.
　During the procedure,
　it was revealed that the peritoneal cavity was grossly contaminated with
　intestinal contents spilling out from a small hole in the distal ileum.
　The cause of the obstruction was found to be a gallstone of 1.18 in (30 mm) in diameter
　that was impacted in the terminal ileum.
　The gallbladder was adherent to the duodenum.
　The entire length of the bowel was examined for other stones, but none were found.
　The stone was gently massaged in order to move it proximally and it was removed via an enterolithotomy.
　The perforation was closed with interrupted sutures and, after copious lavage, the abdomen was closed.

　Cholelithiasis is a common disorder prevalent in 10% of the population,
　with symptomatic manifestation in 20-30% of those affected.[1,2]
　Gallstone disease may present with an assortment of complications
　that are usually the result of stones within the gallbladder and biliary tree,
　with the most common presentation being biliary colic.
　Extrabiliary problems are rare;
　however, some 3-5% of patients with cholelithiasis have a cholecystenteric fistula
　as part of the spectrum of their disease,
　most commonly occurring between the gallbladder and duodenum (71.4%),
　followed by a fistula with the stomach (14.3%) and, lastly, with the colon (6.3%).[3]
　In addition,
　fistulae may arise between the common bile duct and the intestinal tract,
　and other organs and the abdominal wall have also been reported as being involved.
　The possibility of concurrent Mirizzi syndrome
　(a rare condition in which gallstones lodged in the Hartmann pouch or cystic duct
　externally compress the common hepatic duct) should be ruled out
　because an association between these has been suggested.
　Gallstones may migrate into the gastrointestinal tract through such a fistula
　(as in the case of this patient), but the majority of such cases pass without incident.
　Stones larger than 0.7-1.0 in (2-2.5 cm), however, are at risk of becoming impacted.[4]
　Gallstones can grow in diameter as they pass through the intestinal lumen and sediment
　from the bowel contents is deposited onto them.
　In a series of 40 patients,
　the site of impaction was found to be the ileum in 25 patients, jejunum in 9,
　duodenum in 3, and colon in 1.[5]
　A further review of 1001 patient cases delineated these sites further,
　with the terminal ileum and ileocecal valve reportedly being most commonly involved,
　followed by the ligament of Treitz and the pylorus,
　whereas the duodenum and sigmoid colon were relatively rare locations
　for impaction of a gallstone within the enteric tract.[6]
　It should be noted that these sites represent regions of anatomically smaller luminal diameter.
　Colonic obstruction would likely only occur if a pre-existing pathology,
　such as a colonic stricture, were present.

　Mechanical intestinal obstruction with a gallstone was first described by Bartholin in 1654,
　with the term “gallstone ileus”; however, this is a misnomer.
　The symptoms are variable depending on the site of impaction and
　mirror those of intestinal obstruction resulting from any etiology.
　Classically,
　the patient will present with subacute episodes of obstruction
　resulting in abdominal pain and vomiting that subside as the stone spontaneously disimpacts.
　The symptoms will then recur as the stone becomes larger
　(because of accrued bowel sediment) and reobstructs the bowel lumen.
　On a side note, high duodenal or pyloric impaction will produce a clinical picture
　more akin to gastric outlet obstruction and is known as Bouveret syndrome.
　Of all the causes of mechanical intestinal obstruction, gallstones account for 1-4%
　(up to 25% if we consider only patients over 65 with nonstrangulated obstruction) and
　occur more commonly in women.[6]
　The diagnosis is notoriously difficult to make,
　with up to 50% of diagnoses being made at laparotomy.[4]
　Patients often have no previous history of biliary symptoms and
　other causes of obstruction are more common, which can lead to this condition being overlooked.
　Radiographic clues are responsible for the majority of early diagnoses.
　On abdominal radiography,
　the Rigler triad (pneumobilia, small-bowel obstruction, and
　a gallstone usually seen in the right iliac fossa) is considered highly suggestive of gallstone ileus.
　It should be remembered here that only 10% of gallstones are visible on radiographs,
　and gas in the biliary tree and gallbladder has many causes and is most commonly iatrogenic.
　This can be extended to other imaging modalities.
　Current evidence indicates that the Rigler triad can be seen in 15% of patients
　on abdominal radiography, 11% on ultrasonography, and with computed tomography (CT) scans
　demonstrating the triad in 78% of cases;
　in fact, CT scanning was often able to show the fistula itself.[7]
　Further studies support the role of CT scanning in the evaluation of patients
　with gallstone ileus by highlighting its ability to detect the size,
　location, and exact number of ectopic stones, and
　they also laud its overall value in the diagnoses of many cases of acute abdomen.[8]
　Contrast studies of the upper gastrointestinal tract have also been used,
　albeit less frequently, and
　have had some success in defining the site of obstruction and
　demonstrating the fistula via retrograde flow into the biliary tree.
　The success of CT scanning at demonstrating additional ectopic stones raises the issue of recurrence.
　Additional ectopic stones may be present and, rarely,
　may be overlooked, possibly leading to a second episode of obstruction after operation.
　Attention should be paid to the fistula itself;
　determining its presence is essential, as is planning for its remediation.
　This lends credence for the use of CT scanning in the investigations for this condition.
　Although ultrasonography fairs worse than plain films in demonstrating the Rigler triad,
　it remains excellent at demonstrating biliary pathology overall.

　In this case,
　a further complication had occurred, namely ileal perforation proximal to the site of obstruction.
　Only a handful of cases of gallstone ileus report such a complication,
　which normally arises as a result of the pressure of the stone
　causing necrosis of the bowel wall at the site of obstruction,
　or increased wall tension caused by distention proximal to the obstruction.[9]
　Although this patient’s complication occurred because of a delay in presentation,
　it is important to bear in mind that a delay in the diagnosis
　also adds to the already significant mortality and morbidity of this condition
　by allowing the development of further complications and
　decreasing the physiologic reserve of the patient prior to therapeutic management,
　which often includes surgery.
　Typical patients are also elderly and more likely to have comorbidities;
　all of these factors combine to give an overall perioperative mortality of 12-17%.[6]

　Whatever methods are used to guide the clinician, prompt resuscitation and surgery
　are pivotal in offering the best prospects of survival to the patient with gallstone ileus.
　There is significant disagreement over how to surgically approach these patients
　to relieve the obstruction.
　Some favor a laparoscopic approach and argue that it is a diagnostic tool
　in the acute abdomen with the potential for definitive treatment,
　and that the smaller incisions and reduced recovery time suit the patient population better;
　in addition,
　there is also the ability to convert to an open procedure
　if the operation is technically too difficult.
　Laparoscopy, however, can result in decreased venous return as a result of the increase
　in intra-abdominal pressure;
　this can translate into hypotension in a patient who is already hemodynamically unstable.
　This being said, there are numerous case reports of laparoscopic enterolithotomy
　and disimpaction procedures being carried out successfully,
　with patients going on to have uneventful hospital stays and discharge.[10,11]
　The choice of open versus laparoscopic surgery should be based on the surgeon’s skill
　and the anesthesiologist’s opinion.
　Another issue is whether or not definitive biliary surgery,
　namely closure of the fistula and cholecystectomy, should be undertaken and,
　if so, when. Relief of the intestinal obstruction is the first priority and,
　in general, enterolithotomy alone is believed to be the best course of action
　in the typical patient with gallstone ileus.[12,13]
　Closure of the fistula and cholecystectomy can then be performed electively at a later date
　(the so-called “2-stage procedure”).
　Performance of a “1-stage procedure” should only take place in
　a highly select group of low-risk patients,
　as a small but significant increase in perioperative mortality has been observed
　(from 11% to 16.7% in general populations).[12,14]
　Although surgery is the treatment of choice, endoscopic sphincterotomy
　and common bile duct stone extraction have been shown to cause spontaneous healing of fistulas.
　Extracorporeal and electrohydraulic lithotripsy of stones has also been described in cases
　where gas-containing bowel loops were not in the way.
　Finally,
　endoscopic procedures for removing stones from the duodenum and colon
　can also be employed at specialized centers.
　Such procedures are reserved for the treatment of patients
　who are unable to undergo surgery to correct the fistula.[15,16]
　A fact that needs to be stressed is that at the time of surgery the entire length of bowel
　should be examined for further ectopic stones or fragments.

　In conclusion,
　mechanical obstruction of the intestine with a gallstone
　is an uncommon complication of stone disease in the biliary system,
　occurring in less than 0.5% of patients.[6]
　The diagnosis is difficult to make given the lack of antecedent history
　in a large proportion of patients and its relative infrequency as a cause of obstruction.
　A careful history-taking and physical examination,
　in particular excluding adhesion and external hernia,
　and the use of imaging such as CT scanning can expedite the establishment of the diagnosis.
　This should be undertaken when resuscitative measures are being done,
　and should not delay operative intervention when perforation and peritonitis are present.
　The procedure of choice should be chosen bearing in mind
　that obstruction relief is the first priority.

A Forgotten Etiology of Refractory Congestive Heart Failure

Background

A 46-year-old African-American woman is admitted to the intensive care unit (ICU)
with a diagnosis of congestive heart failure after presenting to the emergency department (ED)
with a 4-day history of progressive generalized weakness,
increasing shortness of breath, and leg swelling.
She denies having any recent chest pain, cough, or fevers.
She reports that approximately 7 months ago
she had been admitted to another hospital for chest pain and shortness of breath.
She states that at that time she had elevated cardiac enzymes and
a cardiologist performed an angiogram that showed normal coronary arteries.
Three months ago she was again admitted to a different hospital
with shortness of breath and leg swelling, and she was diagnosed with congestive heart failure.
In addition to the leg swelling and trouble breathing
that had prompted her to call 911 in this instance,
she is also complaining of mild dysphagia, gastroesophageal reflux symptoms,
and difficulty getting up from a sitting position
(which has been getting progressively worse for about 4 weeks).
She mentions that she has lately been using a cane to help her walk.
In addition,
for the last 4 months she has noticed swelling of her tongue with loss of taste sensation,
hair loss, bruising of her eyes, and a nontender, nonpruritic,
ecchymotic rash on her abdomen and chest.

