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The Journal of Thomas Jefferson University Hospital
Department of Internal Medicine
Volume 8, 2006-2007
Can an art masterpiece embody the spirit of a University?
This question was not considered at Jefferson before this year
or until the University pursued the sale of Thomas Eakins’
seminal work, The Gross Clinic.
The depiction of Dr. Samuel Gross, Professor of Surgery, at
work in the surgical amphitheatre captured the emergence of
American Medicine from the shadow of Europe and
foreshadowed the American century which was yet to come.
Viewed in this light, the work is indeed an important part of
the history of Jefferson, Philadelphia, the medical/scientific
community, and the entire nation. Even more significant is the
work in considering that Eakins himself studied anatomy at
Jefferson. Upon learning of the sale many at Jefferson objected
believing that the University was selling its very soul. But as
the fate of The Gross Clinic hung in the balance, I came to
realize that the soul of Jefferson is our students, residents,
fellows, faculty, and alumni - and the good work they all do
every day to prevent illness, seek new cures, report new
discoveries, teach the next generation of physicians and
researchers, heal the sick, and relieve suffering. The painting
symbolizes this soul, but the soul rests in each of us.
The painting is now in a better place for the citizens of the city
and the world to view its magnificence and ponder its impact.
This too, is better for Jefferson. I predict that now that the
sale is final and the work has moved across town to a more
suitable permanent home (one that can better ensure its
preservation), the painting will become an even more
important symbol of our past and also our future.
A painting such as the Gross Clinic - the greatest work of 19th
Century American art - must be in a renowned public
museum where it can be seen by many more Americans who
can appreciate this grand canvas and then come to know
Jefferson’s unique role in the emergence of American
Medicine. We believe that through the public viewing of this
portrait, Jefferson’s ascendant role in American Medicine will
be even more widely appreciated throughout the city, the
region, and the world.
With this edition of The Jefferson Forum, it is clear to me that
the soul of Thomas Jefferson University has never been stronger.
Gregory C. Kane MD, FACP, FCCP
Professor of Medicine
Residency Program Director
Vice-Chairman for Education
Department of Medicine
Jefferson Medical College
As we were completing the final touches on the 8th volume
of The Jefferson Medicine Forum, the members of the
editing staff could not help but note the vast variety of
medicine we are privileged to witness daily. Textbook cases of
malaria, herpes zoster ophthalmicus, and Lyme disease mixed
among patients with migrating prostatic radiation seeds or
reversible encephalophathy due to hypertension are the
perfect example of the marvelous diversity of pathology to
which we are exposed. Our residents have interests ranging
from coronary heart disease to irritable bowel disease and
research throughout the spectrum of internal medicine.
Residents are committed to helping those who are ill, to
scholarly pursuits within medicine, but are also passionate
about photography, art, and poetry.
Thank you to all of our colleagues who shared their
experiences in this edition of The Forum and we hope that
you enjoy!
Senior Editors: Andrew Rose, MD and Karl Kwok, MD
Junior Editors: Neilanjan Nandi, MD, and Utpal Sagar, MD
Editorial Staff: Melissa Gitman, MD, Anthony Lanfranco, MD,
and Tamara Solitro, MD
Graphic Design: JeffGraphics
Research & Review Articles
The Journal of Thomas Jefferson University Hospital
Department of Internal Medicine
Volume 8, 2006-2007
Inverse Expression of Fas Ligand and Asthma-Related Cytokines
in an Aspergillus Challenge Murine Model of Asthma ..............................................................................................2
T. Lin, A. Larkin, S. Sharma, S. Patel, J. Peterson, S. Kierstein, A. Haczku, J. Zangrilli
Cidofovir and Intravenous Immunoglobulin for Treatment of BK Polyomavirus Nephropathy ................................3
Anita Mehrotra, MD, Rajani Dinavahi, MD, and George C. Francos, MD
Changing the Way We Think About Irritable Bowel Syndrome ................................................................................4
Roger Coron, MD, Herve Boucard, MD, and Zamir Brelvi, MD
Coronary Heart Disease Prediction and Prevention ................................................................................................10
Dae Hyun Kim, MD, MPH, Andrew N. Lee, MD
Case Reports
Herpes Zoster Ophthalmicus with Third Nerve Palsy..............................................................................................16
Bonnie Callahan, MD, Utpal Sagar, MD, and Ted Martynowicz DO
Woman with Relapsing Fevers ................................................................................................................................18
Mary Kate McCullen, MD
An Unusual Location for Prostate Brachytherapy Seeds ..........................................................................................21
Sivakumar Srinivasan, MD, and Sandeep Anreddy, MD
Acute Myocardial Infarction after Blunt Chest Trauma............................................................................................22
Sivakumar Srinivasan, MD, Sandeep Anreddy, MD, and Paul Mather, MD
Woman with Anemia and Abdominal Pain..............................................................................................................23
Joanna Kipnes, MD, and Marina Serper MD
Infiltrated Epinephrine ............................................................................................................................................24
Utpal Sagar, MD, Bonnie Callahan, MD, and Ted Martynowicz, DO
Man with New-Onset Jaundice and Severe Cholestasis............................................................................................25
Aarati Malliah, MD
Woman with Facial and Neck Swelling ....................................................................................................................26
Meredith Chiaccio, MSIII and Donna Mscisz Williams, MD
Woman with Fatigue, Shortness of Breath, and Chest Pressure................................................................................30
Neilanjan Nandi MD, Sivakumar Srinivasan MD
Man Feeling Tired and “Lousy” Five Days Following Myocardial Infarction............................................................32
Andra Popescu, MD
Man with Blurry Vision ..........................................................................................................................................34
Brandy Kaneshiro, MD, and Albert Yeung, MD
T-Wave Alternans in a Patient with Left Ventricular Dysfunction ............................................................................36
Saum Shamimi-Noori, MD
Man with Increasing Fatigue and Myalgia................................................................................................................37
Lax Gadde, MD, and Martin Kerrigan, MD
Treatment of Crohn’s Disease in a Patient with Concomitant Hepatitis C and Hemophilia ....................................38
Donna Williams, MD
Man with Methadone-Induced Polymorphic Ventricular Tachycardia......................................................................40
Sandeep Anreddy, MD, and Sivakumar Srinivasan, MD
Woman with AIDS and Status Epilepticus ..............................................................................................................42
Bonnie Callahan, MD
Woman with Polyuria and Polydipsia ......................................................................................................................44
Jeffrey Clough, MSIV, and Andrew Rose, MD
Persistently Elevated Troponin Levels with a Negative Cardiac Workup: Now What?..............................................46
Pamela Cines, MD
Anomalous Origin of Left Circumflex Artery From the Right Coronary Artery ......................................................48
Sivakumar Srinivasan, MD, and Sandeep Anreddy, MD
Research & Review Articles
T. Lin, MD,1 Allyson Larkin, MD,1 S. Sharma, MD,1 S. Patel, MD,1 J. Peterson, MD,1 S. Kierstein, MD,2 A. Haczku, MD,2 J. Zangrilli MD,1
Resolution of inflammation in asthma is typically thought of as a
passive phenomenon in which proinflammatory Th2-type
cytokines wane after the initial trigger. We hypothesized that active
mechanisms, including anti-inflammatory cytokines and proapoptotic factors, contribute to this process. Fas Ligand (FasL)
expression was particularly interesting since important effector cells
in asthma (e.g. eosinophils and T helper cells) are Fas-sensitive.
BALB/c mice were sensitized and challenged with an Aspergillus
fumigatus extract, and sacrificed 1, 7 and 10 days later to capture
events during initiation of the inflammatory response and its
resolution. Endpoints included bronchoalveolar lavage (BAL) cell
counts, protein array analysis of BAL fluid, and cytokine gene
array of total lung RNA. Results: BAL eosinophilia peaked on
day 1 and was associated with a marked increase in both Th1 and
Th2 type cytokines including IL-12, IFNÁ, IL-4, IL-5, IL-6, and
IL-10 and eosinophil-active chemotactic factors. In contrast, FasL
protein and gene expression was suppressed at this time point
compared to baseline. Resolving eosinophilia was coincident with
a marked increase in FasL expression and the return of most
cytokines towards baseline although residual chemokine levels
were noted 10 days after allergen challenge.
We observed an inverse relationship between expression of FasL
and asthma-related cytokines in an experimental asthma model.
These data are consistent with a regulatory role for FasL during
resolution. While Th2 cytokines are thought to orchestrate the
initial response to antigen, multiple classically anti-inflammatory
cytokines appear to be involved as well.
Funded by: NIH HL076646, AI055593
Thomas Jefferson University Hospital, Philadelphia, PA
University of Pennsylvania, Philadelphia, PA
Rickshawing in
New Delhi, India
Photo courtesy of
Vaibhav Menendiratta, MD
Research & Review Articles
Anita Mehrotra, MD, Rajani Dinavahi, MD, and George C. Francos, MD
BK polyomavirus nephropathy (BKN) is an important cause of
renal allograft dysfunction and loss. The mainstay of therapy is
reduced immunosuppression, but definitive protocols for the
diagnosis and management remain to be defined. We report here
a retrospective analysis of 6 patients with BKN treated with
cidofovir and intravenous immunoglobulin(IVIG). The patients
were followed for 6 months from the initiation of therapy. All
patients (3 cadaveric/3 live donors) underwent renal biopsy after
serum BK viral PCR (SBKPCR) was obtained in response to a
rise in creatinine concentration. The mean time from transplantation to diagnosis was 21.7 months (5, 14, 15, 24, 35, 35
months). One patient had positive SBKPCR without biopsy
evidence of BKN. In all patients immunosuppression was
reduced, and therapy with cidofovir (0.25-0.5mg/kg) and IVIG
(25 grams) was instituted weekly or bi-weekly. Mycophenolate
mofetil was discontinued, and the tacrolimus therapeutic trough
was decreased to 2-5 ng/mL in 5/6 patients. Therapy was
continued for 6 months or until SBKPCR was undetectable. The
mean nadir creatinine value after transplantation was 1.3mg/dL
(1,1.1, 1.1, 1.2, 1.3, 1.8). The mean creatinine value at time of
biopsy was 2.3 mg/dL (1.2, 1.4, 1.7, 2.8, 3, 3.6), and the mean
SBKPCR value at diagnosis was 870, 266 copies/mL (1.86, 23,
33, 38, 56, 370 x 104 copies/mL). The average number of
cidofovir doses was 8.3 (4, 6,6, 10, 12, 12 doses) with
concomitant IVIG. The mean SBKPCR at end of 6 months was
44,283 copies/dL (1.1, 1.8, 2.4, 5.4, 10, 245 x 103 copies/mL).
Five of 6 patients experienced a decrease in SBKPCR. The mean
creatinine value at the end of 6 months was 3.0 mg/dL (1.5, 2,
2.9, 3.3, 3.7, 4.4). After nine months from initiation of therapy,
the one patient with positive SBKPCR and biopsy negative for
BKN returned to a nadir creatinine (1.2 mg./dL) and
undetectable SBKPCR. Baseline renal function (the nadir
creatinine prior to the diagnosis of BK infection), was not
recovered in any patient at the end of six months. These data
suggest that the reduction of immunosuppression and addition of
cidofovir and intravenous immunoglobulin can arrest further
progression of BKN. Allograft dysfunction, however, was not
reversed and may reflect fibrosis secondary to the injury sustained
as a result of BKN. The one patient diagnosed by SBKPCR prior
to the development of BKN had the most favorable outcome.
Serologic screening prior to development of allograft dysfunction
may be warranted, but the timing and treatment strategies need
to be confirmed by larger studies.
Yeongbokgung Palace
Seoul, Korea
Photo courtesy of
Eric Choi, MD
Research & Review Articles
Roger Coron, MD,1 Herve Boucard, MD,2 and Zamir Brelvi, MD 2
Irritable bowel syndrome has long been considered a functional
gastrointestinal disorder. However, recent studies have suggested
possible organic causes that can explain the multitude of
symptoms in IBS.
Brief History
The irritable bowel syndrome has been thought of as a functional
gastrointestinal disorder for many years. As long as three thousand
years ago, Hippocrates described a triad of symptoms consisting
of abdominal discomfort, irregular bowel movements and
bloating. In 1817, William Powell reported a case with similar
symptoms as Hippocrates. In 1849, Cumming described a
syndrome of irregular bowel habits consisting of alternating
diarrhea and constipation.1 In 1928, Bockus and his colleagues
described the syndrome as “neurogenic mucous colitis.”2 Bockus
determined that this disease can only be diagnosed by exclusion
which was the belief until the 1970’s.
Today IBS is one of the most common diagnosed medical
problem affecting an estimated 4-35% of the population
worldwide, with a prevalence of 9-22% in the United States.1,3-5
Approximately 12% of office visits in the United States are due to
IBS along with approximately 28% of gastroenterology referrals.1,68
It is the 7th most common outpatient diagnosis. Irritable bowel
syndrome is the second most common cause for absenteeism,
trailing only the common cold. Disability rates are equal to or
more severe than organic GI diseases. The prevalence rate is 2-3
times higher in women.1 This appears to be the case worldwide
except in India and Sri Lanka where there is no known gender
differences.9 Hispanics and Asians are less likely to have IBS. There
have been conflicting studies on the prevalence differences for
Caucasians versus African Americans. The onset usually is in the
late teenage years and twenties. The prevalence peaks in the 3rd
and 4th decades and begins to decline in the 6th and 7th
decades.1,3,4 After diagnosis, up to 75% of patients will remain
symptomatic after 5 years.10
IBS patients miss three times as many work days as the average
person. In the United States, the disease accounts for 3.5 million
office visits, 2.2 million prescriptions and 35,000 hospitalizations
per year. Patients with IBS use more medical resources than the
non-IBS patient. These include physician visits, tests, unnecessary
surgeries and medications. It is currently estimated that IBS costs
the United States between 15-30 billion dollars per year.11-13 This
includes both direct medical costs as well as indirect costs.
Extraintestinal symptoms
Patients with IBS undergo more appendectomies and hysterectomies than non-IBS patients. The most common extraintestinal
manifestations include genito-urinary symptoms such as
dysmenorrhea, dyspareunia, impotence, urinary frequency, as well
as feelings of incomplete bladder emptying. IBS also appears to
affect the perception of sexual function. Eighty-three percent of
IBS patients compared to 16% of non-IBS patients report
impaired sexual functioning.
The diagnosis of irritable bowel syndrome was originally made
using the Manning criteria: pain eased with defecation, pain
associated with change in frequency of bowel movements, pain
associated with change in consistency of bowel movements,
abdominal distention, tenesmus, and mucous in the stool.14 In
1992, the Rome criteria for the diagnosis of irritable bowel
syndrome was published. In 2000, the Rome II criteria was
published (See Table 1)14 In a study of 98 patients, confirmed to
have IBS using a clinicians diagnosis as the gold standard, it was
found that the Rome I criteria in the absence of red flags to be
65% sensitive, 100% specific and 100% positive predictive value.
The cornerstone of the Rome Criteria is abdominal pain. Without
abdominal pain, IBS can not be the diagnosis.1
Table 1. The ROME I Criteria for the diagnosis of IBS was developed in 1992
ROME I Criteria:
Rome 2 Criteria
Red Flags
Presence for at least 12 weeks (not necessarily consecutive)
in the preceding 12 months of abdominal discomfort or pain
that cannot be explained by structural or biochemical
abnormalities and at least two of the following
2 or more of the following,
at least 25% of occasions
or days:
1. Documented weight loss
2. Nocturnal Symptoms
1. Pain relieved with defecation
1. Altered stool frequency
3. Blood mixed in the stool
2. Change in the frequency of bowel movements
2. Altered stool forms
4. Recent antibiotic use
3. Change in the form of the stool
3. Altered stool passage
5. Family history of colon cancer
4. Bloating or feeling
abdominal distention
6. Relevant abnormalities
on physical exam (2)
Thomas Jefferson University Hospital, Philadelphia, PA
University of Medicine and Dentistry of New Jersey, Newark, NJ
Research & Review Articles
Gender and Hormones
Hormones appear to play a role in IBS. The symptoms appear
to be worse in women during menstruation.15 Women on
hormone replacement therapy tend to be more symptomatic
than women not on therapy.16 One study found that men with
IBS are more likely to have lower testosterone and luteinizing
hormone than unaffected men.17 Other studies have found that
men with IBS have more nurturing traits and reduction in the
male-trait score.18,19
within one week compared to just 11% in placebo-treated
patients. Of the patients who bacterial eradication was considered
complete, 75 percent achieved normalization of global
symptoms.26 Another study proved that metronidazole is superior
to placebo in alleviating symptoms in IBS.27 This is further
evidence of bacterial overgrowth as the potential etiology in at
least some IBS patients.
A history of abuse predisposes patients to IBS. In addition to
having a history of abuse of varying types; emotional, sexual, or
physical and/or a history of stressful life events, social stress or
anxiety and having a maladaptive coping style, affect the severity
and clinical course of IBS.20 There is a strong association between
IBS and having a concurrent psychological disturbance. Various
studies have demonstrated a 40-90 percent association rate with
IBS. Psychological disorders associated with IBS include
personality disorders, psychological distress, altered health beliefs
and coping styles.20
In recent years, studies have shown that a high percentage of people
with infectious gastroenteritis develop IBS. This was demonstrated
in two control studies. The first study followed 318 subjects with
gastroenteritis and compared them to a population database of
584,308 controls for one year to see if a diagnosis of IBS was made.
They found that 4% of the post-infectious patients had developed
IBS within 12 months compared to 0.3% of the general
population.28 A second study29 followed post-infectious gastroenteritis subjects and controls for 6 months and found that 17% had
developed IBS compared to only 1.9% of the controls. The odds
ratio was 10 (95% confidence interval, 3-31). This study used the
Rome II criteria for diagnosis of IBS.30 Overall, the incidence of
post-infectious onset IBS has been shown to be between 4-30%.31
Researchers have suggested that IBS can be explained by bacterial
overgrowth in the small intestines. The theory stems from the
finding that regardless of the predominant symptom of IBS, 92%
of the patients complain of abdominal bloating.21 The bloating is
usually postprandial. Numerous imaging studies show increased
intestinal gas in IBS patients. Total hydrogen gas excretion and
the maximal rate of gas excretion following lactulose ingestion
was higher in IBS patients.22 The gases produced are hydrogen
and methane which demonstrates that this abnormal gas
production following lactulose intake in IBS patients cannot be
explained by simply a disaccharide intolerance.
Several studies have shown the presence of increased inflammatory
cell levels in patients with IBS.20 These findings include increased
mast cells in the muscularis externa of the colon and ileum,
increased cellularity of the colonic and ileal mucosa, lymphocytic
infiltrates in the myenteric plexus and increased nitrous oxide
synthetase.32-37 The findings of inflammation occur usually within
three months of infectious gastroenteritis. During this time
period, IBS patients have a higher lymphocyte count in the rectal
mucosa. The count is not high enough to meet the criteria for
lymphocytic colitis.38 A small study of patients with severe IBS
have shown that on full thickness biopsy, a low grade ganglionitis
existed. Two of the ten IBS patients with the low grade
ganglionitis had post-infectious IBS.39 There is also evidence that
low grade inflammation of the small intestine such as the
inflammation following Campylobacter infection could cause bile
acid malabsorption.38 This in turn could cause the symptoms of
post-infectious IBS.
Psychological Factor and Abuse
Normally, it is uncommon for bacteria to grow in the proximal
small intestine. It has been theorized that there is a proximal
spread of bacteria along the small intestines. New bacterial growth
in the proximal small intestine may be the cause of the increased
gas production in IBS patients.23 Nucera et al24 found that out of
200 patients with IBS, 75 percent had abnormal lactulose-glucose
breath tests. This is consistent with bacterial overgrowth of the
small intestine.
Another study found that 78% of IBS patients had an abnormal
breath test. This suggested that a small intestine bacterial
overgrowth may be present. The study consisted of 202 IBS
patients who had met the Rome I Criteria. They were treated with
antibiotics with successful eradication of the bacteria being
measured by a normal breath test. After eradication, half of the
patients no longer met the Rome I Criteria.25 This study was
followed with a double-blind randomized control trial. This
follow-up study consisted of 111 patients with IBS. Thirty-seven
percent of those with IBS had normalization of global symptoms
Enteric nervous system
One of the earliest studies to show that the nervous system played
an important role in IBS involved the difference in perception of
pain in patients with IBS compared to controls. Ritchie40 found
that patients with IBS experienced rectal pain when a balloon was
inflated in the rectum at lower volumes than non-IBS patients. In
this study, fewer than 10% of non-IBS subjects reported pain at a
distending volume of about 60 ml compared to greater than 50%
of IBS patients reporting pain at the same distending volume.
The enteric nervous system (ENS) is a complex system that rivals
the spinal cord and brain in the number of nerves and neurotransmitters involved. It can work both in conjunction with the CNS as
Research & Review Articles
well as on its own as demonstrated in pig intestines in vitro.41
Intrinsic primary afferent neurons(IPAN) are analogous to dorsal
root ganglia of the CNS. They are the peripheral sensors that feed
information to the ENS in order to allow autonomous regulation of
the gut by the ENS. Drugs that activate IPANs stimulate diarrhea
and drugs that inhibit their action cause constipation. One clinical
trial used 5-Hydroxyindalpin to stimulate the IPANs and the result
was diarrhea.42 It has been theorized, however, that a drug that targets
the distal terminal of IPANs may lead to better control of gut
motility.41 When stimulated by 5HT-4, IPANs cause the release of
acetylcholine and calcitonin g related peptide.41 These neurotransmitters induce gut motility. 5HT-4 also causes the increase release of
5HT-4 at neuromuscular junctions and nerve-nerve synapses in the
myenteric plexus.43-45 The combination of these factors is the reason
that Tegaserod, a 5HT-4 receptor agonist, stimulates gut motility.
Tegaserod has been shown to provide relief of IBS-c (constipation
type) over placebo in several trials.41 5HT-3 is the signal used by
the CNS to interpret the intestinal tract environment. Like 5HT-4,
5HT-3 is part of the prokinetic pathway. Antagonizing 5HT-3 is
useful in the treatment of hypermotility states such as IBS-D
(diarrhea type). Alosetron and Cilansetron, 5HT-3 antagonists, have
been effective in the treatment of IBS-D.46-48
Celiac Disease
Celiac disease and irritable bowel syndrome share many common
gastrointestinal symptoms. It was found that patients with
irritable bowel syndrome as diagnosed by ROME II criteria have
a higher association with also having celiac disease as compared to
normal controls. One study tested for the presence of celiac disease
by the presence of serum IgA antigliadin, IgG antigliadin, and
endomysial antibodies in 300 patients diagnosed with IBS.
Positive antibody tests were followed by biopsy for confirmation
of the diagnosis. The results were compared to 300 patients who
did not carry the diagnosis of IBS. They found that 14 patients
with IBS also had celiac disease compared to just 2 of the nonIBS controls (p=0.004, odds ratio = 7.0 [95% CI 1.7-28]).
According to this study, it may be prudent to refer patients with
IBS for Celiac disease testing.49
Another smaller study comparing 34 subjects with dyspepsia, 50
subjects with IBS, and 78 asymptomatic healthy controls did not
show a statistically significant difference in the association with
celiac disease.50 However, in this study celiac disease was diagnosed
solely by serology. Whether there is an actual association between
the diseases or merely celiac patients falsely being labeled with
IBS remains to be seen. Future studies should look into the results
of treating the celiac disease to see if the IBS symptoms remain.
Until recently, the diagnosis of IBS was a diagnosis of exclusion
which required a lengthy battery of tests. With the advent of the
Rome criteria, physicians have been able to make the diagnosis of
IBS on the basis of symptoms in the absence of red flags. Several
studies examined the pre-test probability and prevalence of
organic disease in patients with IBS. Using flexible sigmoidoscopy,
colonoscopy, and barium enema, between 0-1.3% of patients were
found to have organic disease. Other studies using abdominal
ultrasonography and rectal biopsy failed to identify organic disease
in IBS patients. Laboratory studies such as a complete blood
count, chemistry panel and fecal occult blood testing similarly
found organic disease in only 0 to 1.3% of IBS patients. TSH was
abnormal in 0.6 to 6% of patients. Several studies have shown
that IBS patients have abnormal breath tests for lactose
intolerance in 22-26% of cases. However, one study found the
presence of an abnormal breath test in 78% of IBS patients.13 In
addition, Celiac disease was found to be more prevalent in IBS
patients, 5% compared to 1% of the general population.49,50
The alarms or red flags (see Table 1)14 used in the Rome criteria
such as hematochezia, anemia, weight loss, chronic severe diarrhea
and family history of colon cancer, all lead to a high pre-test
probability of organic disease and therefore justify initiating a
targeted work-up. The Rome I criteria was found to be 65%
sensitive, 100 % specific with a 100% predictive value for IBS.1
The etiology of IBS is complex with overlapping etiologies
contributing to the symptoms. (See Figure 1) It has been proposed
that small bowel bacterial overgrowth, post-infectious states,
inflammatory states as well as psychological factors, all contribute
to the vast symptoms of IBS. For this reason, the treatment must
be tailored to each IBS patient. Patients with predominant
psychological etiology may do well with antidepressants and
behavioral therapy. Several studies have looked into treating
patients with antibiotics when bacterial overgrowth is the
suspected etiology. Other therapies are used to control symptoms
such as antispasmodics, bulking agents, and serotonin receptor
agonists and antagonists.
There are two antispasmodics available in the United States,
dicyclomine and hyoscyamine. These drugs are thought to work
by decreasing the spontaneous activity of the intestinal smooth
muscles. Atropine-like adverse effects often lead to intolerance
and the relaxation of the smooth muscle can worsen constipation.
Currently there is only a grade B recommendation for the use of
anti-spasmodic agents for IBS management.20 Five smooth muscle
relaxants were found to have greater efficacy than placebo. These
include cimetropium bromide, pinaverium bromide, octylonium
bromide, trimebutine, and mebeverine.51
Bulking agents
Several bulking agents have been studied including wheat, bran,
corn, fiber, calcium, polycarbophil, ispaghula husk and psyllium.
Bulking agents were effective in improving stool bulk and stool
frequency but they were not found to be more effective than
placebo. Adverse effects of bloating and abdominal discomfort
were worsened by those agents.20
Research & Review Articles
Figure 1: Diagram demonstrating the proposed overlapping etiologies
of IBS.
Figure 2: Algorithm for evaluation and treatment of IBS
Anti-diarrheal agents
though the magnitude of the improvements were different across
the trials. Alosetron has a grade A recommendation by the ACG
for IBS with diarrhea. The most commonly reported adverse effect
is constipation occurring in 22-39% of patients vs 3-14%
controls. Unfortunately, ischemic colitis is unpredictable.
Physicians are advised to adhere the FDA guideline of using
Alosetron for “women with severe, diarrhea-predominant IBS who
failed to respond to conventional IBS therapy” in view of the
potentially serious adverse effects.46-48
Diarrhea can be controlled with many over the counter agents
such as Loperamide which includes Immodium and Kaopectate
II among others. This agent works by slowing gut transit and up
regulating water and electrolyte absorption.52 Prescription Lomotil
can be used if the over the counter agents fail to provide relief.
Serotonin receptor agonist (5HT4)
Serotonin receptor activation stimulates peristalsis thereby
increasing intestinal and colonic transit time and also reduces
visceral sensitivity. Tegaserod is the only 5HT4 currently available.
Several well-designed, randomized, controlled trials using the
ROME criteria for diagnosis have demonstrated significant
improvement of constipation symptoms. The recommended
dosage is 6mg twice daily and the trials duration extended over
12 weeks. Significant reduction of bloating, abdominal discomfort
and improvement of bowel-habit satisfaction were reported but
the magnitude of these improvements were not consistent among
those trials. This is likely secondary to different methodology used
to evaluate the symptoms. 9-10% of patients reported diarrhea as
the most frequent adverse effects compared to 4-5% in the
placebo group.41 Another recent study looking at the efficacy of
Tegaserod for repeated therapy using 2660 patients found that
Tegaserod was superior to placebo in both initial use and repeated
therapy.53 It should be kept in mind that the FDA approved
regimen is only for short duration in females whose primary
symptom is constipation. The role of Tegaserod is not clearly
defined in patients with alternating constipation with diarrhea.
No recommendation exists for males.
Serotonin receptor antagonist 5HT3
5HT3 antagonism slows colonic transit and improves discomfort.