On physical examination, her heart rate is 88 bpm, blood pressure is 88/54 mm Hg,
and respiratory rate is 22 breaths/min.
She has an oxygen saturation of 99% while breathing room air.
Pertinent findings on clinical examination include bilateral subconjunctival hemorrhaging;
periorbital ecchymoses; multiple ecchymotic lesions around the anterior neck,
chest, and, abdomen (see Figure 1); and
bilateral pitting pretibial and prepedal edema.
Localized swelling with imprinted tooth markings (see Figure 2)
are noted on the lateral aspect of the tongue.
Jugular venous distension of 12 cm with normal first and
second heart sounds, decreased air entry with mild rales at both lung bases,
and bilateral proximal leg weakness are also found.

Other relevant findings include a B-type natriuretic peptide (BNP) level of 1026 pg/mL (1026 ng/L),
mildly elevated cardiac enzymes, and
a chest radiograph showing cardiomegaly along with bilateral basal airspace opacities.
Computerized tomography (CT) of the thorax shows bilateral pleural effusion
(which is greater on the right than the left) and a small pericardial effusion.
A urine analysis shows mild proteinuria, but no red blood cells,
white blood cells, or casts are detected.
A 24-hour urine protein collection reveals proteinuria of 135 mg (0.135 g).
Electrocardiography (ECG) demonstrates low voltage complexes with poor R-wave progression.
A serum ferritin level and a panel of autoimmune tests are all normal.
Transthoracic echocardiography is performed (see Figure 3).

Discussion

The clinical findings of multiple ecchymotic lesions, enlarged tongue,
features of congestive heart failure, low voltage complexes on electrocardiography,
and an echocardiographic pattern showing a "ground-glass" appearance
in the myocardium were consistent with cardiac amyloidosis.
Other echocardiographic findings in this patient included
a left ventricle with mildly reduced systolic function
(ejection fraction of 45%; normal range, 55-70%);
moderately dilated left atrial dimension at 5.5 cm;
moderately increased ventricular wall thickness,
with an interventricular septal thickness of 2.0 cm (normal range, 0.7-1.1cm) and
a similarly increased thickness in the posterior wall;
moderate diastolic dysfunction, and a small pericardial effusion.
An abdominal fat pad biopsy to confirm amyloidosis was negative;
however, biopsy of the swollen tongue showed
homogenous extracellular fibrils positive for Congo red staining and
positive for green birefringence (see Figures 4 and 5).
This result was diagnostic of systemic amyloidosis.

Serum protein electrophoresis was negative for monoclonal bands,
but immunofixation electrophoresis revealed
evidence of a monoclonal population of lambda (λ) light chains.
A free light chain (FLC) assay performed on the serum showed
an elevated lambda free light chain level of 270.00 mg/L (normal range, 5.7-26.3 mg/L) and
a kappa-to-lambda ratio (κ:λ) of 0.03 (normal range, 0.26-1.65).
Bone marrow aspiration and biopsy showed hypocellular marrow,
with trilineage maturation and mature plasma cells.
Congo red staining demonstrated microfocal green birefringence within the vessel walls.
Flow cytometry of the bone marrow revealed plasma-cell dyscrasia of the monoclonal lambda type.
A skeletal survey showed no lytic lesions. Based on the above information,
the diagnosis of systemic amyloidosis was made.

A characteristic feature of amyloidosis is
the extracellular deposition of pathogenic insoluble fibrillar proteins.[1]
The age-adjusted incidence of amyloidosis is estimated
to be 5-12 cases per million persons per year.[2]
The causative protein is an immunoglobulin light chain or a fragment of light chain
produced by the monoclonal proliferation of plasma cells.[3,4]
Amyloidosis is a plasma-cell dyscrasia
that has a low plasma cell burden of only 5-10% in the bone marrow.
This is in contrast to multiple myeloma,
which has 10-15% plasma cells that express a lambda-type light chain.

The clinical features of amyloidosis depend on the organs involved.
The 3 most common internal organs affected are the kidneys, the heart,
and the peripheral nerves. Amyloid cardiomyopathy is the second most common presentation.
It can lead to rapidly progressive heart failure,
with predominant features of right-sided heart failure.
Increased ventricular wall thickness resulting from
amyloid deposition leads to diastolic dysfunction.
Systolic dysfunction is a late feature caused by myocyte necrosis and local interstitial fibrosis.
Atrial arrhythmias (in particular, atrial fibrillation)
are common in patients with cardiac amyloidosis.

Many patients with amyloidosis report easy bruising resulting from
amyloid deposits in the capillaries and deficiency of clotting factor X.
Cutaneous ecchymoses may also develop.
It was theorized that the lesions seen on this patient's abdomen
may have been caused by the above mentioned factors.

ECG findings include low voltage in up to 70% of cases and
a pseudoinfarct pattern in up to 75% of cases.[6,7]
Binding of amyloid fibrils to His-Purkinje cells can lead to sudden cardiac death
secondary to atrioventricular block and ventricular dysrhythmias.
An echocardiogram will typically reveal thickening of the ventricular septal and free walls,
normal or reduced ventricular cavity size, dilated atria, and
a normal or slightly reduced ejection fraction;
however, cardiac output is significantly reduced.[6]
Atrial septal thickening with granular sparkling myocardium
is highly specific for differentiating cardiac amyloidosis
from other causes of left ventricular hypertrophy.[8]
Of note, sarcoidosis and hemochromatosis can also present similarly,
with normal or low voltage ECG findings and thickened ventricle walls.
A coronary angiogram will usually be normal;
amyloid deposition involving the epicardial vessels may be rarely seen.[5]

The definitive diagnosis of amyloidosis usually requires tissue biopsy.
Fine needle aspiration of abdominal fat is a simple procedure
that is positive in > 70% of patients with amyloidosis.[9,10]
Biopsies can also be obtained from the minor salivary glands, gingiva, rectum, and skin.
Rarely, obtaining tissue from an affected organ may be necessary.
In some cases of isolated cardiac involvement,
percutaneous endomyocardial biopsy of the right ventricle or interventricular septum may be required.
Other methods of diagnosis include a bone marrow biopsy
to look for a monoclonal population of plasma cells (either kappa or lambda)
or immunofixation electrophoresis to look for monoclonal light chain
in the urine or serum (which is more sensitive than a conventional electrophoresis).
Another, more sensitive method is to do a FLC (free light chain) assay,
which detects circulating free light chains of both the kappa and lambda types.
This assay can also be used for following the progression of the disease and the response to treatment.
A combination of an abnormal kappa-to-lambda ratio and
a positive serum immunofixation can identify 99% of patients with amyloidosis.[11]

The median survival in systemic amyloidosis is only 1-2 years;
patients with symptomatic heart involvement have a median survival of only 6 months.
Elevated N-terminal pro-brain natriuretic peptide, elevated cardiac troponins,
a high circulating level of free light chains, and
increasing wall thickness all portend a poor prognosis.[12]
The thickness of the ventricular septum in diastole is a predictor of survival,
with survival ranging from 2.4 years in patients
with normal wall thickness to 0.4 years in those with increased wall thickness.[13]

The treatment of amyloidosis includes oral chemotherapy (melphalan and prednisone) or
high-dose melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT).
The conventional approach is low-dose oral melphalan with prednisone administered in a cyclical manner;
however, the impact of this regimen is modest and rarely results in
a complete hematologic response or reversal of organ dysfunction.[13]

Studies have demonstrated a 25-75% complete response with HDM/SCT.
A "complete response" is defined as the absence of monoclonal protein
in serum and urine on immunofixation electrophoresis,
a normal serum free light chain ratio, and
a bone marrow biopsy with < 5% plasma cells and no clonal predominance.
In a large study by Skinner et al involving 277 patients,
HDM/SCT had a 40% complete hematologic response, with 47% survival at 5 years.[14]
The major limitation of HDM/SCT is the high rate of treatment-related mortality.

The Boston University amyloid program has put forward the following patient
eligibility criteria for HDM/SCT treatment[13]:

Confirmed tissue diagnosis
Evidence of plasma-cell dyscrasia
Age > 18 years
Left ventricular ejection fraction of > 40%
Supine systolic blood pressure > 90 mm Hg
Room air oxygen saturation of > 95%
Performance status score of 0-2
Heart failure caused by amyloidosis is treated with careful diuresis,
daily monitoring of fluid and salt intake, and
careful use of angiotensin-converting enzyme (ACE) inhibitors.
Calcium-channel blockers and digoxin should be avoided.
Heart transplantation followed by adjuvant chemotherapy
is an option in people with end-stage heart failure.[15]
Although the survival in this group of patients
has been statistically lower than that of other cardiac transplantation patients,
patients with end-stage heart failure still had a 5-year survival of up to 50%.[15]

We would like to draw attention to the fact
that amyloidosis is a rare cause of rapidly progressing heart failure.
An important clue to the diagnosis of cardiac amyloidosis
is the paradoxical finding of low voltage complexes on ECG but
concentric ventricular hypertrophy on echocardiography.
As seen in the patient in this case, coronary angiography is usually normal
because the epicardial vessels are not involved.
This patient was started on furosemide and lisinopril and
was referred to a transplant hematologist for stem cell transplantation and high-dose melphalan. Unfortunately, within 1 month her condition deteriorated and she died of multiorgan failure.

This case also highlights the importance of obtaining a biopsy from an affected organ
if the clinical suspicion is very high,
particularly in cases where the initial fat pad biopsy is inconclusive.
Timely referral to a specialized center is key to treating these patients
because of the high mortality and rapid rate of progression of the disease.

Background

　A 74-Year-Old Man With Acute Myelocytic Leukemia and Dyspnea

　A 74-year-old man presents with easy bruising, fatigue, and generalized weakness.
　The patient's symptoms have been progressing during the past 3 weeks.
　He denies having any other symptoms.
　He has no significant past medical history, and he denies any recent travel,
　tobacco use, or use of illicit drugs.
　The patient is retired from an office administration position.
　He is admitted to the hospital for evaluation of his weakness and easy bruising.
　On admission,
　a chest radiograph is obtained, but no abnormalities are noted.
　An initial complete blood cell count (CBC) is ordered,
　which shows thrombocytopenia,
with a platelet count of 12.0 × 103/μL (12.0 × 109/L),
　and anemia, with a hemoglobin 6.8 g/dL (68 g/L) and a hematocrit of 19% (0.19).
　His peripheral blood smear demonstrates 12% blasts.
　The patient undergoes a subsequent bone marrow biopsy,
　which confirms acute myelocytic leukemia.
　He then receives induction chemotherapy with cytarabine and daunorubicin.
　Following induction, the patient becomes pancytopenic,
　with a 21-day bone marrow biopsy showing chemotherapeutic effect.
　The patient's hospital course is then complicated by febrile neutropenia
　and vancomycin-resistant Enterococcus bacteremia
from a central venous catheter infection.
　He is treated with intravenous linezolid,
　which clears his bacteremia based on repeat blood cultures; however,
　he still suffers persistent fevers.