Alosetron is the first FDA-approved 5HT3 receptor antagonist
for the treatment of IBS with diarrhea. Because of reported cases
of ischemic colitis, its use was stopped in November 2000. The
FDA allowed the marketing of the drug again in June 2002 at the
dose of 1mg twice daily. Four trials resulted in statistically
significant improvement in abdominal pain and fecal urgency
Behavioral and psychotropic therapy
Because of the frequent findings of psychological disorders in IBS,
especially depression and anxiety disorders, behavioral therapies
have been tried for treatment. There have been at least 16
randomized controlled trials. Presence of a psychological disorder
was found in 80% of patients. Unfortunately, these trials
contained flaws in the methodology. Behavioral therapy seems to
improve both the IBS symptoms and the psychological manifestations although the evidence fails to be unequivocal. Currently,
only behavioral therapy has Grade A recommendation for the
treatment of IBS.20
The use of antidepressants has been helpful in some patients.
Those with abdominal pain, bloating and diarrhea seem to be
most susceptible to the benefits of tricyclic antidepressants.54 The
mechanism of action is two-fold. First, they appear to effect
motility and visceral sensitivity as well as central pain perception.55
They also have anticholinergic effects which can help with
diarrhea. More recent studies have found SSRIs to be somewhat
helpful in alleviating symptoms and improving mood.20
Several studies have evaluated the benefit of hypnotherapy in
reducing symptoms of IBS in both the short and long-term. One
study consisted of IBS patients receiving weekly 1-hour session of
gut-directed hypnotherapy for a total of 12 weeks. They found
that the patients improved in the long-term follow-ups.56 Another
study followed 204 patients using questionnaires for 6 years. They
Research & Review Articles
found that initially 71% of the patients had symptom
improvement. After 5 years, only 19% of the patients who initially
responded had regressed. Measures of quality of life, anxiety, and
depression all were statistically significantly improved.57
Future therapy
There is overwhelming evidence that small bowel bacterial
overgrowth is prevalent in a much higher percentage of patients
with IBS compared to the healthy population. There is current
research looking into an algorithm for treating IBS according to
this data. The algorithm calls for a lactulose breath test at the time
of initial patient presentation. If the breath test is positive,
treatment with Cipro/Flagyl have been successful in eradicating
bacterial overgrowth, resulting in a negative breath test.25,26
Following bacterial eradication, patients can then be started on
traditional therapy for IBS up to and including the 5HTa agonists
and antagonists. We are currently studying the efficacy of Xifaxan
400 mg TID and comparing it to Cipro or Flagyl for use in
bacterial eradication in the small bowel. It is our opinion that
small bowel bacterial overgrowth is not the only etiology of IBS
but one of many triggers.
1. Lacy BE, Lee RD. Irritable bowel syndrome: a syndrome in evolution. Journal of
Clinical Gastroenterology. 2005; 39:230-242
2. Bockus HL, Bank J, Wilkinson SA. Neurogenic mucous colitis. American Journal of
Medical Science. 1928;176:813-823
3. Talley NJ, Zinsmeister AR, Van Dyke C, et al. Epidemiology of colonic symptoms
and the irritable bowel syndrome. Gastroenterology. 1991;101:927-934.
4. Drossman DA, Li Z, Andruzzi E, et al. U.S. householder survey of functional
gastrointestinal disorders: prevalence, sociodemography, and health impact. Dig Dis
Sci. 1993;38:1569-1580.
5. Saito YA, Locke GR, Talley NJ, et al. A comparison of the Rome and Manning
criteria for case identification in epidemiological investigations of irritable bowel
syndrome. American Journal of Gastroenterology. 2000;95:2816-2824.
6. Schuster MM. Defining and diagnosing irritable bowel syndrome. Am J Manag
Careh. 2001;7(suppl):246-251.
7. National Ambulatory Medical Care Survey. National Center for Health Statistics:
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with functional gastrointestinal disorders. Gastroenterology. 1987;92:1282-1284.
9. Drossman DA, Corazziari E, Talley NJ, et al. Rome II. The Functional
Gastrointestinal Disorders. Diagnosis, Pathophysiology and Treatment: A
Multinational Consensus, 2nd ed. McLean, VA: Degnon, 2000.
10. Harvey RF, Mauad EC, Brown AM. Prognosis in the irritable bowel syndrome: a
five-year prospective study. Lancet. 1987;1:963-965.
11. Talley NJ, Gabriel SE, Harmsen WS, et al. Medical costs in community subjects
with irritable bowel syndrome. Gastroenterology. 1995;109:1736-1741.
12. American Gastroenterological Association. The Burden of Gastrointestinal Diseases.
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13. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestives
diseases in the United States. Gastroenterology. 2002;122:1500-1511.
14. Vanner SJ, Depew WT, Paterson MD, DaCosta LR, Groll AG, Simon JB, Djurfeldt
M. Predictive vale of Rome Criteria for diagnosing the irritable bowel syndrome.
The American Journal of Gastroenterology. 1999; 94. 2912-2916
15. Heitkemper MM, Cain KC, Jarrett ME, Burr RL, Hertig V, Bond EF. Symptoms
across the menstrual cycle in women with irritable bowel syndrome. Am J
Gastroenterology. 2003;98: 420-430
16. Ruigomez A, Rodriguez LA, Johansson S, Wallander MA. Is hormone replacement
therapy associated with an increased risk of irritable bowel syndrome? Maturitas.
2003;44: 133-140
17. Houghton LA, Jackson NA, Whorwhell PJ, Morris J. Do male sex hormones protect
from irritable bowel syndrome? Am J Gastroenterology. 2000; 95:2296-2300.
18. Miller V, Whitaker K, Morris JA, Julie A, Whorwell PJ. Gender and irritable bowel
syndrome: the male connection. Journal Clinical Gastroenterology. 2004; 38:558-560
19. Ali A, Richardson D, Toner B. Feminine gender role and illness behaviour in
irritable bowel syndrome. Journal of Gender Culture Health. 1998;3:59-65
20. Drossman DA, Camilelleri M, Mayer EA, Whitehead WE. AGA technical review on
Irritable Bowel Syndrome. Gastroenterology 2002;123:2108-2131
21. Chami TN, Schuster MM, Bohlman NE, Pulliam TJ, Kamal N, Whitehead WE. A
simple radiological method to estimate the quantity of bowel gas. American Journal
of Gastroenterology. 1991;86:599-602.
22. King TS, Ekua M, Hunter JO. Abnormal colonic fermentation in irritable bowel
syndrome. Lancet. 1998;352:1187-1189
23. Lin HC. Small intestinal bacterial overgrowth: a framework for understanding
irritable bowel syndrome. JAMA. 2004 852-858
24. Nucera C. Lupascu AM, Gabriella M, et al. Sugar intolerance in irritable bowel
syndrome: the role of small bacterial overgrowth. Gastroenterology. 2004;126(4): A511
25. Pimental M, Chow E, Lin HC. Eradication of small intestine bacterial overgrowth
reduces symptoms in irritable bowel syndrome. American Journal of
Gastroenterology. 2000. 3503-3506.
26. Pimental M, Chow E, Lin HC. Normalization of lactulose breath testing correlates
with symptom improvement in irritable bowel syndrome: a double blind
randomized controlled study. Gastroenterology 2003;98 412-419.
27. Nayak A, Karnad D, Abraham M, Mistry FP. Metronidazole relieve symptoms in
irritable bowel syndrome: the role of small bacterial overgrowth: the confusion with
so called “chronic amebiasis.” Indian Journal of Gastroenterology. 1997; 16: 137-139.
28. Rodriguez LA, Ruigomez A. Increased risk of irritable bowel syndrome after
bacterial gastroenteritis: cohort study. BMJ 1999; 318:565-566
29. Parry SD, Stansfield R, Jelly D, Gregory W, Phillips E, Barton JR, Welfare MR .
Does bacterial gastroenteritis predispose people to functional gastrointestinal
disorders? A prospective, community-based case-control study. American Journal of
Gastroenterology 2003; 98 1970-1975.
30. Parry S, Forgacs I. Intestinal infection and irritable bowel syndrome. European
Journal of Gastroenterology and Hepatology. 2005; 17: 5-9
31. Neal R, Barker L, Spiller RC. Prognosis in post-infective irritable bowel syndrome: a
six year follow-up study. Gut. 2002;51:410-413
32. Hiatt RB, Katz L. Mast cells in inflammatory conditions of the gastrointestinal
tract. Am J Gastroenterol 1962;37:541–545.
33. Weston AP, Biddle WL, Bhatia PS, Miner PB Jr. Terminal ilealmucosal mast cells in
irritable bowel syndrome. Dig Dis Sci 1993;38:1590–1595.
34. O’Sullivan M, Clayton N, Breslin NP, Harman I, Bountra C, McLaren A,
O’Morain CA. Increased mast cells in the irritable bowel syndrome.
Neurogastroenterol Motil 2000;12:449–457.
35. Salzmann JL, Peltier-Koch F, Bloch F, Petite JP, Camilleri JP. Methods in laboratory
investigation: morphometric study of colonic biopsies: a new method of estimating
inflammatory diseases. Lab Invest 1990;60:847–851.
36. Tornblom H, Lindberg G, Nyberg B, Veress B, Inst K. Histopathological findings in
the jejunum of patients with severe irritable bowel syndrome (abstr).
Gastroenterology 2000;118:A140.
37. O’Sullivan MA, Clayton N, Wong T, Bountra C, Buckley MM, O’Morain CA.
Increased inos and nitrotyrosine expression in irritable bowel syndrome (IBS)
(abstr). Gastroenterology 2000;118:A702.
38. Spiller RC. Inflammation as a basis for functional GI disorders. Best Practice and
Research Clinical Gastroenterology. 2004;18:641-661.
39. Tornblom H, Lindberg G, Nyberg B, Veress B. Full thickness biopsy of the jejunum
reveals inflammation and enteric neuropathy in irritable bowel syndrome.
Gastroenterology 2000; 123: 1972-1979.
40. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the
irritable colon syndrome. Gut 1973;14:125-132
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41. Gershon MD. Nerves, reflexes, and the enteric nervous system: pathogenesis of the
irritable bowel syndrome. Journal of Clinical Gastroenterology. 2005; 39: S184-S193
42. Branchek T, Mawe G, Gershon MD. Characterization and localization of a
peripheral neural 5-hydroxytryptamine receptor subtype with a selective agonist, H5-hydroxyindalpine. J Neuroscience. 1088; 8:2582-2595
43. Craig DA, Clarke DE. Pharmacological characterization of a neuronal receptor for
5-hydroxytryptamine in guinea pig ileum with properties similar to 5-hydroxytryptamine4 receptor. Journal of Pharmacol Exp Ther. 1990; 252:1378-1386.
44. Galligan JJ, Pan H, Messori E. Signaling mechanism coupled to 5-hydroxytryptamine4 receptor mediated facilitation of fast synaptic transmission in the
guinea pig ileum myenteric plexus. Neurogastroenterol Motil. 2003;15:523-529.
45. Pan H, Galligan JJ. 5-HT1A and 5-HT4 receptor mediated inhibition and
facilitation of of fast synaptic transmission in enteric neurons. American Journal of
Physiology. 1994;266:G230-G238.
46. Mangle AW, Northcutt AR. Review article: the safety and efficacy of alosetron, a 5HT3 receptor antagonist, in female irritable bowel syndrome patients. Aliment
Pharmacol Ther. 1999;13(suppl2):77-82
referred to secondary care. Lancet 2001; 538: 1504-08
50. Locke GR, Murray JA, Zinsmeister AR, Melton LJ III, Talley NJ. Celiac disease
serology in irritable bowel syndrome and dyspepsia: A population-based case-control
study. Mayo Clinic Proceedings 2004; 79: 476-482
51. Poynard T, Naveau S, Mory B, Chaput JC. Meta-analysis of smooth muscle
relaxants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther.
52. Cann PA, Read NW, Holdsworth CD, Barends D. Role of loperamide and placebo
in management of irritable bowel syndrome. Dig Dis Sci. 1984;29:239-247.
53. Tack J, Muller-Lissner, Bytzer P, et al. A randomised controlled trial assessing the
efficacy and safety of repeated tegaserod therapy in women with irritable bowel
syndrome with constipation. Gut 2005; 54(12): 1707-1713
54. Jackson JL, O'Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment
of functional gastrointestinal disorders with antidepressant medications: a metaanalysis. Am J Med. 2000;108:65-72.
55. Hameroff SR, Weiss JL, Lerman JC, et al. Doxepin's effect on chronic pain and
depression: a controlled study. J Clin Psychiatry. 1984;45(pt 2):47-53.
47. Humphrey PP, Bountra C, Clayton N, Kozlowski K. Review article: the therapeutic
potential of 5-HT3 receptor antagonist in the treatment of irritable bowel
syndrome. Aliment Pharmacol Ther. 1999;13 (suppl 2):31-38
56. Gonsalkorale WM, Houghton LA, Whorwell PJ. Hypnotherapy in irritable bowel
syndrome. A large-scale audit of a clinical service with examination of factors
influencing responsiveness. Am J Gastroenterol. 2002;97:955-961
48. Coremans G, Clouse RG, Carter F, et al. Cilansetron, a novel 5-HT3 antagonist,
demonstrated efficacy in males with irritable bowel syndrome with diarrhea
predominance (IBS-D). Gastroenterology 2004; 126 (suppl 2):105454
57. Bhuket T, Chey W. Hypnotherapy for irritable bowel syndrome: effectively
expanding the arsenal? Evidenced-Based Gastroenterology 2004;5(2)54-55
49. Sanders DS, Carter MJ, Hurlstone DP. Association of adult coeliac disease with
irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria
Forgotten Perspectives
Drawing courtesy of
Shruti Tewari, MD
Research & Review Articles
Dae Hyun Kim, MD, MPH, Andrew N. Lee, MD
Prediction of coronary heart disease (CHD) is based on
multivariable risk equations developed from population-based
observational studies in which people without clinical CHD at
the initiation of study were examined and followed until their
first CHD events. The risk equations from the Framingham Heart
Study have been widely used in our clinical practice1-3 and
research.4,5 The recent report of the third National Cholesterol
Education Program-Adult Treatment Panel (NCEP-ATP)
incorporated the Framingham risk equations to predict ten-year
absolute CHD risk and to identify certain patients who are at
high risk and more likely to benefit from primary prevention with
aggressive lipid-lowering treatment.1 In addition to CHD
prediction, population-based observational studies also provide
the clue to understand how much of CHD can be prevented by
modifying major cardiovascular risk factors such as serum
cholesterol level, blood pressure level, and current smoking.4,6,7
In this narrative review, we described how CHD prediction works
and how it can be improved by including nontraditional cardiovascular risk factors. We also discussed about how likely it is to
prevent the majority of CHD.
How Do We Predict CHD?