　On day 30 postinduction,
　the patient develops shortness of breath and complains of a progressive, nonproductive cough.

　On physical examination,
　the patient has a blood pressure of 136/60 mm Hg.
　His heart rate is 92 bpm, he is febrile, with a temperature of 101.2°F (38.4°C),
　has a respiratory rate of 28 breaths/min,
　and his pulse oximetry reading is 93% on a nonrebreather face mask.
　The patient appears to have increased respiratory effort and diminished breath sounds;
　additionally,
　rhonchi are detected in the right upper lung field.
　He also has minimally decreased breath sounds at the lung bases bilaterally.
　The remainder of his examination is unremarkable.

　New laboratory studies are obtained, which show that the patient remains pancytopenic.
　He has 27.0 × 103/μL (27.0 × 109/L) platelets,
　and an absolute neutrophil count of 800 cells/mm3.
　Plain-film radiography and a computed tomography (CT) scan of the chest
(see Figures 1 and 2)
　show a dense right upper-lobe consolidation,
　with narrowing of the right upper-lobe bronchus and mediastinal lymphadenopathy.

　The patient then undergoes flexible bronchoscopy (FOB) that reveals
　a necrotic endobronchial lesion completely obstructing
　the anterior segment of the right upper lobe (see Figure 3).
　Endobronchial biopsies are taken of this lesion.
　Histology slides are provided (see Figure 4).
　Rigid bronchoscopy is subsequently performed,
　with electrocautery of the endobronchial lesion and
　near-complete reestablishment of the right upper lobe anterior segment lumen,
　without complications.

Discussion

　Zygomycetes are a ubiquitously distributed group of fungi found commonly in soil,
　decaying organic matter, and on fruit and bread.
　The members of this group of fungi that infect humans include Mucor,
　Rhizopus, Absidia, and the Cunninghamella species.
　Given the wide distribution of these fungi,
　most humans are exposed to these organisms on a daily or weekly basis.[1,2,3]

　Although first described by Paltauf in 1885,
　these infections were virtually unrecognized in the lungs
until the advent of antimicrobial, 　immunosuppressive, and antineoplastic therapy.
　They rarely cause disease in immunocompetent hosts
because of the low virulence of the organisms;
　however,
　they are now the third most common cause of invasive fungal infection
　in immunocompromised patients,
　especially stem-cell transplant recipients and patients
with underlying hematologic malignancies.[4]
　These spore-forming saprophytes infect hosts
via inhalation of aerosolized spores
　or from hematogenous spread.
　Colonization may be transient or persistent and
　depends upon host mucosal defense mechanisms and fungal virulence.
　After colonization,
　local disease may form and can progress to disseminated illness in susceptible hosts.
　Mucor are molds in the environment that become hyphal forms in the body tissues.
　Once the spores begin to grow,
　fungal hyphae invade blood vessels and produce tissue infarction, necrosis,
and thrombosis. Neutrophils are the key host defense against these fungi;
　therefore,
　individuals with neutropenia or neutrophil dysfunction (diabetes, steroid use) are
at highest risk.
　Few cases of mucormycosis have been reported in patients with AIDS,
　suggesting that the host defense against this infection
　is not primarily mediated by cellular immunity.[2,3,5]

　The clinical manifestations of infection have traditionally been divided
into 6 separate syndromes: 　
rhinocerebral, pulmonary, cutaneous, gastrointestinal,
central nervous system (CNS), and disseminated disease.
　Rhinocerebral and pulmonary involvement are the 2 most common syndromes.
　Rhinocerebral disease, the most common form, is most often seen in diabetics,
　particularly those suffering from diabetic ketoacidosis.
　Between 50% and 75% of pulmonary mucormycosis infections occur
　in patients with hematologic malignancies.[1]

　Overall, mucormycosis remains extremely rare.
　A recent review of mucormycosis cases at 1 United States cancer center found
　that 0.7% of patients were found to have mucormycosis at autopsy,
　and that 20 patients per 100,000 admissions had the disease.[2,5,6]
　It was found in 1% of patients with acute leukemia
in an Italian multicenter review.[7]
　Mucormycosis carries a very high mortality rate of 50-85%.
　Pulmonary and gastrointestinal diseases carry an even higher mortality rate
　because these forms are typically diagnosed late in the disease course.
　Rhinocerebral disease causes significant morbidity
　in patients who survive because treatment usually requires extensive,
　and often disfiguring, facial surgery.[3]

　The vast majority of pulmonary mucormycosis infections present
　with diffuse lung involvement and a rapidly progressive clinical course.
　Patients report symptoms of rapidly progressive cough, fever,
and pleuritic chest pain.
　Patients are often profoundly ill,
　with marked gas-exchange abnormalities and
　rapidly advancing respiratory failure despite therapy with conventional antibiotics.
　Reported chest abnormalities found on radiography include
nodular, lobar, or wedge-shaped infiltrates,
　which may be seen in 58% of cases.
　Other signs include mediastinal widening, bronchopneumonia,
solitary nodule, miliary pattern, cavitation, air crescent sign,
bronchopleural fistula, pulmonary artery pseudoaneurysm, and pleural effusions.
　The CT halo sign has been shown to represent pulmonary infarcts
with surrounding hemorrhage and edema.
　More typical findings seen on chest radiographs
are those of fungal vascular invasion.
　The invasion of large vascular structures leads to thrombosis
and infarction of the lung parenchyma.
　This may begin as a nodular or nonspecific acinar infiltrate,
　which subsequently develops into a wedge-shaped density.
　In some instances, it progresses to lobar consolidation.
　The major complication associated with pulmonary mucormycosis
is massive hemoptysis;
　therefore,
　treatment of pulmonary Zygomycetes infections is usually surgical.
　Despite this, the radiographic variability is vast,
　and pulmonary mucormycosis cannot be diagnosed or excluded
on radiographic grounds alone.[3,4,8]

　The results of sputum cultures are usually negative,
　but a positive culture for Mucor from sputum
is highly suggestive of invasive infection.
　A definitive diagnosis requires a histologic investigation.
　There must be tissue invasion with characteristic broad (5-50 μm),
　nonseptate hyphae with right angle branching,
and blood vessel invasion must be seen.
　Culture of histologic material will give variable results as well.
　Percutaneous needle biopsy, open lung biopsy,
　and pleural fluid culture have been successful methods to obtain these samples.
　Bronchoscopic examination is often chosen as a relatively safe
　and less-invasive technique to obtain histologic material for diagnosis;
　however,
　the results may be negative in patients with large areas of lung infarction
　secondary to mucormycosis vascular invasion.[1,3,4]

　Treatment generally starts with control of the patient's underlying disease,
　which is often difficult to accomplish.
　Withdrawal of immunosuppressive agents and corticosteroid drugs, glycemic control,
　and correction of acidosis are all advisable.
　Amphotericin B remains the only antimicrobial agent with evidence of antifungal efficacy in mucormycosis.
　There is variability in the sensitivity to amphotericin between isolates.
　Host factors, such as infarcted tissue,
　and poor host immunocompetence will impact the success of treatment.
　Early and aggressive surgery for localized disease
appears to offer the best chance of recovery,
　especially in diabetics with hemoptysis.[3,5]

　Presentation with endobronchial disease is distinctly rare.
　Even less common is presentation with endobronchial disease
confined to a well-localized area.
　Again,
　treatment of endobronchial mucormycosis is primarily surgical.
　The high degree of vascular invasion and
　resultant infarction make it unlikely that amphotericin
　will be effectively delivered to the involved areas.[9]
　It is therefore important to recognize that the presentation of pulmonary mucormycosis
　depends on the associated clinical disorder.
　Patients with leukemia and lymphoma often have diffuse parenchymal disease
　refractory to medical and surgical therapy.
　Some patients have localized disease amenable to surgery
with or without amphotericin.
　Overall,
　early consideration of pulmonary mucormycosis should lead to earlier diagnosis,
　appropriate medical and surgical therapy, and an increased survival rate.[3]

　The patient in this case was treated with intravenous amphotericin B for 4 weeks
　along with endobronchial resection of the lesions.
　Radiographically and clinically he completely improved after this treatment.
　This is a rather interesting exception to the normal treatment
for endobronchial disease,
　since he was not primarily managed with surgery.
　His antifungal regimen did not appear to impact his leukemia treatment,
　as his induction chemotherapy with cytarabine and daunorubicin showed
　chemotherapeutic effect at day 21 postinduction,
which was demonstrated with a bone marrow biopsy.
　The patient recovered bone marrow function in a timely fashion.

A 16-year-old boy is presented to the emergency department (ED)
with an 11-day history of low-grade fever.
He complains of decreased appetite and a 7-lb weight loss
　during approximately the past 11 days.
　He denies any recent travel or unusual exposures.
　His symptoms began with an erythematous rash on his feet,
　bilateral ankle swelling, and pain while walking.
　The symptoms partially improved with the use of ice packs and bed rest.
　The patient was seen in his pediatrician's office with the same complaints 3 days ago;
　he was prescribed amoxicillin/clavulanate at that time,
　but he has not experienced any further improvement.
　The patient has no significant previous medical or surgical history,
　and he denies using alcohol, cigarettes, or other drugs.
　He lives in a residential urban home with his parents and sibling.

　On the initial physical examination,
　he has a temperature of 100.9°F (38.3°C), but otherwise his vital signs are normal.
　His weight is noted to be in the third percentile for his age.
　Shoddy, deep cervical lymphadenopathy is present bilaterally,
　and asymmetrically enlarged, tender anterior cervical and
　submental lymph nodes are detected (more prominently on the left than right).
　He is noted to have a slightly scaly erythematous macular rash on his face and
　involving the bridge of the nose, with sparing of the nasolabial folds
　 (see Figure 1; the image shown is not of the actual patient,
　but it exhibits the same findings as described in this case).
　The rash has sharp edges and is not pruritic.
　His physical examination is otherwise unremarkable.

　The initial laboratory results reveal pancytopenia,
　with a white blood cell (WBC) count of 1.6 × 103/μL (1.6 × 109/L),
　a hemoglobin of 10.4 g/dL (104 gL), a hematocrit of 30%, and
　a platelet count of 71 × 103/μL (71 × 109/L).
　His erythrocyte sedimentation rate (ESR) is elevated at 80 mm/h.
　The patient is admitted to the hospital for fever of unknown origin.
　Cultures of blood, urine, and sputum are obtained, and
　he is subsequently started on broad-spectrum antibiotics.
　Serology tests for tick-borne illnesses, HIV, systemic lupus erythematosus (SLE),
　and Epstein-Barr virus (EBV) are sent.
　While awaiting the laboratory results,
　he is given 1 dose of intravenous immunoglobulin empirically for atypical Kawasaki disease,
　with no response.
　He is sent for bone marrow aspiration and biopsy,
　which shows hypocellular bone marrow for his age,
　with all 3 cell line elements present and without evidence of malignancy.
　Computed tomography (CT) imaging reveals bilateral axillary,
　anterior mediastinal, retroperitoneal, external iliac, supraclavicular,
　and inguinal lymphadenopathy (images not available).
　Biopsies of the left cervical and submandibular lymph node are performed,
　but they are not consistent with lymphoma or other malignancy.

　Throat, urine, and blood cultures remain negative after 4 days.
　Antinuclear antibody (ANA) titers are positive, with a titer of 1:640 and a speckled appearance.
　The patient is scheduled for a second lymph node biopsy
　because of the incongruence of the radiographic and histologic studies.
　Prior to the procedure,
　bilateral small pleural effusions are discovered on the chest radiographs.
　As a result of his anemia and thrombocytopenia,
　he is transfused packed red blood cells and platelets,
　without marked improvement in these indices.
　A second bone marrow biopsy and left axillary lymph node biopsy are performed,
　but the results are unchanged from the prior biopsy results.

Discussion

Figure 1.
　Systemic lupus erythematosus (SLE) is a rheumatic multisystem disease of unknown cause
　that is characterized by the presence of autoantibodies directed against self-antigens.
　These antibodies cause inflammatory damage to target organs, i
　ncluding the kidneys, blood-forming cells, and the central nervous system (CNS).
　The natural history of the disease is unpredictable.
　Untreated or undertreated SLE may be followed by spontaneous remission,
　years of smoldering disease, or rapid death.
　Conversely, early diagnosis and appropriate treatment can greatly improve the prognosis.[1]

　The incidence of SLE is approximately 1 in 2000 population,
　with a prevalence estimated at 1 in 10,000.
　The condition has greater prevalence
　in Native Americans, Asians, Hispanics, and African-Americans.
　Although onset before 8 years of age is unusual,
　SLE has been diagnosed during infancy.
　Female-to-male predominance is 4:1 before puberty and 8:1 afterwards.[1]

　Childhood SLE was once viewed as a uniformly fatal disease.
　With progress in the diagnosis and treatment,
　the 5-year survival rate is greater than 90%;
　however, a significant proportion of patients die prematurely because of disease complication.
　Major causes of death in patients with SLE include
　nephritis, CNS disease, infections, pulmonary hemorrhage and myocardial infarction.[1]

　The cause and disease mechanism of SLE remain unknown.
　The hallmark of SLE is autoantibody production against self-antigens,
　particularly DNA, as well as other nuclear antigens, ribosomes, platelets,
　coagulation factors, immunoglobulin, erythrocytes, and leukocytes.
　Elevated levels of immunoglobulin, particularly antidouble-stranded DNA antibodies,
　are associated with circulating and tissue-bound immune complexes.
　These lead to complement fixation and recruitment of inflammatory cells,
　 which results in tissue injury.
　The autoantibodies are synthesized and secreted by activated polyclonal B-lymphocytes.
　The dysregulation is potentially triggered by exposure to viral elements or drugs.
　The net result is that circulating self-reactive lymphocytes
　that normally undergo apoptosis before birth remain active.
　Other forms of immune dysfunction have also been described in SLE,
　including defects in macrophage phagocytosis, complement abnormalities,
　and abnormal complement receptors.
　Drug-induced lupus has been characterized
　by the presence of antihistone antibodies and corresponding immunofluorescent staining.[1]

　Multiple simultaneous mechanisms lead to end-organ damage in SLE.
　Vasculitis is a hallmark finding, with fibrinoid deposits
　in the blood vessel walls of affected organs and parenchymal changes
　with hematoxylin bodies that most likely represent degenerated cell nuclei.
　Immune-complex depositions with activated complement, rheumatoid nodules,
　and even granuloma in affected tissues having been described.[1]

　Because SLE is a multisystem disease, it can mimic many medical problems.
　It is considered in the differential diagnosis for a variety of symptoms,
　including fever of unknown origin, lymphadenitis, arthralgia, nephritis,
　cytopenias, abdominal pain, dizziness, weight loss, and rashes.[1,2]

　Four out of 11 accepted criteria are required to establish the diagnosis of SLE.
　They are used both in the research setting and by clinicians to better define a disease
　that presents in such diverse ways and is often difficult to diagnose.
　he criteria are listed as the following[1,3]:

　Hematologic finding (eg, anemia, thrombocytopenia)
　Positive test for ANA
　Serositis (eg, pleural effusion)
　Arthritis
　Malar rash
　Discoid rash
　Immunologic disorder (eg, positive double-stranded DNA)
　Photosensitivity
　Oral ulcers
　Renal disease
　Neurologic disorder

　Besides the findings necessary to fulfill the diagnostic criteria,
　other associated findings include dermatologic, musculoskeletal,
　gastrointestinal, renal, and cardiopulmonary dysfunction.
　Cutaneous manifestations include photosensitivity to sun-exposed areas;
　erythematous macular eruptions on the fingers, palms and soles;
　Raynaud phenomenon; and purpura.
　Mucus membrane changes range from erythema to ulceration,
　particularly in the palatal and nasal mucosa.
　 Musculoskeletal lesions include arthralgia, arthritis, tendonitis, and myositis.
　Serositis can affect the pleural, pericardial, or peritoneal surfaces.
　Manifestations of digestive disease include
　hepatosplenomegaly and mesenteric vasculitis leading to abdominal pain, diarrhea, and melena.
　Cardiac involvement may cause valvular thickening and verrucous endocarditis,
　cardiomegaly, cardiac failure, coronary artery disease, and thrombosis.
　Pulmonary manifestations include interstitial pneumonitis,
　pulmonary infiltrates, chronic fibrosis, and pulmonary hemorrhage.
　Neurologic manifestations may involve the central and peripheral nervous system.
　Memory loss, cognitive dysfunction, and neuropsychiatric manifestations may be severe.[1,3]

　In addition,
　the occurrence of arterial and venous thrombosis is suggestive of
　antiphospholipid antibody syndrome and needs to be considered
　in the setting of recurrent arterial thrombus or fetal loss.
　There is a wide spectrum of renal disease presentations in SLE;
　these range from hypertension, peripheral edema, electrolyte imbalance,
　nephritis, and acute renal failure.
　Renal biopsy is employed to confirm and stage lupus nephritis.[3]

　Elevated ANA titers should prompt the clinician to screen for SLE,
　as this finding is present in at least 90% of patients;
　however, it is not pathognomic and can be associated with rheumatic conditions,
　such as vasculitic syndromes, chronic autoimmune hepatitis,
　infectious mononucleosis, scleroderma, and hyperextensibility syndromes.
　Antidouble-stranded DNA findings are more specific for lupus than the ANA titer.
　The serum levels of hemolytic complement (CH50), C3, and C4
　are decreased in about two-thirds of pediatric SLE patients.
　Hypergammaglobulinemia is frequently found.
　The maternal immunoglobulin G (IgG) against Ro, La, and/or U1-ribonucleoprotein
　can be passively transported across the placenta
　and result in the heart block condition that is seen in neonatal lupus erythematosus.[1]

　In the patient in this case,
　hematologic irregularities (anemia, leukopenia, lymphopenia, and thrombocytopenia),
　abnormal ANA titer, serositis (pleural effusion), and a history of arthritis were present.
　There remained uncertainty about the diagnosis until the classical malar rash appeared.
　Afterwards,
　antidouble-stranded DNA titers were found to be elevated,
　and the complement levels were low, which helped to confirm the diagnosis.

　Although depression of 1 or 2 hematologic cell lines is common in SLE,
　pancytopenia occurs in fewer than 10% of patients.
　Depression of cell lines is caused by the destruction of peripheral cells
　by circulating autoantibodies.
　When found, pancytopenia is most often attributed to myelofibrosis,
　hemophagocytic syndrome, or infection.[4,5]

　The bone marrow biopsy specimen in this patient revealed only hypocellularity,
　without any reticulin fibrils or fibrosis.
　In this patient, the mechanism accounting for the pancytopenia is probably multifactorial.
　The anemia and thrombocytopenia did not increase as expected after transfusion,
　which was suggestive of peripheral destruction by autoantibodies.
　In addition,
　bone marrow hypocellularity and diminished reticulocyte count
　support the possibility of impaired synthesis as a contributing factor.