The Framingham Heart Study has developed mathematical
functions to assess the relative importance of CHD risk factors
and to quantify absolute CHD risk for individual patients.8-10
Detailed methods of derivation of CHD risk equations were
described elsewhere.8 Briefly, sex-specific CHD risk equations
were derived from a population-based sample of 2489 men and
2856 women, 30 to 74 years of age, who were free of overt cardiovascular disease at the time of their 11th examination of the
original Framingham Cohort or the initial examination of the
Framingham Offspring Study in 1971 to 1974. CHD risk factors
were routinely and systematically measured during these
examinations and twelve-year follow-up was obtained for the
development of “hard” CHD events, defined as myocardial
infarction and CHD death. Sex-specific Cox proportional hazards
regression was performed to calculate the relative importance of
CHD risk factors using age, current smoking, presence of
diabetes, the fifth Joint National Committee on Hypertension
blood pressure categories, and the second NCEP-ATP cholesterol
categories as covariates. (Table 1) In addition, score sheets were
developed from the beta-coefficients of Cox proportional hazards
models to provide ten-year absolute CHD risk and to make it
easy to implement as part of a screening program. They were
adopted by the NCEP-ATP III guideline.1 (Figure 1) The
predictive capability of the model using a continuous variable or
a categorical variable for cholesterol level was almost identical.8
The equation is particularly useful when there are multiple mild
abnormalities that increase CHD risk synergistically.
In the Framingham risk equation, several candidate risk factors
such as family history of CHD, elevated fibrinogen levels, left
ventricular hypertrophy on the electrocardiogram, postmenopausal
estrogen replacement therapy, physical activity, high serum
triglyceride, and body mass index, were not included for practical
reasons, although they may contribute to the risk of CHD.8
Table 1. Multivariate-Adjusted Relative Risks (RR) for CHD from the Framingham
Heart Study: Twelve-Year Follow-Up of 2489 Men and 2856 Women
(Adapted from Wilson et al8)
Risk Factors
Age (Years)
Blood Pressure
High Normal
Hypertension Stage I
Hypertension Stage II
Cigarette Use (Yes/No)
Diabetes (Yes/No)
LDL Cholesterol (mg/dL)
HDL Cholesterol (mg/dL)
95% CI
95% CI
* 0.01 < P < 0.05, † 0.001 < P < 0.01, ‡ P < 0.001.
How Well Does CHD Prediction Equation Work?
The performance of the CHD risk prediction models has
been examined according to discrimination and
calibration.4,5 From the coefficients of the prediction
model, a risk score can be calculated for each person by
multiplying the person’s risk factor level by the associated
coefficient for that risk variable, then summing all these
products. Those with a higher risk score from a
prediction model are expected to have higher CHD
events. Discrimination is the ability of a predictive model
to separate those who experience hard CHD events from
those who do not. It can be quantified by c-statistic or
the area under a receiver operating characteristic (ROC)
curve (AUC) which indicates the probability that a
person who had an incident CHD event within a
specified time had a higher risk score than a person who
did not have an event by that time.11,12 The AUC has a
range between 0.5 and 1. When the variables in the
prediction model are unrelated to the event, the expected
AUC would be 0.5. The greater the AUC is, the better
the prediction model works. Calibration, another
measure of performance of the prediction model,
measures how closely predicted outcomes agree with
actual outcomes.
Research & Review Articles
Figure 1. Score Sheets for Estimation of Ten-Year CHD Risk for Men and Women (Adapted from NCEP-ATP III Guideline1)
Since the Framingham risk equation was derived from a
community sample of white middle-class individuals from a
suburb of Boston, concerns have existed regarding its generalizability to other populations.8 To test the validity, the sex-specific
Framingham risk equations were applied to six prospectively
studied, ethnically diverse cohorts including the Atherosclerosis
Risk in Communities Study (ARIC), Physicians’ Health Study,
Honolulu Heart Program, Puerto Rico Heart Health Program,
Strong Heart Study, and the Cardiovascular Health Study.5 The
performance of the predication equation was compared using
discrimination and calibration. For white men and women and for
black men and women, the Framingham risk equations performed
reasonably well within five years of follow-up. (Figure 2) Among
Japanese American and Hispanic men and Native American
women, the equation overestimated the risk. However, after taking
into account different prevalence of risk factors and underlying
CHD rates, it performed well in these populations.
Then, how much of incident CHD events are explained by known
risk factors? The CHD prediction equations have been used to
answer this question. In the Seven Countries Study, the prediction
equation using systolic blood pressure, cholesterol, smoking, and
age derived from the US railroad workers was applied to men in
Research & Review Articles
five European countries.13 Fifty one percent of CHD events
occurred in top quintile of the predicted CHD risk. Based on this
finding, it is often said that only 50 percent of the CHD is
explained by the known risk factors. In another study, the
Framingham equation was applied to the National Health and
Nutrition Examination Survey I, a probability sample of the US
population.14 Thirty nine percent of CHD deaths in men and 59
percent in women occurred in top quintile of the predicted risk.
Based on these findings, can we say that approximately 40 to 60
percent of CHD mortality is due to known causes and the
remaining percent is due to unknown causes? This is a very
common misinterpretation. Counting cases attributable to the
upper end of the risk distribution defined by an arbitrarily high
cut point on the scale is misleading, because most of the risk
factors have a continuous graded relationship to risk.15
In a study using five large cohorts of young and middle-aged adults
in the Multiple Risk Factor Intervention Trial (MRFIT) and Chicago
Heart Association Detection Project in Industry (CHA) who were
free of diabetes and myocardial infarction, low-risk participants who
had cholesterol level less than 200 mg/dL, blood pressure less than
or equal to 120/80 mmHg, and no current smoking, experienced
significantly and markedly lower CHD death rates by 77 to 92
percent than the rest of the cohorts during the mean follow-up
period of 16 years for MRFIT and 22 years for CHA.6 This suggests
that three major risk factors – serum cholesterol level, blood pressure,
and smoking – account for the majority of CHD death. Similar
results were found in the ARIC study.4 Not being in the bottom
decile of risk score derived from traditional risk factors accounted
for 72-75 percent of CHD risk in men and 89-93 percent in women.
Evidences from numerous cohort studies with long follow-up have
shown that the major established risk factors explain at least 75% of
the CHD events within populations and there is no evidence
supporting the only-50-percent claim.
Can We Improve CHD Risk Equation?
If traditional risk factors in the Framingham risk equation – total
cholesterol, HDL cholesterol, current smoking, diabetes, and
blood pressure – can explain 75 percent of incident CHD events,
how can the remaining 25 percent be explained? Investigators in
the ARIC study examined the improvement in the predictive
capability of the basic risk equation by adding the following
nontraditional risk factors: body mass index, waist-hip ratio, Keys
score, albumin, white blood cell count, “residual” forced expiratory
volume at 1 second (FEV1) (calculated as the difference between
measured FEV1 and the predicted FEV1 from age, height, and
sex), fibrinogen, factor VII, von Willebrand Factor, lipoprotein(a),
heart rate, pack years cigarette smoking, sport activity index, and
creatinine.4 Among the nontraditional risk factors considered, no
single factor provided a large improvement in predictive capability
of the basic equations only including total cholesterol, HDL
cholesterol, systolic blood pressure, antihypertensive medications,
current smoking, and diabetes. When nontraditional risk factors
and intima-media thickness were added to the basic model, the
predictive capacity of the model was significantly improved, as
measured by the gain in the AUC above the 0.5. (Table 2)
Have We Reached the Limits in CHD Prediction?
In the ARIC study, 531 CHD events occurred among 4287 white
men during ten years of follow-up period since the baseline
examination in 1987.4 If we were able to predict CHD perfectly,
we could identify those 531 high-risk men at baseline: 100 percent
of them should develop CHD events within ten years and none
of the remaining 3756 low-risk men would have events. This is
theoretically impossible because the CHD risk exists in
continuum in a population. Some practical limitations also exist.
The CHD events can be unrecognized because of silent
myocardial infarction, microinfarction, or unwitnessed deaths.
Oftentimes deaths are falsely attributed to CHD. In addition,
true CHD risk may relate more closely to lifetime cholesterol level
or blood pressure level rather than their levels measured at one
point or during a relatively short period. Blood tests may not
precisely measure atherogenic or thrombogenic processes. There
is always a possibility of unmeasured or undiscovered risk factors
as well. Even if the science were complete, there still exists a source
of variation from random effects. For these reasons, we will never
be able to predict CHD perfectly.
Table 2. Area Under the ROC Curves Comparing Basic and Full Models
(Adapted and modified from Chambless at el4)*
Black Women
N=1798; n=90
White Women
N=5006; n=198
Black Men
N=1102; n=101
White Men
N=4082; n=504
* N indicates sample size and n indicates the number of CHD events.
† Basic model included total cholesterol, HDL cholesterol, systolic blood pressure, antihypertensive medications, current smoking, and diabetes.
‡ Full model included body mass index, waist-hip ratio, Keys score, albumin, residual
FEV1, fibrinogen, factor VII, von Willebrand Factor, lipoprotein(a), heart rate, pack
years cigarette smoking, sport activity index, and intima-media thickness.
If research since 1979 has improved overall
prediction so little, have we discovered all the
important risk factors? Is there any evidence that
we could predict CHD events better? Some
indirect historical evidences suggest that there is
more to be discovered. In William Osler’s lecture
to Royal College of Physicians in 1910,16 the
number of angina cases per hospital admissions
was approximately 1 case per year in large
hospitals. In his perspectives,17 Paul Dudley
White, a graduate of Harvard Medical School
in 1911 and founding member of the American
Heart Association and International Council of
Cardiology, described that there were very few
angina cases after review of his voluminous notes
Research & Review Articles
Figure 2. Five-Year Prediction for Hard CHD Events: Performance Measures for Atherosclerosis Risk in Communities Study Men and Women
(Adapted from D’Agostino et al5)
X-axes refer to decile of predicted risk based on the Framingham Heart Study function.
during his medical internship at the Massachusetts General
Hospital from 1912 to 1913. Among his 100 publications in his
early career between 1913 and 1926, there were only two papers
related to CHD. According to these evidences, CHD may have
been a rare disease in 1910. However, problems exist with historical
evidences: they were mainly personal observations and there are
major concerns about diagnostic accuracy such as the unavailability
of electrocardiogram or cardiac enzyme tests. It is also possible that
people did not live long enough to develop CHD.
Besides historical evidences, ecological evidences provide an
opportunity to examine the different characteristics and their
potential contribution to incident CHD events among populations
in different geographic locations. In the International
Atherosclerosis Project18 where 21302 autopsies from 15
geographic locations and four race-sex groups were assessed, the
age-adjusted percent of intimal surface of coronary arteries
involved with raised atherosclerotic lesions varied up to three folds
from 6 percent in Durban Bantu or Guatemala to 18 percent in
New Orleans whites and Oslo. Prevalence of coronary stenosis
among those aged 45 to 54 years also varied from 0 percent in
Durban Bantu to 20 percent in New Orleans whites. Another
autopsy study compared the prevalence of myocardial infarction
between African Americans and Africans in Nigeria and between
Asian Americans and Asians in Japan and Korea.19 The authors
concluded that very low prevalence of myocardial infarction in
Africa and Asia was due to environment, not genetics. In a study
comparing CHD incidence in men aged 45 to 64 years who
participated in three large National Heart Lung Blood Institutesupported cohort studies in the 1960s, the incidence of CHD in
Honolulu Japanese and Puerto Rico men was only 40 percent of
that observed in the Framingham Heart Study.20 It was suggested
that lower levels of risk factors during early lifetime might be
responsible for lower CHD incidence. In the Seven Countries
Study, ten-year CHD mortality in 16 cohorts was strongly
associated with median serum cholesterol levels and the incidence
of CHD mortality in low-rate cohorts was 11 percent of that in
high-rate cohorts.21 Similar findings between serum cholesterol
level and CHD mortality were observed in other studies.7,22
Estimated CHD reduction effect of lowering cholesterol by
0.6mmol (23.2 mg/dL) was 27 percent in cohort studies and 38%
percent in ecological studies.7 Like historical evidences, ecologic
evidences are not free from limitations: interpretation may be
Research & Review Articles
Figure 3. Incidence of CHD According to Diastolic Blood Pressure, Serum Cholesterol, and Body Mass Index (Adapted from Law et al25)
Data were obtained from cohort studies. Incidence was plotted on arithmetic scale (left hand plots) and logarithmic scale (right hand plots).
affected by possible genetic difference. In addition, secular changes
in many populations have diminished research opportunities.
Despite abovementioned limitations, both historical and ecological
evidences suggest that some human adult populations have
extremely low CHD event rates and provide a unique perspective
to better understand the incidence of CHD events.
Is It Possible to Prevent 90 Percent of CHD Events?
Historical and ecological comparisons have suggested the potential
for preventing a large proportion of CHD events in contemporary
western countries.7,18,20-24 It may be possible to prevent 90 percent of
CHD events by reducing standard risk factors to optimal levels. In
the MRFIT and CHA studies, young non-smoking men with
cholesterol level less than 200 mg/dL and blood pressure less than
or equal to 120/80 mmHg had 86 to 92 percent less CHD events
than the rest of male participants.6 Similar results were observed in
the ARIC study.4 The benefit from low risk profile was greater for
individuals with persisting low risk profile. These studies are
prospectively conducted and their estimates are unbiased. Is it
feasible for high-risk individuals to reduce their risk to optimal
levels? A meta-analysis of risk factor associations with CHD showed
that a given change in a risk factor reduces the risk of CHD by a
constant proportion of the existing risk regardless of the starting
level of the existing risk.25 (Figure 3) The authors also emphasized
that individuals should be selected for preventive treatment only
based on a person’s absolute risk level and high-risk individuals
should receive interventions to modify all reversible risk factors
simultaneously.25 With good motivation from high-risk individuals
and aggressive strategies against multiple modifiable risk factors, we
may be able to achieve large risk reduction. Then, we can ask
whether entire populations can reduce their risk to optimal levels.
When the exposure to a risk factor is homogeneous within a
population, the case-control and cohort methods will fail to detect
Research & Review Articles
the risk factor as a cause of an outcome. As a result, the approach
aiming at high-risk individuals without a population approach will
only protect susceptible individuals, but will not control the causes
of incidence in the population.26 According to population-based
studies,4,6 more than 90 percent has higher than optimal risk levels.
People at less than highest risk are less motivated to change their
risk levels and interventions have lower benefit to risk ratios.