　The CT scan of this patient revealed generalized lymphadenopathy resembling lymphoma,
　which is not uncommon in cases of SLE.
　Recent studies have extended the use of PET scans,
　as this may help differentiate lymphoma from other inflammatory disorders.[2,6]

　Necrotizing histiocytic lymphadenopathy is a rarely observed clinical entity reported
　in association with SLE.
　It should be included in the differential diagnosis,
　especially in patients presenting with generalized lymphadenopathy,
　which is a fairly uncommon presenting complaint.
　The affected lymph nodes have a distinct pattern of paracortical necrotic foci
　surrounded by proliferating histiocytes and large atypical mononuclear cells,
　with a paucity of neutrophils.
　Corticosteroids have been demonstrated to control the symptoms and autoantibody production in SLE.
　The patient in this case was started on intravenous glucocorticoids
　and was discharged to home on 60 mg oral prednisone daily.
　Other immunosuppressive treatments, such as antimalarials,
　cyclophosphamide, azathioprine, methotrexate, and cyclosporine,
　are also used to avoid the detrimental effects of long-term steroid use.
　Newer treatments, such as mycophenolate mofetil and various biological agents,
　are now being employed as well.[7]

RTA type I

Generalized Weakness in a 23-Year-Old Woman CME

Greg P. Hansen, DO; Christo T. Philip, MD; Larissa I. Velez, MD, FACEP

A 23-year-old woman presents to the emergency department (ED)
with a 3-day history of progressively worsening, generalized muscle weakness and nonbilious emesis.
She has been vomiting 1-2 times a day, mostly upon awakening.
The emesis does not seem to be associated with oral intake.
She also admits to intermittent hematuria, without any flank pain or dysuria.
She denies having any fever, diarrhea, chills, headache, abdominal pain, visual disturbances,
or paresthesias.
Before the onset of symptoms, the patient was in good health,
with a past medical history significant only for renal colic 8 months prior to presentation.
She had a cosmetic rhinoplasty 2 years ago, but otherwise she has not had any prior major surgery.
She has no known allergies and is not taking any medications. Her last menstrual period was 1 month ago.
She recently moved to the United States from Mexico, works as a waitress,
and denies any tobacco or illicit drug use.

On physical examination, her oral temperature is 99.0°F (37.2°C).
Her pulse is regular, with a rate of 75 bpm. Her blood pressure is 112/60 mm Hg,
and she has a respiratory rate of 18 breaths/min with an oxygen saturation of 98% while breathing room air.
She appears uncomfortable and generally fatigued, but is alert and oriented.
The extraocular muscles are intact, with no nystagmus.
Her pupils are symmetric and equally reactive to light, and the optic discs appear normal.
Her mucous membranes are moist, and the remainder of the head, ears, nose,
and throat examination is normal.
Her lungs are clear to auscultation and she exhibits normal respiratory effort.
The heart rhythm is regular and without murmurs, rubs or gallops.
Her abdomen is nontender, without masses, and there is no appreciable costovertebral angle tenderness.
The extremities are without edema and the radial pulses are strong bilaterally.
The skin is clear and without any rash, petechiae, or ecchymoses.
Cranial nerves II-XII are normal and symmetric.
Otherwise, the neurologic examination reveals 2/5 strength throughout both upper and lower extremities,
with 1/3 patellar, triceps, and Achilles reflexes bilaterally.
She has negative Babinski and Hoffmann signs.
Finger-to-nose coordination and gait could not be assessed as a result of her weakness.

An electrocardiogram (ECG; see Figure 1), urine analysis, urine pregnancy test,
and basic metabolic panel are completed soon after arrival.
The pregnancy test comes back positive.
She has a serum glucose concentration of 97 mg/dL (5.38 mmol/L) and
a hemoglobin level of 13.4 g/dL (134 g/L).
As a result of a low bicarbonate finding on the metabolic panel,
an arterial blood gas is subsequently performed;
this shows a pH of 7.25, a partial pressure of carbon dioxide (pCO2) of 22 mm Hg,
a partial pressure of oxygen (pO2) of 100 mm Hg, and a bicarbonate (HCO3) of 9 mEq/L (9 mmol/L).
The urine analysis shows a pH of 7.0, with moderate blood, negative nitrates, and small leukocytes.
A renal ultrasound is completed prior to admission (see Figure 2).

○Discussion

The diagnosis of distal renal tubular acidosis was made on the basis of
the patient's presentation of profound weakness, history of renal colic,
ECG findings consistent with severe hypokalemia, renal ultrasound showing nephrocalcinosis,
and arterial blood gas showing a profound metabolic acidosis.
Initial laboratory testing revealed a sodium of 138 mEq/L (138 mmol/L; normal range, 135-145 mEq/L),
potassium of 1.6 mEq/L (1.6 mmol/L; normal range, 3.6-5.0 mEq/L),
chloride of 116 mEq/L (116 mmol/L; normal range, 98-109 mEq/L),
bicarbonate of 10 mEq/L (10 mmol/L; normal range, 22-31 mEq/L),
anion gap of 12 mEq/L (12 mmol/L; normal range, 6-16 mEq/L),
blood urea nitrogen (BUN) of 12 mg/dL (4.3 mmol/L; normal range, 7-21 mg/dL) and
a creatinine of 0.83 mg/dL (73.4 μmol/L; normal range, 0.6-1.2 mg/dL).
These values were consistent with a nonanion gap metabolic acidosis,
with associated hypokalemia and no evidence of chronic kidney disease.
Her pregnancy-induced hyperemesis gravidarum was undoubtedly the inciting factor
for the progression of hypokalemia to such a critical level.

The ECG (see Figure 1) from the patient showed very prominent "U" waves,
which are classically associated with hypokalemia;
in cases where the U wave is taller than the T wave, severe hypokalemia is usually present.
The chest radiograph (not shown) showed subtle diffuse osteopenia.
The patient's prior history of renal colic would be consistent with a history of urinary stones
that often occurs in RTA patients resulting from alkaline urine and hypercalciuria.
The renal ultrasound (see Figure 2) showed hyperechoic regions in the renal medulla
consistent with nephrocalcinosis.
The arterial blood gas demonstrated a profound metabolic acidosis with a pH of 7.25,
further confirming the diagnosis.
It was possible to characterize the type of RTA by looking at the urine pH, which in this patient was 7.0.
This is consistent with renal tubular acidosis (RTA) type I, also known as distal renal tubular acidosis.

Distal RTA (RTA type I) is a rare renal disorder characterized
by a nonanion gap hyperchloremic acidosis and hypokalemia.
In this condition, the alpha intercalated cells of the cortical collecting duct of the distal nephron
fail to secrete acid into the urine.
This failure of acid secretion leads to an inability to acidify the urine to a pH <5.5.
Because renal excretion is the primary means of eliminating acid from the body,
there is consequently a tendency towards systemic acidemia.
This leads to the clinical features of RTA type I, which include:

Normal anion gap hyperchloremic metabolic acidosis
Hypokalemia (from multiple mechanisms, but often severe during periods of stress)[1]
Nephrocalcinosis[2]
Nephrolithiasis (related to an inability to acidify urine, hypercalciuria, and low urinary citrate)
Loss of calcium from bones (which can cause rickets in children and osteomalacia in adults)
During periods of stress caused by illness, or in this particular case the vomiting of hyperemesis gravidum, patients can have episodes of profound hypokalemia resulting in flaccid paralysis, rhabdomyolysis, cardiac arrest, and even death.

RTA type I is either inherited or acquired. Inherited RTA type I can be either autosomal-dominant or autosomal-recessive.
Autosomal-recessive RTA type I often presents in infancy,
whereas autosomal-dominant RTA type I may not present until adolescence or young adulthood.[3]
Some patients with autosomal recessive distal RTA have associated sensorineural hearing loss.[4]
Mutations in the genes encoding carbonic anhydrase (CA) II, kidney anion exchanger-1 (kAE1),
and subunits of the H+-ATPase have been identified in patients with distal RTA.[5]
Some genetic disorders, such as Ehler-Danlos syndrome, Fabry disease, or Wilson disease,
have also been associated with RTA type I.[6]
In the acquired form, the disorder can be caused by drugs, autoimmune diseases,
or by infection.[6] Some of the more common acquired forms are caused by
Sjogren syndrome, lupus, hepatitis, treatment with amphotericin B,[7]
toluene toxicity,[8] and chronic pyelonephritis.

The clinical manifestations of RTA type I depend upon the disease severity
and whether it is acquired or inherited.
The inherited form of RTA type I causes similar metabolic abnormalities,
but it is more likely to result in decreased bone mineralization and growth retardation.[9]
Both forms, however, have hypokalemia, which results in muscle soreness,
flaccid paralysis, and electrical cardiac disturbances.
The most common cause of death related to RTA type I is hypokalemia-induced cardiac dysrhythmia.

The second type of RTA is proximal renal tubular acidosis (RTA type II),
which is caused by an inability to reabsorb bicarbonate in the proximal tubules.
RTA type II may occur secondary to generalized dysfunction of the proximal tubules
and can be associated with increased urinary excretion of glucose, uric acid, phosphate,
amino acids, and protein.[10]
The disorder most often occurs in the context of Fanconi syndrome,
light chain nephropathy, multiple myeloma, or drug exposures.[10] S
ince the clinical features of both RTA type I and RTA type II can be similar,
distinguishing between them can be a diagnostic challenge.
These 2 causes of nonanion gap acidosis with hypokalemia can be distinguished relatively easily,
however, with some laboratory testing.
The easiest and most readily tested laboratory examination is the urine pH.
In RTA I, the distal tubule is unable to acidify the urine and results in a urine pH
that is above 5.5.
RTA type II, however, has intact distal acidification which,
together with an ability of the proximal tubule to reabsorb filtered bicarbonate
once its concentration has fallen below its abnormally low tubular reabsorptive capacity,
results in a urine pH <5.5.
With these mechanisms, RTA II usually does not cause as profound a serum acidosis as RTA I.
For example,
it is not uncommon to have a serum bicarbonate of less than 10 mEq/L (10 mmol/L) with RTA type I,
whereas in RTA type II the bicarbonate is usually greater than 15 mEq/L (15 mmol/L).

Type III RTA is the rarest of the 4 forms,
and it is basically a combination of both type I and type II RTA.
Type III RTA is usually the result of an inherited carbonic anhydrase II mutation,
and it gives rise to an autosomal-recessive syndrome of metabolic acidosis,
hypokalemia, osteoporosis, cerebral calcification, and mental retardation.

RTA type IV, also called hyperkalemic RTA,
is caused by either aldosterone deficiency or resistance of the renal tubule to the actions of aldosterone. This form is readily distinguished from RTA types I and II
because RTA type IV results in hyperkalemia rather than hypokalemia.

This table (adapted) summarizes the distinguishing features of the different RTAs.[11]

The diagnostic studies used to diagnose RTA type I include
serum electrolytes, renal electrolytes, urine analysis, and 24-hour urine citrate and calcium.
In a patient with a borderline acidosis and hypokalemia, an acid load test can often be diagnostic.
This test entails giving an acid load of 0.1 g/kg of ammonium chloride or fludrocortisone/furosemide
and then checking the urine pH 4-6 hours later.[17]
The test is considered positive if the urine pH remains above 5.5.
The acid load test, however, is not advisable during periods of profound acidosis,
and it should be used only among stable patients in otherwise nondiagnostic cases.
An ECG should be done if there is suspicion for severe hypokalemia,
which often presents as muscle weakness.
Renal imaging can often show evidence of nephrolithiasis or nephrocalcinosis.

The cornerstone of medical treatment for RTA type I first entails
addressing the underlying metabolic derangements.
This is accomplished by replenishing potassium with
oral and intravenous potassium chloride or potassium citrate.
The latter is often more beneficial in patients with recurrent renal stones.[13]
In addition, oral sodium bicarbonate (1-2 mEq/kg/day) can often help meet the alkali requirements
and compensate for the lost bicarbonate.
In inherited RTA type I, early medical therapy can mitigate growth retardation and bone demineralization.

The patient in this case was treated with large amounts of oral and
intravenous potassium chloride and admitted to the medical intensive care unit (ICU) for further management. During her 1-week hospitalization, nephrology and obstetrics were both consulted.
Obstetrics performed a transabdominal ultrasound,
which demonstrated an intrauterine 8-week embryo with normal cardiac motion.
She was initiated on a regular regimen of oral potassium citrate, bicarbonate,
folate, and prenatal vitamins. On the day of discharge,
the patient's electrolyte derangements had corrected with oral therapy,
and her nausea was controlled with oral odansetron.
The patient was discharged to home on hospital day 7,
and she had a normal basic metabolic panel 3 weeks after discharge.

Progressive Neurologic Deterioration in a 23-Year-Old Man

Background

A 23-year-old man in Cuba is brought to the hospital by his family
with complaints of malaise, fatigue, a 22-lb (10-kg) weight loss, and
a 10-month history of diminished appetite.
He is also complaining of painful tongue erosions which are covered with a white, creamy exudate.
Three days after admission to the hospital,
the patient develops a progressively declining mental status,
which evolves from drowsiness to mental confusion.
He is eventually found by the nursing staff to be stuporous.
Soon afterwards, the patient begins suffering from generalized tonic-clonic seizures and
the sudden development of a dense left hemiparesis.
At the time that the patient develops altered mental status,
his family states that he has also been having increasingly severe headaches,
but they deny any complaints of neck stiffness or incidence of fevers.
The patient has not had any known trauma.
He does not have any known risk factors for
tuberculosis nor has he had contact with anyone known to be sick.
He has no previously diagnosed medical conditions and has not been taking any medications.
There is no significant family history of disease.
His social history is remarkable only for sexual relationships with men.

On physical examination during the development of his altered mental status,
the patient's temperature is 97.7°F (36.5°C), his pulse is regular at a rate of 100 bpm,
his blood pressure is 100/50 mm Hg, and his respiratory rate is 16 breaths/min.
A normal S1 and S2 are auscultated, with no murmurs or rubs.
His lungs are clear in all fields.
Palpation of the abdomen reveals no tenderness, masses, or enlargement of the liver or spleen.
His mucous membranes are pale and the tongue has diffuse, creamy white exudates which,
when scraped, leave a bleeding, ulcerative surface.
The neurologic examination reveals a stuporous mental status,
with a dense left-sided hemiparesis, seventh cranial nerve palsy,
and an extensor plantar response.
No pupillary abnormalities are noted.

Laboratory testing is performed and includes a complete blood count (CBC)
that reveals anemia with a hemoglobin concentration of 9.4 g/dL (94 g/L)
and a hematocrit of 29% (0.29).
His white blood cell (WBC) count is normal except for 63% (0.63) lymphocytes.
The erythrocyte (globular) sedimentation rate is elevated at 62 mm/hr.
A complete metabolic panel, including electrolytes and liver enzymes, is normal.
Cerebrospinal fluid is not initially obtained
because of a concern for increased intracranial pressure.
A computed tomography (CT) scan of the brain is performed (see Figures 1-4)
and specific serologic studies are ordered to confirm the diagnosis.

Discussion

The noncontrast CT scan revealed large,
hypodense lesions located in the right frontal cerebral hemisphere,
bilateral thalami, and basal ganglia extending into the centrum semiovale,
with mild compression of the right lateral ventricle.
Subsequent administration of contrast resulted in enhancement of the peripheral zone of the lesions
in a typical ring pattern, suggesting CNS toxoplasmosis (images not available).
Toxoplasmosis is caused by the protozoan Toxoplasma gondii.[2,3]
The organism is a ubiquitous coccidian parasite
which infects more than 50% of individuals in some populations
but does not commonly cause active disease.
It exists in 3 forms:

Oocysts, which are excreted in cat feces (the definitive host);
Tachyzoites, which multiply intracellularly; and
Tissue cysts, the end product of this intracellular multiplication,
which can persist as viable parasites in the brain
and striated muscles throughout the life of the host.
Toxoplasmosis infection usually occurs via the ingestion of oocysts or tissue cysts.
The infection has 4 stages: acute, subacute, chronic, and reactivation.
After the organisms invade and multiply within the gastrointestinal tract,
they spread through the lymphatic system and the bloodstream to distant organs (acute stage).
Cellular and humoral immune responses then suppress disease progression
and limit the parasite burden in organs.
In immunocompetent hosts,
the parasite encysts and will persist without any inflammatory process (chronic stage).
When the host becomes immunocompromised, bradyzoites
are released and the parasite becomes an opportunistic agent causing disease.

CNS manifestations are the most frequent form of disease and occur in 10-25% of AIDS patients.
The affinity of T gondii for brain tissue has been conferred to low local immunity.
These manifestations are initially protean and may develop insidiously.
Focal neurologic signs may arise, exhibited by generalized cerebral dysfunction
(drowsiness progressing into coma) and often accompanied by language disturbance.
Seizures may be present and may be generalized or focal.
Hemianopia, aphasia, ataxia, and cranial nerve palsies may also be observed.
Low-grade fever and progressive headaches are frequent symptoms.
The clinical signs of CNS toxoplasmosis are typically vague and vary among patients,
so it is important to confirm the diagnosis by performing radiologic and serologic studies.[2,3]

Many other conditions may mimic CNS toxoplasmosis,
such as chronic meningitis (especially from fungi or syphilis),
cytomegalovirus encephalitis, herpes simplex encephalitis, HIV encephalitis,
primary CNS lymphoma, progressive multifocal leukoencephalopathy, and malignancy (brain metastases).
In patients with focal neurologic abnormalities,
the presence of cerebrovascular disease (stroke) may need to be ruled out.[2,3]

Although serologic data are essential for confirmation,
such tests are not solely diagnostic
because the antibody is present in relatively high numbers in many populations.
Rising serum immunoglobulin G titers are usually observed,
and an immunoglobulin M antibody response is seen in cases of newly acquired toxoplasmosis.
Antibody levels may be unexpectedly low in AIDS patients, even in the presence of active disease.
Isolation of T gondii from blood or body fluids or identification of tachyzoites
in tissue sections or smears of body fluids (such as cerebrospinal fluid) signify acute infection.
Polymerase chain reaction (PCR) amplification for the detection of T gondii DNA
may also be used to clearly establish acute infection.[3]

Imaging is essential in the diagnosis of CNS toxoplasmosis.
CT scans may reveal single or multiple bilateral, hypodense lesions with possible mass effect.
In 70-80% of cases, the lesions will enhance in a homogeneous or ring pattern with contrast.
Diffuse toxoplasmosis may appear on images as either normal or
with findings suggestive of HIV encephalitis.
Magnetic resonance imaging (MRI) is more sensitive in disclosing multiple lesions.
When a single lesion is found in a patient with AIDS and clinical manifestations of CNS involvement,
primary lymphoma is more likely, but this does not rule out toxoplasmosis.
Multiple lesions may be incorrectly interpreted
as multiple metastases in patients without a known history of HIV infection,
so HIV and CNS toxoplasmosis must be considered in individuals with these findings and HIV risk factors. Ultimately, single-photon emission computed tomography (SPECT)
may be useful in differentiating lymphoma from toxoplasmosis.
Whenever the diagnosis is uncertain, a brain biopsy is advocated.
This option most often arises in the setting of a single mass lesion
with negative serologic results and no response to empiric therapy.[2,3]

Toxoplasmosis treatment is often empiric
in the appropriate clinical setting pending confirmatory testing.
The standard regimen for treating acute infection is a combination of 3 drugs given for 6 weeks:
pyrimethamine, sulfadiazine, and folinic acid.
Cotrimoxazole (trimethoprim-sulfamethoxazole) can be used as an alternative regimen;
it is better tolerated and there are no differences in the clinical outcomes.
In cases of allergy to sulfa drugs, clindamycin, clarithromycin,
azithromycin, or atovaquone combined with pyrimethamine and folinic acid are viable alternatives.
The treatment of acute infection should last from 4 to 6 weeks
and is followed by long-term suppressive therapy at reduced doses.
The initiation of highly active antiretroviral therapy (HAART)
is as important as the treatment of acute infection.
Suppressive therapy should continue until CD4 counts remain >200 cells/μL
and lesions are no longer detected on MRI.[1]

In this patient, the history of sex with men
combined with the physical finding of lesions on the tongue
compatible with thrush led to the suspicion of HIV infection.
Because the neurologic state of the patient had declined and there was a possibility of immunodeficiency,
a decision was made to treat for bacterial meningitis and to also treat empirically for CNS toxoplasmosis,
given the results of the noncontrast CT scan of the head pending the serologic results.
A lumbar puncture was considered
but was deferred as a result of concern for neurologic complications
stemming from evidence of increased intracranial pressure on the noncontrast CT scan of the head.
HAART was also initiated empirically.
With treatment, the patient's mental status improved and,
over a period of time, he progressively returned to normal mentation.
HIV infection was confirmed by serologic studies
(ie, enzyme-linked immunosorbent assay [ELISA] and Western blot),
and the patient was noted to have a decreased CD4 count (<150 cells/μL).
A week later, therapy with pyrimethamine, sulfadiazine, and folinic acid was initiated.
The patient was eventually discharged with only a mild language disturbance
and a discreet motor deficit in his left leg.