Therefore, a population strategy is essential for substantial effect.26
There is also evidence that today’s average levels of risk factors
should not be considered normal.25 When risk factor levels in our
ancestors were estimated through studies of isolated communities
with a hunter-gatherer lifestyle typical of the Stone Age, the rise in
risk factor levels that is currently seen in Western populations did
not occur in hunter-gatherer communities and the shift in the
Western distributions made current averages high in relation to the
prehistoric values. (Table 3) Moreover, lowering all risk factors to
optimal levels might not be necessary to prevent the majority of
CHD, because even low-risk populations did not have optimal
levels of all risk factors. In the Seven Countries Study, the
population in Crete had average blood pressure of 134/80 mmHg
and 57 percent of smokers and the population in Japan had average
blood pressure of 130/72 mmHg and 75% of smokers.21 It seems
that very low cholesterol level itself may suffice.
There are evidences supporting the importance of risk factor levels
during early life. The Ni-Hon-San study24 suggested early life
risk factors may play “predominant role” and geographical
comparisons showed that low serum cholesterol level was
associated with lower CHD rate than that estimated from withincountry cohort studies.7,21 This emphasizes the need for
population strategies to alter lifetime risk factor levels. Lifetime
low cholesterol levels can be achieved through early dietary
modification such as Mediterranean and low-saturated fat diets.
11. Nam B-H. Discrimination and Calibration in Survival Analysis [dissertation].
Boston, MA: Boston University; 2000.
Prevention of CHD can be improved by new risk factor
discoveries. Major areas of investigation include inflammation,
lipoprotein oxidation, vulnerable atherosclerotic plaque,
hemostasis, endothelial vasoprotection, and microvascular disease.
Even though they improve the CHD prediction only slightly, their
preventive potential may be large. In addition, markers of critical
processes may be targets of primary or secondary prevention.
Coronary heart disease is not an inevitable consequence of aging.
Major established risk factors can explain 75 to 90 percent of the
incidence of coronary heart disease within populations. If the
entire population could reduce known risk factor levels to 1st
decile, up to 90 percent prevention might be achieved.
If persistent low cholesterol levels can be achieved by population
strategies affecting childhood, it alone might achieve 90 percent
prevention when the children become adults.
Although nontraditional risk factors add little to overall risk
prediction, they might provide effective prevention opportunities.
1. Executive Summary of The Third Report of The National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood
Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285(19):2486-2497.
2. Summary of the second report of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993; 269(23):3015-3023.
3. The fifth report of the Joint National Committee on Detection, Evaluation, and
Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993; 153(2):154-183.
4. Chambless LE, Folsom AR, Sharrett AR et al. Coronary heart disease risk prediction
in the Atherosclerosis Risk in Communities (ARIC) study. J Clin Epidemiol 2003;
5. D'Agostino RB, Sr., Grundy S, Sullivan LM, Wilson P. Validation of the Framingham
coronary heart disease prediction scores: results of a multiple ethnic groups
investigation. JAMA 2001; 286(2):180-187.
6. Stamler J, Stamler R, Neaton JD et al. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large
cohorts of young adult and middle-aged men and women. JAMA 1999;
7. Law MR, Wald NJ. An ecological study of serum cholesterol and ischaemic heart
disease between 1950 and 1990. Eur J Clin Nutr 1994; 48(5):305-325.
8. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB.
Prediction of coronary heart disease using risk factor categories. Circulation 1998;
9. Gordon T, Kannel WB. Multiple risk functions for predicting coronary heart disease:
the concept, accuracy, and application. Am Heart J 1982; 103(6):1031-1039.
10. Kannel WB, McGee D, Gordon T. A general cardiovascular risk profile: the
Framingham Study. Am J Cardiol 1976; 38(1):46-51.
12. Sackett D, Haynes R, Guyatt G, Tugwell P. Clinical Epidemiology: A Basic Science for
Clinical Medicine, 2nd Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 1991.
13. Keys A, Aravanis C, Blackburn H et al. Coronary heart disease: overweight and
obesity as risk factors. Ann Intern Med 1972; 77(1):15-27.
14. Leaverton PE, Sorlie PD, Kleinman JC et al. Representativeness of the Framingham
risk model for coronary heart disease mortality: a comparison with a national cohort
study. J Chronic Dis 1987; 40(8):775-784.
15. Magnus P, Beaglehole R. The real contribution of the major risk factors to the
coronary epidemics: time to end the "only-50%" myth. Arch Intern Med 2001;
16. Osler W. The Lumleian lectures on angina pectoris. Lancet 1910; 1:697-701.
17. White PD. Perspectives. Prog Cardiovasc Dis 1971; 14(3):250-255.
18. Tejada C, Strong JP, Montenegro MR, Restrepo C, Solberg LA. Distribution of
coronary and aortic atherosclerosis by geographic location, race, and sex. Lab Invest
1968; 18(5):509-526.
19. Lee KT, Nail R, Sherman LA et al. Geographic Pathology of Myocardial Infarction.
Am J Cardiol 1964; 13:30-40.
20. Gordon T, Garcia-Palmieri MR, Kagan A, Kannel WB, Schiffman J. Differences in
coronary heart disease in Framingham, Honolulu and Puerto Rico. J Chronic Dis
1974; 27(7-8):329-344.
21. Keys A. Coronary heart disease, serum cholesterol, and the diet. Acta Med Scand
1980; 207(3):153-160.
22. Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W. Serum cholesterol
concentration and coronary heart disease in population with low cholesterol concentrations. BMJ 1991; 303(6797):276-282.
23. Robertson TL, Kato H, Rhoads GG et al. Epidemiologic studies of coronary heart disease
and stroke in Japanese men living in Japan, Hawaii and California. Incidence of myocardial
infarction and death from coronary heart disease. Am J Cardiol 1977; 39(2):239-243.
24. Robertson TL, Kato H, Gordon T et al. Epidemiologic studies of coronary heart
disease and stroke in Japanese men living in Japan, Hawaii and California. Coronary
heart disease risk factors in Japan and Hawaii. Am J Cardiol 1977; 39(2):244-249.
25. Law MR, Wald NJ. Risk factor thresholds: their existence under scrutiny. BMJ
2002; 324(7353):1570-1576.
26. Rose G. Sick individuals and sick populations. Int J Epidemiol 1985; 14(1):32-38.
Case Reports
Bonnie Callahan, MD, Utpal Sagar, MD, and Ted Martynowicz, DO
Herpes zoster is a recurrent infection of the varicella-zoster virus.
When it infects the periorbital region, the virus often involves the
ocular structures, and may lead to more disastrous sequelae,
including blindness. Despite advancements, including
immunization and antiviral therapy, zoster ophthalmicus persists in
the population.1 Therapy mitigates, but does not obviate, many of
the complications of infection.2 Our paper describes a patient with
herpes zoster ophthalmicus that presented from the community.
Case Presentation
The patient is an 85 year-old male with a past medical history of
HTN, BPH, and open-angle glaucoma who was in his usual state
of health until approximately two weeks prior to admission, when
he began having episodes of nausea and emesis. A few days later,
the nausea and emesis resolved, and he developed rhinorrhea. The
next day, he noticed a series of “scabby,” non-painful sores on the
left side of his nose. At that time he also noted an intermittent
stabbing headache in the area of his left eye and a yellowish,
purulent discharge from his left eye with left eye swelling. He was
unable to voluntarily open his left eyelid. Vision was preserved in
the left eye. Five days prior to presentation he saw his primary
care physician who prescribed a regimen of antihistamine,
levofloxacin, and ketorolac eye drops. However, his nose lesions
and eye swelling worsened, and he then visited an ophthalmologist
on the day of presentation to the hospital. The ophthalmologist’s
exam revealed elevated intraocular pressure and possible anterior
chamber involvement.
On admission he reported no facial trauma and no recent sick
contacts. He also denied any headache or eye pain in the last few
days. He did report continuing eye discharge and inability to
voluntarily open his left eye. Further review of the patient’s past
medical history was significant for a history of rectal carcinoma,
prostate cancer, hyperlipidemia, bronchitis, chickenpox as a child,
and prior basal cell carcinoma of his left eye. Surgical history
included a skin cancer removal and “prostate surgery.” Patient
reported no known medication allergies. His outpatient
medications were felodipine, simvastatin, and finasteride. He was
not taking any over-the-counter or herbal medications. Social
history was negative for tobacco, alcohol, or substance abuse. He
lives with his wife with no pets. He is an army veteran of World
War II and is currently retired. He reported no recent travel or
occupational exposures. On review of systems, he reported no
fever, chills, genitourinary, or musculoskeletal complaints. On
exam, he appeared to be in no acute distress. His temperature was
99.8° F, his heart rate 80 beats per minute, his blood pressure
142/76 mmHg, and respiratory rate 20. He appeared comfortable.
Head was atraumatic, however his left periorbital region was
swollen and mildly erythematous, and the patient, despite
encouragement, was unable to open his eyelid voluntarily. Upon
raising the eyelid on exam, the patient had purulent discharge from
the medial canthus, the sclera was minimally injected, and the left
pupil was 3.5-4 mm and non-reactive to light. The right pupil was
2.5- 3 mm and reactive to light. Visual
acuity was preserved bilaterally.
Extraocular movements of the right eye
were intact, while the left eye could
abduct, but could not adduct, elevate,
or move downward. The patient had
lesions on the left forehead, eyelid, and
tip of the nose that were scab-like. They
were not painful, nor were they actively
bleeding (Figure 1). The remainder of
Figure 1.
the patient’s physical exam was
unremarkable. Admission laboratory work showed that the patient
had no leukocytosis or anemia, and aside from a serum potassium
of 3.1, laboratory evaluation was normal.
The patient had already failed outpatient presumptive therapy for
bacterial conjunctivitis. The dermatomal distribution of his
lesions, corresponding to more than one branch of the ophthalmic
division of the trigeminal nerve, the cranial nerve III palsy, along
with the acuity and the time course of the illness, were consistent
with herpes zoster ophthalmicus infection.
Upon admission, brimonidine ophthalmic drops were started to
decrease the intraocular pressure in the setting of open-angle
glaucoma. Anterior chamber involvement was noted, for which
steroid eye drops were started. Systemic antiviral therapy with
acyclovir was also initiated. MRI/MRA of the brain was performed
and ruled out aneurysm as an etiology of CN III palsy. The day
after admission the patient was again seen by ophthalmology, and
artificial tears and timolol were added to the patient’s medication
regimen for his increased intraocular pressure and history of openangle glaucoma. The patient did well on the above prescribed
course, and was discharged to home with outpatient follow-up
four days after initial presentation. Our last report of follow-up
was sixteen days after initial presentation to the VAMC, when the
patient was noted to have slow improvement. At that time, he was
able to raise his eyelid and maintain it voluntarily for increasing
periods of time. His visual acuity remained unaffected by the
Herpes Zoster Ophthalmicus, and the edema around his eye was
noted to be significantly improved at that time.
Herpes zoster is an extremely common neurological affliction,
which often occurs at least one time in a person’s life. Estimates
have placed the incidence at approximately 2.2-7.1 cases per 1000
person-years.4 Herpes zoster generally occurs in the elderly, and is
caused by reactivation of the varicella-zoster virus. Patients are
initially infected by age ten, and the presentation is commonly
recognized as chickenpox. The virus then becomes latent in
sensory ganglia, and later reactivates, spreading via spinal or
cranial nerves to a dermatome. Patients thereafter present with
the typical unilateral exanthem, and concomitant acute pain due
to inflammation of sensory neurons and skin insults.5
Case Reports
Reactivation is often
seen in the setting of
common to the elderly
as well as the immunocompromised patient.
Prospective studies have
shown that the most
common location of
zoster reactivation is the
ophthalmic nerve.4 In
Figure 2- Hutchinson's sign, as seen in
fact, ophthalmic herpes
our patient, involving the nasociliary
zoster is seen in 10-20%
branch of the ophthalmic division of
of all zoster case.5 Often,
trigeminal nerve.
affected patients have
severe and persistent pain. Other features include keratitis, uveitis,
and optic neuritis of the affected eye, all of which require
immediate attention to prevent vision impairment. Decreased
corneal sensitivity may result as well, leading to dry eyes, and
eventual corneal ulceration.5
And, while the frontal branch of the ophthalmic division of the
trigeminal nerve almost always is involved, involvement of the
nasociliary branch is quite rare. The appearance of skin lesions at
the side of the nose, known as Hutchinson’s sign, has been
considered a prognostic feature for ocular inflammation in
patients with acute herpes zoster ophthalmicus.4 (See Figure 2)
Our patient presented with complete ptosis and essentially
paralysis of the oculomotor nerve, which is particularly rare in
herpes zoster ophthalmicus. An extensive review of the literature
returned only one recent case review found in French literature,
reporting two cases of oculomotor paralysis.3 Furthermore, it has
been postulated that involvement of cranial nerves other than the
trigeminal nerve occurs by secondary vasculitis in the orbital apex,
resulting in diplopia.5
In the early stages of herpes zoster ophthalmicus, patients report
malaise, pain, pruritis, low-grade fever, and photophobia. Skin
hypersensitivity occurs on the forehead, followed by erythematous
macules, which evolve to papules and vesicles in the affected
dermatome. Generally the skin rash precedes ocular lesions by
several days. Periorbital edema is seen early in the course of the
disease. Conjunctivitis, episcleritis, and corneal epithelial defects
are all commonly observed phenomena. As with our patient,
anterior chamber involvement is observed, with the release of viral
antigens causing a mild uveitis with concomitant elevation in
intraocular pressure.5
Early and immediate therapy with oral acyclovir is the cornerstone
of treatment of this disorder, and has been proven to significantly
decrease the incidence of negative sequelae of eye disorders.
Patients should be evaluated within one week of starting acyclovir.
Patients who present with Hutchinson’s sign or visual complaints
merit referral to an ophthalmologist.5
1. Mandell, Bennett, & Dolin: Principles and Practice of Infectious Diseases, 6th ed.,
Copyright © 2005 Churchill Livingstone, An Imprint of Elsevier.
2. Liesegang TJ. Herpes zoster virus infection. Curr Opin Ophthalmol. 2004
Dec;15(6):531-6. Review.
3. Schoenlaub, P., et al. Ocular motor paralyses and complete ptosis in herpes zoster
ophthalmicus: two cases. Ann Dermatol Venereol. 1997; 124:401-403.
4. Zaal, MJ, et al. Prognostic value of Hutchinson’s sign in acute herpes zoster
ophthalmicus. Graefes Arch Clin Exp Ophthalmol, 2003, 241: 187-191.
5. Opstelten W, et al. Managing ophthalmic herpes zoster in primary care. BMJ. 2005
Jul 16;331(7509):147-51.