A 5-year-old boy presents to his primary care provider
with a 1-week history of a 'gleam' that was noticed in the child's left eye in dim light.
His parents do not report any fever or concurrent illnesses.
The patient has taken no recent medications (except for multivitamins).
His parents deny any history of allergies, and his vaccination schedule is up to date.
The patient was born full term and has no siblings.
The family history is significant only for maternal gestational diabetes and hypothyroidism.
There is no parental consanguinity.

The physical examination reveals a well-nourished child in no distress.
The patient's height and weight are at the 60th and 50th percentiles, respectively.
His oral temperature is 98.6°F (37.0°C).
His pulse shows a regular rhythm, with a rate of 80 bpm, and his blood pressure is 110/65 mm Hg.
His lungs are clear to auscultation, with normal respiratory effort.
The S1 and S2 heart sounds are normal.
The abdomen is soft and nontender.
The peripheral arterial pulses in the upper and lower extremities are normal.
The examination of his head and neck shows mild esotropia, normal lids, clear corneas,
and moderate conjunctival congestion in the left eye.
The left eye is tender to the touch and, as a result,
the child does not cooperate with a complete examination of the eye.
He is scheduled for another examination under anesthesia by a pediatric ophthalmologist.

During the second examination, the eyes are noted to have anisocoric pupils
that are round and regular, with an afferent pupillary defect in the left eye.
The red reflex is normal in the right eye, but it is absent in the left.
Funduscopic examination with dilated pupils reveals normal fundus in the right eye;
in the left eye, a yellowish mass with dilated vessels and total retinal detachment are noted.
The crystalline lens is clear in both eyes.
Fluorescein angiography is performed,
which shows fluorescein leakage from neovascularization of the iris.
Gonioscopy reveals a closed anterior chamber angle, with no view of any angle landmarks.
The retina exhibits telangiectatic vessels, microaneurysms, and irregular and dilated vessels.
The intraocular pressure is measured at 15 mm Hg in the right eye and 50 mm Hg in the left eye.
B-scan (bidimensional scan) ultrasonography is performed,
which shows total serous retinal detachment in the left eye.

A review of family's old pictures reveals
that the abnormal red reflex has been present for several months.

Pictures of the patient's dilated left eye and the fluorescein angiography are shown (see Figures 1 and 2).


Discussion

◆Coats disease is a rare idiopathic retinal condition, first described by George Coats in 1908,
in which ◆abnormal telangiectatic retinal vessels cause
intra- and subretinal exudates and retinal detachment.[1]
It typically occurs unilaterally in children, and most commonly in young boys.
Males account for approximately 80% of cases.
Adults and adolescents may be affected as well.
The mean age at diagnosis is 5 years.
It may be seen as early as 1 month of age, and most cases are diagnosed before the age of 10 years.
The severity of the condition is worse in younger patients (especially those younger than age 3 years),
in whom the disease progresses more rapidly.
The disease is unilateral in 95% of cases.
There is no racial or laterality predilection.
The incidence and prevalence are unknown.
Coats disease has a sporadic occurrence, and
it is not known to be associated with other organ abnormalities,
ocular conditions, or systemic conditions.
It is known to have a vascular etiology.
There is no evidence of genetic predisposition;
however, it has been associated with retinitis pigmentosa,
muscular dystrophy, deafness, and Norrie disease.[6]

Clinically, Coats disease presents with decreased vision, strabismus,
leukocoria (white pupillary reflex or 'cat's eye reflex'), and redness.
It may, however, be detected incidentally.[2]
It is not generally associated with pain, except for in advanced cases
with secondary associated neovascular glaucoma.
It has not been associated with infectious or inflammatory conditions,
and the great majority of patients have no associated systemic medical problems.
The clinical presentation shows great variability.
Typically, the ophthalmoscopic examination reveals a localized area of subretinal exudates
associated with vascular abnormalities.
Vascular changes may include peripheral retinal telangiectasia,
capillary and small vessel dilatation and tortuosity,
sheathing, capillary nonperfusion,
and small aneurysms located at the equator of the eye and the ora serrata (most commonly, inferotemporal).
The posterior pole is less frequently affected.
Exudation is a common feature that presents in most cases as flat intraretinal and subretinal exudates.
These exudates initially appear in areas of telangiectasia and progress to become more widespread.
Macular protein accumulation can occur directly from macular telangiectasia
or indirectly from peripheral disease.
A dense exudate or white nodule in the macula can progress to a disciform lesion
that indicates a poor visual prognosis.
Retinal hemorrhages may be seen.
The vitreous remains clear until the advanced stages.
Retinal cysts may be seen and are common in chronic retinal detachments of different etiologies.[6]

The diagnosis may be suspected clinically by indirect ophthalmoscopic evaluation of both eyes,
but ancillary testing is extremely helpful to differentiate Coats disease from retinoblastoma,
which is a more feared disease. A- and B-scan ultrasonography
will show low internal reflectivity consistent with an exudative retinal detachment,
and it will rule out the presence of a solid tumor.
Intravenous fluorescein angiography helps to visualize the telangiectatic vessels
as irregular dilated tortuous vessels filling in the late arterial and early venous phases.
Microaneurysms are seen as "lightbulb aneurysms".
The angiogram will also show progressive leakage from abnormal vessels,
adjacent areas of capillary dropout, and late staining of intraretinal exudates.[5,6]

Based on the clinical appearance and progression,
Coats disease may be classified in 5 grades, as follows[3]:

Grade I: Isolated focal exudates
Grade II: Massive elevated exudation
Grade III: Partial retinal detachment
Grade IV: Total retinal detachment
Grade V: Secondary complications

A more recent classification system has emerged, which is based on the prognosis.
It grades the disease in the following manner[4]:

Grade I: Telangiectasias only
Grade II: Telangiectasias and exudation
Grade III: Exudative retinal detachment
Grade IV: Total retinal detachment with secondary glaucoma
Grade V: End-stage disease

Spiral computed tomography (CT) scanning has been used to rule out intraocular calcifications
that more commonly present in retinoblastoma.
It is important that the clinician consider and rule out the possibility of retinoblastoma because,
if left untreated, it is fatal.
As a result of concerns about radiation exposure,
CT scanning is less frequently used today for diagnosing intraocular pediatric tumors.
Magnetic resonance imaging (MRI) with gadolinium enhancement is very helpful
in evaluating the optic nerve and the globe.
It is not, however, as valuable as CT scanning or ultrasonography
for detecting the intraocular calcium deposits commonly found in association with retinoblastoma tumors.
MRI scanning is also very helpful for evaluating the pineal gland in cases of familiar retinoblastoma.
Subretinal fluid will appear hyperintense on T1- and T2-weighted images.
Solid tumors are hyperintense on T1-weighted images, but they are hypointense in T2-weighted images.

The differential diagnosis of Coats disease is similar to the differential diagnosis of leukocoria
(which is extensive).
It includes retinoblastoma; persistent fetal vasculature (PFV);
retinopathy of prematurity; rhegmatogenous, exudative,
or tractional retinal detachment; ocular toxocariasis,
familial exudative vitreoretinopathy (FEVR); r
etinal capillary hemangiomatosis (Von Hippel-Lindau disease);
cataract; glaucoma; uveitis; vitreous hemorrhage; and colobomas of the choroid and optic disc.
Leber miliary aneurysm disease is an early or nonprogressive form of Coats disease.[5,6]

If untreated, Coats disease shows progressive worsening in most cases,
with a variable speed;
therefore, early treatment is recommended.
The disease does not respond to steroid or antibiotic treatment.
Recommended treatments depend mainly on the stage of the disease,
and they include observation, laser photocoagulation, cryotherapy,
retinal detachment repair with pars plana vitrectomy and/or scleral buckle, and enucleation.
Because treatment involves general anesthesia and frequent follow-up,
discussions with a patient's parents (if the patient is a minor)
regarding diagnosis, prognosis, and treatment goals are of extreme importance.
Laser treatment has been used with a high success rate in cases with less exudation.
Treatment is directed to areas of vascular leakage and nonperfusion,
which decreases or eliminates further exudation and
leads to resolution of the exudates and serous detachment.
Fluorescein angiography is very useful in guiding laser treatment.
Peripheral lesions are better treated with cryotherapy or a combination of laser and cryotherapy.
Treatment may have to be repeated, as recurrences may follow.
In more advanced cases, drainage of the subretinal fluid may be necessary,
with or without the use of a scleral buckle.
Pars plana vitrectomy has been recently used to treat exudative and tractional retinal detachments.
Despite the resolution of exudates, subretinal fibrosis and scarring may limit the visual prognosis.
Because the disease is unilateral in most cases, patients can live a normal life
with the use of polycarbonate glasses for protection of the fellow eye,
especially during sports activities.[4,6]

Associated complications of Coats disease include neovascular glaucoma (approximately 10% of patients),
angle closure glaucoma, anterior chamber cholesterolosis (3%),
retinal/disc neovascularization, vitreous hemorrhage,
secondary retinal vasoproliferative tumor, and intraretinal cysts.[4]

In this patient, enucleation was the preferred treatment
because of the poor visual prognosis, advanced stage of the disease,
the presence of neovascular glaucoma, elevated intraocular pressure,
closed anterior chamber angle, and strabismus.
The eye was sent for pathology examination, and the pathology report confirmed the clinical diagnosis.
During the surgery, the eye was replaced with a hydroxylapatite implant.
The 4 rectus muscles were attached to the implant.
Six weeks later he was fitted with a prosthetic, with excellent cosmetic results and good motility.

A 48-year-old man presents to the emergency department (ED) after an incident
in which he tripped while working in the bed of his pickup truck, falling forward onto a log.
He suffered a direct blow to his perineum and penis,
which initially resulted in intense pain that lasted for approximately 5-10 minutes.
The pain subsequently subsided, and he continued his activity without discomfort;
however,
when he attempted to urinate after his work was complete,
the patient experienced severe, burning pain in his penis and noted a large amount of hematuria.
His symptoms persisted with each episode of urination over the next few hours,
leading him to seek evaluation in the ED.