They say God protects fools and the innocent
They say God protects the innocent and the souls of children
Unfortunately the years of childhood has passed me
I doubt that God looks upon me as innocent
So I pray to be the fool
God protects the fools
The fools that don’t know any better
Those who live by folly
Those who are compared to, throughout his scripture
Why does God protect those who he mocks throughout his book
The fool in the book of wisdom is the enemy
The fool is the ass in Psalms
The fool in Sirach is the Anti
The fool is what you don’t want to be
The fool is what God tells you not to be
But he protects them
He understands them
He created them
If that is what I need in order to have his shield
I pray to be the fool
I pray to be protected
Maybe that is why ignorance is bliss at times
Maybe that is why they say that
Maybe a fool said that
And see how his words still last?
But maybe he didn’t last
Because with that statement
I think he lost his ignorance
Because he knew it was bliss
His ignorance, no longer folly, but purpose
And I don’t even know his name
But was that fool protected?
I hope he was
For my sake....
For our sake.
Marshall Fleurant, MD
Case Reports
Mary Kate McCullen, MD
Case Presentation
A 50 year-old Nigerian woman with a past medical history
significant for type II diabetes and hypertension presented to the
ED with a chief complaint of recurrent fevers and chills. The
patient was in her usual state of health until approximately 6 weeks
prior to admission, while during a visit with family in Nigeria she
noted the onset of high fevers and general malaise. Initially, her
fevers occurred daily for a period of one week, and were associated
with chills, fatigue, loss of appetite, and myalgias. During this time,
she was not evaluated by a physician, nor did she take any
medication. Her symptoms seemed to resolve however, and she
felt reasonably well. She then returned home to the United States,
approximately 4 weeks prior to admission. Upon return, she again
experienced one week of recurring fevers/chills, as well as the above
generalized symptoms. With no evaluation or intervention, her
symptoms improved. Two weeks later, the same pattern of
symptoms returned and the patient reported to the ED.
Figure 1.
Upon presentation, the patient complained of subjective high
fevers, shaking chills, anorexia, fatigue, generalized weakness,
myalgias, and 15 pound weight loss during the prior 6 weeks. She
denied sick contacts and known TB exposures. She traveled with
her son, who remained in his usual state of health. She reported
that the areas to which she traveled were heavily mosquito-infested.
Her past medical history was significant for type II diabetes and
hypertension. Her home medications included metformin 500
mg twice daily and diovan/HCTZ 160/25 once daily. There were
no recent medication changes and she denied drug allergies. She
had no history of alcohol, tobacco, or substance abuse. Her
mother and father were both alive and well, living in Nigeria. She
is employed as a chef, but had not been to work since before her
visit to Nigeria.
Figure 2.
Physical exam revealed a well-nourished woman in no apparent
distress. Her temperature was 102.8; pulse 88 beats/minute; blood
pressure 144/78 mm Hg; respiratory rate 16 breaths/minute; and
pulse ox 100% on room air. Her sclera were anicteric and mucous
membranes were dry. She had a normal S1S2, with a regular rate
and rhythm, and no murmurs, rubs, or gallops. Her lungs were
clear to auscultation bilaterally and she had no peripheral edema.
Her abdomen was soft, non-tender, non-distended, with no
hepatosplenomegaly. Her neurologic exam was non-focal; she was
awake, alert, and oriented to person, place, and time.
Laboratory evaluation showed a normal complete blood count,
chemistry panel, and liver function panel. A urinalysis revealed
trace protein and trace ketones. Her EKG showed NSR with no
ischemic changes. A blood smear was reviewed and revealed intraerythrocytic ringforms consistent with Plasmodium (Figures 1
and 2). A diagnosis of malaria was made and the patient was
immediately started on quinine and doxycycline. Despite oral
therapy, the patient was admitted to the hospital to follow her
fever curve and await speciation. The patient remained afebrile
after ~ 36 hours of antibiotic therapy. The microbiology lab
Figure 3.
performed a Giemsa stain of thin and thick smears, revealing
Plasmodium falciparum with a 20% parasitemia level. Her labs
were followed in house as well, with no evidence of renal
compromise or LFT abnormalities. She was discharged home to
complete a 7 day course of quinine and doxycycline.
Case Reports
increased resistance of the Anopheles mosquito to insecticides,
climate changes, and increased travel to endemic regions. Globally,
the areas of greatest transmission include Oceania and sub-Saharan
Africa; other regions with high risk of transmission, in descending
order, are the Indian subcontinent, Southeast Asia, South America,
and Central America. Travelers from industrialized countries are at
risk for malaria as well; approximately 30,000 of them contract the
disease each year. Worldwide, an alarming 700,000 to 2.7 million
deaths occur each year.
Figure 4.
Malaria transmission occurs predominantly via a bite from the female
Anopheles mosquito. There are other rare means of transmission,
including congenital acquisition, blood transfusion, needle sharing,
and organ transplant. In the United States, Anopheles mosquitoes
are present in all states, except Hawaii. Although extremely rare,
mosquito-borne transmission in the US has occurred. An outbreak
of malaria was reported in West Palm Beach, Florida in 2003, with 7
documented cases of Plasmodium vivax infection.
There are four species of Plasmodia: P. falciparum, P. vivax, P.
ovale, and P. malariae. Human infection by each of them occurs
when sporozoites are transmitted from an infected anopheline
mosquito during a bite. The sporozoites travel via the bloodstream
to the liver, where they invade hepatocytes and divide thousands
of times into mature tissue schizonts. Each schizont contains
thousands of daughter merozoites. After 6-16 days, the liver
schizonts rupture, releasing merozoites into the bloodstream
where they invade red blood cells.
Figure 5.
Within the RBCs, merozoites mature from ring forms to
trophozoites to mature red cell schizonts (asexual); daughter
merozoites are then released and able to infect new red cells. Some
merozoites will differentiate into male and female gametocytes
(sexual) which circulate in the bloodstream until they are ingested
by a blood-feeding anopheline mosquito. Sporozoites then form
in the mosquito and will eventually reinfect humans.
Mosquito-transmitted P. vivax and P. ovale infections carry a
unique risk; some parasites remain dormant in the liver and may
cause late relapse by reactivating after several months.
The pathogenesis of malaria is several-fold. All four species may
cause anemia via alteration of red cell membranes resulting in
hemolysis, accelerated splenic clearance, and digestion of red cell
proteins and hemoglobin. Additionally, red cell lysis releases
tumor necrosis factor alpha, which in turn suppresses
hematopoiesis. Thrombocytopenia may result from increased
splenic sequestration and decreased platelet survival time.
Figure 6.
Approximately 300 to 500 million cases of malaria occur annually
worldwide, particularly in children living in tropical developing
countries. Infection rates have increased in recent years, secondary
to factors including increased resistance of parasites to drug therapy,
P. falciparum may cause especially severe or fatal disease via
formation of “sticky knobs” on the surface of erythrocytes. These
may bind to receptors on endothelial cells in capillaries and
venules, leading to sequestration and subsequent obstruction to
blood flow, which can result in secondary organ dysfunction.
Case Reports
Several genetic factors have been suggested as protective
mechanisms against severe infection. For example, presence of the
sickle cell trait has been shown to lower the risk of P. falciparum
malaria, lower parasite densities, and lower rates of hospital
admissions. Alpha and beta thalassemia have been shown to be
associated with decreased rates of parasite multiplication, as well.
Individuals who live in endemic areas may develop partial immunity
to disease after repeated infections; they become “semi-immune.”
This does not completely prevent infection however; after a bite
from an infected mosquito, they will develop parasitemia, but the
severity of symptoms may be less. This partial immunity often wanes
after leaving an endemic area. Therefore, when these individuals
return home to endemic areas, they must take prophylaxis.
Malaria infections usually become symptomatic during the
erythrocytic stage of the parasite life cycle; incubation periods for
P. falciparum are usually 12 to 14 days, 2 months for P. vivax and
P. ovale, and finally 35 days for P. malariae. The erythrocytic stage
of infection usually lasts approximately one to four weeks.
Malarial signs and symptoms may vary, but essentially all infected
patients exhibit fever; it develops with the release of merozoites
from rupture red blood cells. Fevers occur in paroxysms which
are often daily and irregular. Other common symptoms may
include chills, sweats, headache, myalgias, fatigue, nausea,
vomiting, abdominal pain, diarrhea, and cough. Signs of infection
may include anemia, thrombocytopenia, splenomegaly,
hepatomegaly, and jaundice. Nephrotic syndrome occurs in some
cases, and is most commonly associated with P. malariae.
P. falciparum in particular has been noted to have severe morbidity
and mortality. Untreated falciparum infections can be fatal. This
species has the ability to invade red cells of all ages, thereby allowing
high levels of parasitemia, sometimes involving more than 50% of
red cells. As noted above, P. falciparum is more likely to lead to
secondary end organ damage than the other species because of its
ability to adhere to blood vessels and create obstruction to flow.
Cerebral malaria is one rare, but potentially fatal effect of the
infection. It usually presents with an impaired state of consciousness
or seizures, and may result in coma or death; 20% of treated adults
and 15% of children may die. Other complications of P. falciparum
include oliguric renal failure, pulmonary edema/ARDS,
hypoglycemia, anemia, and gastroenteritis.
Conventionally, malaria has been diagnosed by light microscopy
of a Giemsa-stained thick and/or thin blood smear; this is the
gold standard. The thick smear is more sensitive in the diagnosis
of malaria, however the thin smear facilitates exam of the parasite
morphology which aids in species identification. The thin smear
is also used to quantify the percentage of parasitized red cells.
PCR-based techniques are also available; they detect nucleic acid
sequences specific to Plasmodium species and are helpful when
light microscopy is equivocal in species identification. The
sensitivity and specificity of PCR approach 100 percent. Other
antigen detection methods and serologic assays are available, but
their sensitivity decreases with lower levels of parasitemia.
Most patients with P. vivax, P. ovale, and P. malariae can be treated
as outpatients. Those with P. falciparum however, should be
admitted to the hospital for initiation of their treatment and
observation for any evidence of complications. None of the
available anti-malarial drugs act on all stages of the malaria life
cycle to kill the parasite; therefore, patients require multi-drug
regimens. Choosing an appropriate regimen depends upon the
species and pattern of drug resistance.
P. ovale, P. malariae, and chloroquine-sensitive P. vivax can be
treated with oral chloroquine, with cure rates exceeding 95 percent.
Patients with chloroquine-resistant P. vivax may be treated with a
combination of mefloquine or quinine sulfate and doxycycline. In
P. vivax and P. ovale infection, relapse after chloroquine therapy is
common secondary to the presence of liver hypnozoites lying
dormant. Therefore, primaquine should be given to all of these
patients for fourteen days, immediately after finishing their course
of chloroquine. All patients must be screened for G6PD deficiency
before starting primaquine therapy to avoid hemolysis.
Chloroquine-resistant falciparum is now widespread throughout
most countries; therefore, P. falciparum infections should be
presumed to be chloroquine-resistant in almost all cases. The most
commonly recommended regimen for this is oral quinine plus
pyrimethamine-sulfadoxine or doxycycline for seven days. An
alternative is quinine plus clindamycin, particularly for pregnant
women or young children. Quinine-based regimens have greater
than 90 percent efficacy in most parts of the world, except
Southeast Asia where resistance is prevalent. There are alternative
regimens as well, including mefloquine, atovaquone-proguanil,
and artemisinin derivatives.
It is essential to stress the importance of taking chemoprophylaxis
when patients travel to endemic areas. Most cases of malaria in
the US are in patients who have not taken prophylaxis or those
who have stopped taking it too soon after return home.
Chloroquine should be used for areas where there is no
chloroquine-resistant P. falciparum; it should be started 1-2 weeks
before the patient departs and continued for 4-6 weeks after
leaving the endemic area. Travelers to chloroquine-resistant areas
should take mefloquine for prophylaxis. After travel to areas with
P. vivax and P. ovale, patients should take primaquine during the
last two weeks of a prophylaxis period.
1. Baird, J. Effectiveness of antimalarial drugs. New England Journal of Medicine 2005; 352: 1565.
2. Greenwood, B. Malaria. Lancet 2005; 365: 1487.
3. Kain, K. Malaria in travelers. Epidemiology, disease, and prevention. Infectious
Disease Clinics of North America 1998; 12: 267.
4. Leder, K. Malaria. UpToDate version 14.2. Available at www.uptodate.com. Accessed
October 2006.
5. Stanley, J. Malaria. Emergency Medicine Clinics of North America 1997; 15: 113.
6. White, N. The treatment of malaria. New England Journal of Medicine 1996; 335: 800.
Case Reports
Sivakumar Srinivasan, MD, and Sandeep Anreddy, MD
Vascular migration of radioactive seeds to the lungs after prostate
brachytherapy is known phenomenon. Here in we report a case
of prostate brachytherapy seed migration into the right ventricle.
Case Presentation
An 83 year-old male with a past medical history significant for
hypertension, hyperlipidemia, and prostate cancer status post
prostate brachytherapy seed implantation was brought to the
Cardiac catheterization lab for an elective catheterization for
further evaluation of a recent stress test revealing antero-apical
ischemia with an ejection fraction of 49%. The Cardiac catheterization films are shown below (Figures 1 and 2).
Figure 1.
Prostate brachytherapy is achieved with radioactive seed
implantation carrying iodine-125 or palladium-103. This
procedure is a well-accepted therapeutic option for patients with
localized prostate cancer. The small size of the seed allows for
potential displacement from the periprostatic insertion site to
adjacent prominent periglandular venous plexuses. The most
common site of prostatic seed migration is the pulmonary
vasculature barring a congenital arterio-venous malformation or
congenital heart disease.
Prior reports indicate that the percentage of patients who have at
least 1 seed migrate to the chest following prostate brachytherapy
varies widely from 0.7% to 55%, whereas the total percentage of
seeds that eventually migrate is less than 1%. Seed embolization
to the heart is extremely rare. The true incidence rate has not
been reported. Seed migration to the heart can rarely cause cardiac
arrhythmias. A chest X-ray is commonly recommended following
brachytherapy and during routine follow-up evaluation.
Figure 2.
1. Davis BJ, Wilson TM et al., Prostate brachytherapy seed migration to the right
ventricle found at autopsy following acute cardiac dysrhythmia. J Urol 2000;
2. B.J. Davis, J.F. Bresnahan and S.L. Stafford et al., Prostate brachytherapy seed
migration to a coronary artery found during angiography, J Urol 2002; 168:1103.
3. H.F. Blair, A. Porter and Q.S. Chen, In vivo detection of an 125I seed located in the
intracardiac region after prostate permanent brachytherapy. Int J Radiat Oncol Biol
Phys 2004; 58: 888–91.
Case Reports
Sivakumar Srinivasan, MD, Sandeep Anreddy, MD, and Paul Mather, MD
Coronary artery injury rarely occurs after blunt chest wall trauma.
It can, however, lead to extensive myocardial infarction. We report
a rare case of acute anterolateral myocardial infarction in a young
man after blunt chest trauma.
Case Presentation
A 30 year-old man was transferred to the emergency room after a
motor vehicle accident. He was an unrestrained passenger in an
ambulance and was ejected from the vehicle on impact resulting
in multiple injuries including blunt chest trauma. Upon arrival to
the emergency room his blood pressure was 118/69 mmHg and
pulse rate 95/min. Initial physical examination revealed multiple
large abrasions across bilateral anterior chest wall and normal
cardiovascular, respiratory and abdominal examinations. Routine
EKG showed Q wave and ST segment elevation throughout the
precordial leads as well as leads I and aVL (Figure1).
The initial laboratory results including chemistry panels and
blood counts were normal, however cardiac specific troponin was
152.40 ng/mL. Urgent two-dimensional echocardiography
showed apical, septal, and anterior wall akinesis with resultant
severely depressed left ventricular function.
A diagnostic coronary angiogram revealed 100% occlusion of the
proximal LAD distal to the origin of the first septal perforator.
The lesion was associated with a moderate filling defect consistent
with thrombus. Percutaneous coronary intervention was
successfully performed for the lesion and the post-procedural
angiogram showed excellent coronary flow without residual
stenosis (Figures 2 and 3). Follow up cardiac specific troponin I
on day 9 was 2.90 ng/mL.
Figure 1.
This case presents a rare complication of blunt chest trauma. To
save myocardium from ischemic injury, prompt diagnosis is vital
and routine EKG check should be performed in all the patients
with chest trauma. Observations from case series suggest that the
mechanism leading to myocardial infarction after blunt chest
trauma is a shear force applied to the coronary artery with
resultant intimal tearing. This injury precipitates platelet
aggregation and intracoronary thrombosis. The higher incidence
of left anterior descending artery involvement may be due to the
proximity of this artery to the chest wall. Most trauma patients
will not be candidates for thrombolytic therapy because of the
high risk of bleeding from concomitant injuries. Given a skilled
catheterization laboratory team, direct PTCA can be performed
in seriously ill patients quickly and with outstanding results
without the necessitate for thrombolytic agents.
1. Suhr H. Hambrecht S. Mauser M.
Fleischmann D. Foesel T. [Blunt
chest trauma with severe pulmonary
contusion and traumatic myocardial
infarction]. [German]
Anasthesiologie, Intensivmedizin,
Notfallmedizin, Schmerztherapie
2000; 35(11):717-20.
2. Rohe G. Feyerherd F. Mox B.
Hachenberg T. [Acute traumatic
myocardial infarction with
cardiogenic shock in severe
polytrauma--a case report].
[German] Anasthesiologie,
Intensivmedizin, Notfallmedizin,
Schmerztherapie 2000; 35(4):262-5.
3. Grossfeld PD. Friedman DB. Levine
BD. Traumatic myocardial infarction
during competitive volleyball: a case
report. Medicine & Science in Sports
& Exercise 1993; 25(8):901-3.
Figure 2.
Figure 3.
Case Reports
Joanna Kipnes, MD, and Marina Serper MD
Case Presentation
The patient is a 36 year-old African American female with a 15
year history of Crohn’s disease complicated by severe perianal
involvement not responsive to steroids or immunomodulating
medication. The patient had undergone a proctocolectomy and
diverting ileostomy two years ago secondary to refractory disease
and had been symptom-free until 6 months prior to admission.
At that time, the patient noted pain, vaginal discharge, and
ulcerations in the perineal region. Three weeks prior to admission,
she began to have almost daily vaginal bleeding as well as
weakness, dizziness, and increased fatigue. She had no subjective
fevers or chills and had no changes in output from the ileostomy.
Outpatient medications included ciprofloxacin and metronidazole
started 3 days ago by her gastroenterologist.
On physical examination, the patient was a well-nourished female
in no apparent distress. Her blood pressure was 126/72 mmHg,
the pulse was 80 beats per minute, the temperature was 98.6° F
and the oxygen saturation was 100% on room air. She was anicteric
with moist mucous membranes and normal skin turgor. On
cardiac examination there was a 1/6 systolic ejection murmur heard
best at the left sternal border. The lungs were clear to auscultation.
The abdomen was soft, diffusely tender, with the ileostomy
draining odorless bilious material. She had normal bowel sounds.
No lower extremity edema and no rashes were present.
Gynecologic examination revealed left labial swelling, and two
ulcerations, 1 to 2 cm in size, between the labia major and minora.
There was another linear midline ulceration extending from the
gluteal cleft to the perineum. At that time, an internal
examination could not be performed secondary to severe pain.
Admission labs were notable for hemoglobin of 5.9 g/dL, MCV
of 60 fl, CRP of 2.3 mg/L, and ESR of 63 mm/hr. A CT scan of
the abdomen and pelvis showed marked distension of the vaginal
lumen and vaginal stenosis likely secondary to inflammation.
The patient’s profound iron deficiency was treated with a blood
transfusion and IV iron. A differential diagnosis for the perineal
lesions included enterovaginal fistulae, cutaneous Crohn’s disease,
Bechet’s disease, and sexually transmitted diseases.
A vaginal exam conducted under anesthesia revealed extensive
linear vulvar ulcerations extending from the perineum to the
gluteal cleft. During the examination a copious amount of green
malodorous fluid was extracted from the vaginal vault. No
fluctuant masses, internal vaginal lesions, or fistulous tracts were
identified. A pelvis MRI showed a vaginocutaneous fistula, but
no communication between the vagina and the GI tract. A small
bowel follow-through showed a normal mucosal pattern and no
enterovaginal fistula. The patient also had a negative charcoal
challenge test in which a tampon was placed in her vagina and
the patient drank activated charcoal. No charcoal was identified
on the tampon (a negative test) indicating that no enterovaginal
fistula was present.
Figure 1. High powered view of vulvar biopsy showing a dense
inflammatory inflitrate, along with giant cells and a granuloma.
This pathology is consistent with Crohn’s disease.
Vulvar biopsy (Figure 1) showed dense diffuse inflammation with
multinucleated giant cells and granulomas consistent with Crohn’s
disease. Further workup for infectious etiologies (HSV, syphilis,
H. ducreyi, Chlamydia, Gonorrhea) was negative. The presence of
histology consistent with Crohn’s disease and the absence of an
enterovaginal fistula established the diagnosis of cutaneous Crohn’s
disease also known in the literature as metastatic Crohn’s disease.
Crohn’s disease is a chronic, relapsing disease that may affect any
part of the alimentary tract from the mouth to the anus. Skin
lesions are well recognized as an extra intestinal manifestation of
Crohn’s disease. Cutaneous lesions may be divided on the basis of
whether or not they have a granulomatous histologic appearance.
Lesions without a granulomatous appearance are more common
and include erythema nodosum, pyoderma gangrenosum, Sweet
syndrome, and epidermolysis bullosa acquisita.
Granulomatous cutaneous lesions of Crohn’s disease most
commonly affect the skin through direct contiguous extension
from the involved bowel. However lesions that form noncaseating
granulomas in sites noncontiguous with the gastrointestinal tract
have been termed “metastatic Crohn’s disease.” The lesions of
metastatic Crohn’s disease were first described by Parks et al. in
19651 and have since been reported involving the face, axilla,
pulmonary mucosa, vulva, vagina, penis, scrotum, forearms, shins,
breast, back, perianal region, and groin. The lesions may appear
as ulcers, nodules, ulcers, or plaques.2,3 Because of its variable
appearance it has been misdiagnosed as cellulitis, erysipelas,
lichenoid eruptions, or various sexually transmitted diseases.
Metastatic Crohn’s disease has been reported in the absence of
any active gastrointestinal disease,4 however it more commonly
occurs in those with colonic involvement and does not parallel
Case Reports
gastrointestinal disease activity.2 Due to the relative rarity of
these noncontiguous granulomatous lesions, there are no
clinical trials to guide current treatment. Therapy with
steroids, metronidazole, azathioprine, sulfasalazine, and
tetracyclines has been used with variable success.2,3
Metastatic Crohn’s disease exhibits variable clinical features
and may resemble many other dermatoses. In this case of a
female patient with active Crohn’s and vulva and perineal
ulcers other diagnoses such as Bechet’s disease and a variety of
sexually transmitted diseases were entertained. The diagnosis
was ultimately made by biopsy of the patient’s lesions. It is
the recommendation of many experts in the field of inflammatory
bowel disease that any unusual cutaneous lesion or any lesion that
doesn’t resolve with standard therapy be biopsied.2,3
1. Parks AG, Morson BC, Pegum JS. Crohn’s disease with cutaneous involvement. Proc
R Soc Med 1965;58:241-2.
2. Marotta PJ, Reynolds RPE. Metastatic Crohn’s disease. Am J Gastroenterol
3. MacayaA, Marcoval J, BordasX, Morena A, Vazquez S, Peyri J. Crohn’s disease
presenting as prepuce and scrotal edema. J Am Acad Dermatol 2003;49:S182-3.
4. Guest GD, Fink RL. Metastatic Crohn’s disease: case report of an unusual variant and
review of the literature. Diseases of the Colon and Rectum 2000;43:1764-6.
Utpal Sagar, MD, Bonnie Callahan, MD, and Ted Martynowicz, DO
Case Presentation
The patient is a 67 year-old male with past medical history of
CAD s/p CABG, CHF with EF of 15%, BiV- ICD, who was
recently admitted to an outside hospital in Delaware with SOB
and weakness, and was found to have frequent bouts of VT.
During that hospitalization, he had suffered cardiac arrest as well,
and epinephrine was administered emergently through a
peripheral IV site located in his right hand. He was thereafter
loaded with amiodarone for the ventricular tachycardia. It was
later found that the epinephrine had infiltrated into the skin of
his right hand from the peripheral IV site. Following stabilization
at the outside hospital, the patient requested transfer to
Wilmington VAMC for further treatment and rehabilitation. The
photograph below (obtained with permission), illustrates the vast
degree of skin necrosis and surrounding erythema that resulted
from skin infiltration of epinephrine in this patient.
Vasoactive drugs are often administered immediately before,
during, and after an arrest to support cardiac output. Drugs may
be selected to improve chronotropy, inotropy, or arterial pressure.1
The emergent nature of a cardiac arrest code often demands
expedient administration of IV medications, at times through a
peripheral IV site. This is done, however, with a certain amount
of risk. In the event that extravasation develops, immediately
infiltrate 5 to 10 mg of phentolamine diluted in 10 to 15 mL of
saline into the site of extravasation to prevent tissue necrosis,1 such
as that observed in the above photograph.
Photograph Courtesy of the Wilmington
VA Medical Center.
1. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and
Emergency Cardiovascular Care, Circulation. 2005;112:IV-78 – IV-83.
Case Reports
Aarati Malliah, MD
Case Presentation
The patient is a 69 year-old male with new onset jaundice of two
weeks and a 6 month history of progressive hyperbilirubinemia
with cholestasis who was admitted for evaluation. Physical
examination revealed a well developed and well nourished,
jaundiced male with scleral icterus, a II/VI systolic murmur at
apex, mild abdominal discomfort over epigastrum on palpation
without discernable hepatomegaly, normal distal pulses, no lower
extremity edema, and no stigmata of chronic liver disease.
Laboratory investigation revealed a total bilirubin of 19.3 mg/dL,
alkaline phosphatase 693 U/L, and AST and ALT of 140 U/L
and 117 U/L, respectively. CT scan of the abdomen and pelvis
showed multiple foci of arterial enhancement, periportal edema
without biliary dilatation, concerning for acute fulminant
hepatitis. The patient had a dramatic and rapid decline the day
following admission, developing cardiac arrhythmia and
hypotension and subsequently died despite resuscitative efforts.
Figure 2. Liver portal triad with Congo stain
Autopsy revealed amyloidosis AL, kappa light chain type
involving the liver (Figures 1 and 2), heart (Figures 3 and 4),
lungs and bone
Although hepatic involvement is a common manifestation of
primary amyloidosis, systemic amyloid presenting with jaundice
and severe cholestasis is rare and portends a poor prognosis.
Amyloidosis manifesting as cholestatic liver disease has the
shortest mean survival of any presentation of the disorder,
approximately 3 months from the identification of jaundice; only
25% of patients live longer than 6 months. While the most
common cause of death in amyloid is due to congestive cardiomyopathy or sudden death due to VF or asystole, the presence of
heart failure suggests a six month clinical predictor of survival.
Patients with AL often suffer from rapid-onset heart failure. ■
Figure 3. Left ventricle
Figure 1. Liver portal triad
Figure 4. Left ventricle with Congo stain
Case Reports
Meredith Chiaccio, MSIII and Donna Mscisz Williams, MD
Case Presentation
A 28 year-old Caucasian female, 3.5 months postpartum,
presented to the TJUH ED with facial and neck swelling. She was
in her usual state of health until approximately 1 month prior to
admission when she noted the gradual onset of neck swelling. The
neck swelling progressed to her face 4 days prior to admission;
swelling in both areas was progressive and increasingly
uncomfortable. Two months prior, the patient was treated for
sinusitis with a course of antibiotics by an allergist; this treatment
was unsuccessful, and she was referred her to an otolaryngologist,
who performed a neck ultrasound and lab work. The patient
reported that several enlarged lymph nodes were found in her
neck. The patient was then sent for a CT of the neck and chest,
which showed a mass in her mediastinum. She was planning to
follow up with a cardiothoracic surgeon, however she developed
symptomatic swelling and intermittent dysphagia. The patient
described a sensation of choking and strangulation; these
sensations came and went at random times. She also reported
tolerating only small amounts of soft foods, such as apple sauce,
Jell-O, and yogurt. The dysphagia was present only with solid
foods, not with liquids.
The patient also complained of dull upper back pain located in
her upper right trapezius area for the past month which was
exacerbated by holding her child and other physical activities and
was alleviated somewhat by ibuprofen; this pain felt like a pulled
muscle and she rated it 4/10. She stated that chest pain, located
at her right anterior chest, had bothered her for the last 4 days;
she described this pain as piercing, sharp, 9/10 in severity, and
intermittent, with no exacerbating or ameliorating factors.