Upon presentation, the patient reports no pain while at rest.
He denies any trauma to his flank or abdomen as a result of the fall.
He denies any abdominal pain, nausea or vomiting, difficulty or pain while walking,
and scrotal swelling or bruising.
There is no significant past medical history, and he does not take any medications.

On physical examination,
the vital signs are normal, with a heart rate of 80 bpm and a blood pressure of 132/76 mm Hg.
The patient is afebrile and appears to be in no acute distress.
The initial examination of the genitourinary and perineal region reveals
blood at the urethral meatus (see Figure 1).
A paper towel that the patient has been using to keep his underwear clean
is soaked with a moderate amount of blood.
There are no external lacerations, abrasions, or ecchymosis identified at the urethral meatus,
on the remainder of the penis, or in the perineum.
Inspection of the scrotum and palpation of the testicles is unremarkable.
There is no tenderness to palpation in the abdomen and
no flank or costovertebral area tenderness is noted.
The remainder of the physical examination,
including examination of the heart, lungs, and musculoskeletal system,
is unremarkable for any abnormalities or evidence of additional trauma.

A urine sample at the bedside is noted to be the color of red wine,
and a formal urine analysis confirms the presence of gross hematuria.
A complete blood cell (CBC) count is ordered and the results are unremarkable,
with a normal white blood cell (WBC) count and a hematocrit of 45% (0.45).
A coagulation profile is conducted, also with unremarkable results.
A series of plain radiographs of the pelvis are performed, and they are normal,
with no evidence of fracture. A retrograde urethrogram is subsequently obtained (see Figure 2).

Discussion:

Figure 1 shows blood at the urethral meatus, which, in the setting of trauma,
should raise an immediate suspicion of genitourinary injury, most specifically a urethral injury.
The finding of blood at the meatus is also relevant in that a urethral catheter
should not be passed without first performing a retrograde urethrogram (RUG).
Otherwise,
the catheter can unintentionally convert a partial laceration into a full disruption.
An RUG shows extravasation of dye from the anterior urethra,
consistent with a contained urethral tear (see Figure 2).
An incidental urethral stricture was also identified and,
as a result of increased intraluminal pressures from the urethral stricture,
contrast medium had to be injected under such force that
it was absorbed into the venous plexus (see Figure 3).

The adult male urethra measures between 17 and 20 cm in length and is divided into 3 sections:
the anterior urethra,
which is subdivided into the penile (also known as pendulous) and bulbar segments;
the short membranous urethra (the portion that passes through the external urethral sphincter);
and the posterior or prostatic urethra.
Pendulous urethral injuries (such as in this case) are relatively uncommon,
consisting of only approximately 10% of lower urinary tract injuries and
37% of all urethral injuries.[1-2] Unlike posterior urethral injuries,
anterior urethral injuries are typically isolated.[3]
The anterior urethra may be injured when the penis is compressed against the symphysis pubis
during a fall or with a straddle injury (as in this case) or, occasionally,
from a direct blow, such as a kick.
Posterior urethral injuries most commonly occur
as a result of a pelvic fracture from a high-force mechanism.
In particular,
they are associated with bilateral pubic rami fractures.
A posterior urethral injury can also occur
without associated pelvic fracture
when significant shear forces stretch the urethra at the prostate-urethral junction.

Symptoms of urethral injury may include pain,
hematuria or meatal bleeding, dysuria, and urinary retention.
Signs may include blood at the meatus, a high-riding prostate,
or evidence of concomitant trauma (such as contusions, lacerations, or pelvic fractures).
Approximately half of patients,
however, will not have blood present at the urethral meatus.
In the setting of a multisystem blunt trauma in the ED,
the diagnosis of urethral injury may often not be initially suspected or confirmed,
with the initial consideration only occurring with resistance
being encountered at the time of placement of the urethral catheter (ie, Foley catheter).
Other potential physical examination findings include
the presence of a perineal hematoma, sleeve-like ecchymosis around the penis, or
soft-tissue swelling resulting from the extravasation of urine and/or blood.
In the setting of multisystem blunt trauma,
other potential or confirmed life-threatening injuries demand attention
before the evaluation of urethral injuries.
After the patient has been adequately stabilized,
however, an assessment for possible urethral injury should be carried out.

The initial diagnostic study of choice for suspected urethral injury is the RUG.
In this study,
through a catheter placed just inside the meatus,
20-30 mL of water-soluble contrast medium is gently injected
under fluoroscopy or with multiple plain film views.
Depending on the patient,
the contrast material may or may not overcome
reflex constriction of the urinary sphincter mechanism,
which can mimic a stricture but is in fact the normal urethra traveling through the sphincter.
In addition to the anterior-posterior (AP) views of the urethrogram,
oblique views are important as well;
extravasation of the contrast material, if directly posterior or anterior,
will be missed without the oblique views.
Urethral injury will be noted as the presence of contrast medium
outside the normal columnar space of the urethra.
A partial tear is diagnosed when extravasation
is seen and the contrast material still reaches the bladder;
a complete tear is diagnosed when extravasation is present and
no contrast material is present in the bladder or proximal to the urethral disruption.
The relative frequency of partial tears versus complete tears is highly variable in the literature.

A classification of RUG findings that is sometimes used to define urethral injury,
based on the anatomic findings of injury for urethral injuries (both anterior and posterior),
is the Goldman classification.[6] The classification defines 5 major types of urethral injuries:

Type I urethral injury:
The urethra remains intact, but it is severely stretched,
resulting in rupture of the puboprostatic ligament and thus allowing the prostate to move superiorly.
No extravasation of contrast material is seen with radiography,
and continuity is maintained with the bladder.


Type II urethral injury:
The trauma results in a posterior urethral injury
with tearing of the urethra superior to the urogenital diaphragm.
Contrast-agent extravasation is seen within the extraperitoneal pelvis,
but contrast material is not present within the perineum.
The urogenital diaphragm is intact, preventing the spread of the contrast material inferiorly.


Type III urethral injury:
There is disruption above the urogenital diaphragm, with the injury extending
through the urogenital diaphragm to include the proximal bulbous urethra.
In this injury,
extravasation of the contrast material can be found
within the extraperitoneal pelvis and within the perineum.


Type IV urethral injury:
The tear involves the bladder neck and extends into the proximal urethra.
Contrast-agent extravasation is seen in the extraperitoneal pelvis around the proximal urethra.
Such injuries can damage the internal urethral sphincter,
resulting in incontinence; therefore, proper diagnosis of the tear is essential.


Type V urethral injury:
All cases of this type of injury are isolated to the anterior urethra and
occur distal to the urogenital diaphragm.
They are usually associated with perineal crush or straddle injuries.
There may be a partial tear of the bulbous urethra.
Contrast-agent extravasation occurs inferior to the urogenital diaphragm.
If the Buck fascia is intact, the extravasation is limited to the penile shaft;
if the Buck fascia is disrupted,
the contrast material is contained within the limits of the Colles fascia and
may be found in the lower abdomen, thighs, and scrotum.
Under certain circumstances,
all of the clinical signs of urethral disruption may be present,
but contrast extravasation may be completely absent.
In such a case, a diagnosis of urethral contusion is often made.
If the urethrogram is normal, further evaluation with a cystogram may be indicated.

As a result of the relative infrequency of anterior urethral injuries,
the best method of treatment is not certain.
Some sources recommend that simple urethral injuries
can be treated with 7-10 days of splinting by Foley catheter
along with analgesia and antibiotic prophylaxis;
however,
a catheter should only be passed with extreme caution under the advisement of a urologist
after the urethrogram has been performed and it has been deemed safe to proceed.
Partial tears can be converted into complete disruptions with catheterization;
therefore,
most experts advocate the initial placement of a temporary transcutaneous suprapubic catheter.
Delayed surgical repair (often weeks later) may be required as a definitive treatment.[4]
Severe injuries, complete transections, or injuries
in which there is an inability to pass a urethral catheter will likely require surgical repair.

In fact, penetrating anterior urethral injuries
should generally be explored with examination of the area of injury and
debridement of any devitalized tissue to minimize tissue loss.
Primary repair via a direct anastomosis over a catheter
is acceptable for defects up to 1.5 cm in the penile urethra,
whereas
longer defects should be reconstructed at a later point
in time to allow for resolution of other injuries and
for planning of any required tissue transfers.
A urinary diversion via placement of a suprapubic catheter may be performed.
All cases should be discussed with a urologist while the patient is in still in the ED.
Long-term complications are more common in posterior injuries,
and they may include impotence, strictures, and urinary incontinence.

The patient in this case had a type V urethral tear as well as an incidental stricture.
After discussion,
the on-call urologist recommended treatment with a Foley catheter by the ED staff.
Because the presence of a stricture raised concern that
it would be difficult to pass a Foley catheter,
as well as possible confusion over
whether any resistance was being caused by the tear or the stricture,
this recommendation was declined and the urologist was requested to come to the hospital.
Adequate drainage was established by the urologist with a Coude catheter,
and the patient was discharged to home on a 7-day course of ciprofloxacin.
On the eighth day,
the catheter was removed and the patient was soon able to urinate
with only mild discomfort and microscopic hematuria.
The stricture remained asymptomatic and was managed expectantly.


The adult male urethra is divided into 3 sections: the anterior urethra,
which is subdivided into the penile (also known as pendulous) and bulbar segments;
the membranous urethra, which passes through the external urethral sphincter;
and the posterior (or prostatic) urethra.
Pendulous urethral injuries are relatively uncommon,
seen in only 10% of lower urinary tract injuries and 37% of all urethral injuries.
Unlike posterior urethral injuries, anterior urethral injuries are typically isolated.
The anterior urethra may be injured
when the penis is compressed against the symphysis pubis during a fall,
with a straddle injury, or from a direct blow.
Posterior urethral injuries most commonly occur
as a result of a pelvic fracture from a high-force mechanism;
they are particularly associated with bilateral pubic rami fractures.
A posterior urethral injury can also occur
without an associated pelvic fracture
when significant shear forces stretch the urethra at the prostate-urethral junction.