The patient’s past medical history included intermittent migraines
for several years which were well-controlled and a full term
Figure 1. Low power image of mediastinal mass shows nodular
demarcation of cells by fibrous bands.
Figure 3. High power image of Reed-Sternberg cells in a mixed
inflammatory background.
Figure 2. Higher power image showing large multi-nucleated
cells with clear cytoplasm
Figure 4. Immunostain showing CD15+ staining of binucleated
Reed Sternberg cells.
Case Reports
uncomplicated vaginal delivery four months prior after which she
breast fed for 6.5 weeks. Her surgical history was significant only
for appendectomy and breast augmentation. She was taking no
medications and reported allergies to penicillin, latex, iodine, and
shellfish, which all cause pruritic rash. She denied alcohol, tobacco,
or substance abuse. Her family history was noncontributory.
Her review of systems was significant for 7 lb weight gain in the
last week, congested and swollen right ear, bilateral sinus pressure,
hoarseness, bulging veins which appeared in left neck 1 week ago,
and occasional pulsations in her neck bilaterally. She reported
edema in the right hand, bilateral swelling of hands and fingers
(right greater than left, worsening recently), as well as tingling and
numbness in the right fingertips. The patient reported feeling lightheaded when sitting up from supine or when bending over to pick
something up off floor, and she felt that her neck swelling worsened
when leaning forward. The patient also reported intermittent
throbbing headaches, minimally relieved by ibuprofen.
On physical exam, the patient was in no acute distress with stable
vital signs. The head and neck exam was significant for an
enlarged, well-developed neck with visible tortuous collateral
vessels bulging on the left side. Neck circumference was 31.5 cm.
Sternocleidomastoids were prominent bilaterally. There was no
cervical or supraclavicular lymphadenopathy, nodules, or enlarged
thyroid. The patient had maxillary and frontal sinus tenderness to
palpation bilaterally, right greater than left. No stridor was
appreciated. Generalized distension in neck prevented clear
assessment of jugular venous pressure. Pemberton sign was
negative. Examination of the lungs revealed decreased breath
sounds on right side. Extremity exam revealed dusky/dark
appearance of the skin of right extremities and edema of right
hand. No axillary or inguinal lymphadenopathy present.
The constellation of this patient’s history, signs and symptoms,
labs, imaging studies, and knowledge of presence of mediastinal
mass were consistent with Superior Vena Cava (SVC) Syndrome.
This diagnosis was supported by known presence of anterior
superior mediastinal mass with SVC displacement, swelling of the
neck and face, development of collateral neck vessels, unilateral
cyanosis, swelling and tingling and numbness of the upper
extremity, and positional lightheadedness.
Hospital course
Initial serologic studies were unrevealing. Chest x-ray in the ED
revealed a widened superior mediasinum. CT of the chest
performed shortly prior to presentation forwarded from an
outside institution showed a large homogeneously enhancing
anterior mediastinal soft tissue mass insinuating between aortic
branch vessels, displacing the SVC laterally with compression.
The mass was measured at 9.4cm x 4.9cm x 13.8cm. The patient
underwent bronchosopy and transbronchial biopsy of the
mediastinal mass, but pathology was indeterminate.
Cardiothoracic surgery was consulted for mediastinoscopy, and
biopsies revealed Hodgkin’s lymphoma, nodular sclerosing
subtype (see Figures 1-4). Both Medical Oncology and Radiation
Oncology were consulted, and treatment plan was made. The
patient underwent bilateral bone marrow biopsies which were
negative. Remainder of the staging work-up was significant only
for enlarged lymph nodes in the prevascular and pretracheal
spaces. The patient’s disease was staged at IIA.
Superior Vena Cava syndrome (SVCS) occurs when the SVC is
invaded or externally compressed by a mass or thrombosed. SVCS
encompasses a classic constellation of signs and symptoms including
facial edema, dyspnea, tachypnea, cyanosis, venous distension,
headache, and plethora. Other signs include cough, arm edema, a
feeling of head fullness often exacerbated by lying down or bending
forward; more seriously, it could present as respiratory distress from
tracheal involvement. Pemberton’s sign is the development of facial
plethora, inspiratory stridor, and non-pulsatile JVP elevation when
a patient with SVC syndrome lifts the arms over the head. While
dysphagia, hoarseness, and stridor are not included in the definition
of SVCS because they result from compression of mediastinal
structures other than the SVC (esophagus, laryngeal nerve, and
trachea respectively), their presence is negatively correlated with
prognosis. Presentation depends on both the location and rate of
growth of the mass; growth rate also determines how well the
syndrome can be compensated by new collateral circulation.
Important collateral veins arise from the azygos, lateral thoracic,
paraspinous, and internal mammary veins.
Approximately 85% of cases of SVCS are caused by malignant
tumors; the rest are due to infection and thrombosis. Up to 60%
of patients presenting with SVCS due to underlying malignancy
present without a known diagnosis of cancer. The most common
malignant causes of SVCS are lung cancer, lymphoma, thymoma,
mediastinal germ cell tumors, and solid organ tumors metastatic
to the mediastinum. Bronchogenic carcinoma and lymphoma
alone account for 94% of cases of SVC syndrome. Fibrosing
mediastinitis accounts for up to 50% of nonmalignant causes of
SVCS. This clinical entity is often caused by excessive host cell
response to a prior Histoplasma capsulatum infection; however,
other causative infections include aspergillosis, blastomycosis,
actinomycosis, tuberculosis, and Bancroftian filariasis. SVC
thrombosis can also occur secondary to indwelling central venous
catheters and pacemaker leads.
Lung carcinoma is the most common cause of SVCS and does so
via compression or direct SVC invasion by tumor or via
mediastinal lymphadenopathy. Two to four percent of patients
with lung carcinoma develop SVCS during the course of their
disease. Up to 20% of patients with small cell lung cancer develop
SVCS because of the central location of these tumors; peripherally
arising lung tumors, including adenocarcinoma and large cell
carcinoma, are less likely to cause SVC involvement. Small cell
Case Reports
lung cancer accounts for approximately 40% of all cases of SVC
syndrome due to lung cancer, with squamous cell carcinoma
making up another 18%.
Lymphoma, almost always Non-Hodgkin’s type, is the second most
common cause of SVCS. Approximately 2-4% of patients with
lymphoma develop SVCS, via lymph node enlargement. The most
common lymphomas associated with SVCS are diffuse large B-cell
and lymphoblastic lymphomas. Hodgkin’s lymphoma, despite its
common presentation with mediastinal lymphadenopathy, rarely
causes SVCS.
In addition to lung carcinoma and lymphoma, thymoma and
germ cell tumors are also among the more common malignant
causes of SVC syndrome.
Anterior Mediastinal Masses
Approximately 2/3 of all mediastinal tumors are benign. Anterior
mediastinal masses make up 60% of all mediastinal masses. The
most common neoplasias of the anterior mediastinum include the
“4 Ts” – thymoma, thyroid tumor, germ cell tumors (teratomas),
and “terrible” lymphomas. Other anterior mediastinal neoplasms
include thymic carcinoid, thymolipoma, and parathyroid
adenomas. Thymic cyst, lymphangioma, and intrathoracic goiter
comprise the non-neoplastic causes of anterior mediastinal masses.
Lymphoma is the second most common primary anterior
mediastinal tumor, second only to thymoma, and accounts for
10-20% of primary mediastinal masses overall. While lymphoma
can affect any mediastinal compartment, most are located in the
anterosuperior mediastinum and the remainder in the middle
mediastinum. These lymphomas typically present with large,
bulky tumors, often with involvement of adjacent intrathoracic
structures. While Hodgkin’s lymphoma represents only 25-30%
of all cases of lymphomas, it is the most common mediastinal
lymphoma; the nodular sclerosing subtype is the most common,
and it has particular predilection for the anterior mediastinum.
Hodgkin’s lymphoma will be discussed below. The most common
primary mediastinal Non-Hodgkin’s lymphomas are large B-cell
lymphoma and lymphoblastic lymphoma. Patients with NHLs
are typically older than age 55; 85% present with advanced disease
and typically have constitutional (“B”) symptoms, generalized
lymphadenopathy, and extensive extranodal disease at time of
diagnosis. Indolent NHLs, as compared to aggressive NHLs,
generally have a more favorable histologic condition, occur
nodally, and are more clinically advanced at presentation.
Treatment of NHL depends on histologic classification, site of
presentation, and disease extent. Patients with indolent NHLs are
treated palliatively with radiation and chemotherapy if necessary,
as they typically have a more prolonged disease course, are rarely
cured, and almost always have recurrence. Patients with aggressive
NHLs are treated with combination chemotherapy and radiation,
with possible bone marrow transplantation. Negative prognostic
factors for NHLs include extensive extranodal disease and large
tumor size at presentation, and slow response to treatment.
Hodgkin’s Lymphoma: Diagnosis, Staging, and Treatment
Hodgkin’s lymphoma, first described by Sir Thomas Hodgkin in
1832, is a malignant lymphoma with a bimodal peak incidence in
the second and fifth decades, more commonly found in males.
Diagnosis of Hodgkin’s lymphoma requires presence of the classic
Reed-Sternberg cell – with its abundant basophilic cytoplasm and
two large nuclei with pale chromatin and distinct eosinophilic
nucleoli – in a mixed inflammatory background of reactive
lymphocytes, macrophages, plasma cells, eosinophils, and a
disrupted nodal architecture with fibrotic stroma. Only recently
were Reed-Sternberg cells discovered to be of B-cell origin; though
these cells lack B-cell markers such as CD20 and the B-cell receptor,
their precursors are definitively germinal center B-cells that escape
negative selection and apoptosis by acquisition of a survival
advantage through an as yet unknown mechanism. Epstein-Barr
Virus is thought to play a role in the malignant transformation of
Reed-Sternberg precursor cells by upregulation of antiapoptotic
genes and inhibition of the FAS-signalling pathway.
The two main types of HL are classic HL and lymphocytepredominant HL; classic HL is further classified into 4 subtypes,
including nodular sclerosing, lymphocyte rich, lymphocyte
depleted, and mixed cellularity. Classic HL accounts for 95% of
all cases of HL. This discussion will center around the nodular
sclerosing subtype as it is the most common, accounting for nearly
80% of cases of HL. With a predominance in young, female
patients, the nodular sclerosing subtype is characterized by a
nodular growth pattern with sclerosing/fibrotic collagenous
banding. The pathology report for the patient in the above case
stated that “the lymph node architecture appeared effaced by
bands of collagen fibrosis, which subdivide the lymph node into
smaller nodules.” Nodular sclerosing Hodgkin’s lymphoma has a
unique predilection for the anterior mediastinum, especially the
thymus, and may manifest itself as a discrete, lobulated anterior
superior mediastinal mass.
The most common clinical presentation of HL is enlarged
nontender cervical and/or supraclavicular lymphadenopathy, and
bulky mediastinal lymphadenopathy is additionally characteristic
of nodular sclerosing HL. Patients with mediastinal involvement
tend to be younger than those without mediastinal disease;
mediastinal involvement can manifest as chest pain, cough,
wheezing, dysphagia, or SVC syndrome, discussed above. At
presentation, 25% of patients with HL have constitutional “B”
symptoms of fever (including cyclic Pel-Ebstein curves), weight
loss and night sweats. There is also an unusual association between
alcohol consumption and lymph node pain or generalized pruritis
in patients with Hodgkin’s lymphoma.
Case Reports
The Modified (Cotswold) Ann Arbor Staging Classification is typically used to stage HL
Single node region
or a lymphoid structure
(spleen, thymus,
Waldeyer’s ring) or
involvement of a single
extralymphatic site)
Two or more node
regions on the same
side of the diaphragm,
localized contiguous
involvement of only one
extranodal organ or side
and node region on the
same side of the diaphragm
Node regions involved
on both sides of
diaphragm, and/or
involvement of spleen,
or localized contiguous
involvement of only
one extranodal organ
site or both.
With or without
involvement of
splenic, hilar, celiac,
or portal nodes.
With involvement
of para-aortic, iliac,
and mesenteric nodes.
Diffuse or disseminated
involvement of one
or more extranodal
organs or tissues,
with our without
associated node
constitutional “B” symptoms absent
fever > 38°C, weight loss > 10%
in 6 months, night sweats
bulky disease (widened mediastinum
by >1/3 or presence of nodal mass
w/ max dimension >10cm)
involvement of a single extranodal
site that is contiguous or proximal
to the known nodal site
Anatomic staging helps distinguish patients that would likely
benefit from radiation therapy alone from those requiring
systemic treatment. Most patients with HL present with disease
localized above the diaphragm; approximately 50% of patients
present in stage I or II, and less than 5-10% have extranodal
disease at time of diagnosis. Subtype and stage are the two most
important prognostic factors in HL: the nodular sclerosis subtype
carries a very good prognosis, while lymphocyte-depleted HL
carries the worst prognosis of the HL subtypes. Constitutional
symptoms, age greater than 45, extranodal or bulky mediastinal
disease, high ESR or LDH, and greater than five splenic disease
foci are adverse prognostic factors.
effects during the initial treatment phase and had increased
incidence of late complications of sterility and secondary
malignancies, especially myelodysplastic syndrome and secondary
acute leukemia, without any gain of efficacy. Four cycles of ABVD
are used in early-stage disease and six to eight are used in advancedstage disease. Relapsed disseminated disease is treated with highdose chemotherapy and autologous bone marrow transplantation.
The patient described in the above case can expect a 12-year
freedom from progression of approximately 94% and an overall
survival rate of 94%.
Patients with stage IA, IB, IIA, and IIB disease are treated with
combined-modality therapy of combination chemotherapy plus
involved-field irradiation. This concept has replaced prior
treatment plans of radiation therapy alone, which was associated
with a high incidence of complications including gonadal toxicity
and secondary malignancies. Combined-modality therapy also
provides improved disease control and lower morbidity. Patients
with stage III or IV disease receive combination chemotherapy in
occasional combination with radiation.
The chemotherapeutic regimen of choice for Hodgkin’s lymphoma
is ABVD: doxorubicin, bleomycin, vinblastine, and dacarbazine.
The MOPP regimen (mechlorethamine, vincristine, procarbazine,
prednisone) was the first drug regimen that produced a high
proportion of complete remissions in Hodgkin’s lymphoma;
ABVD was later introduced as a potentially curative salvage
regimen and was shown in 1992 to be superior to the MOPP
regimen as it is more efficacious and does not cause sterility. A
2003 trial comparing ABVD to a hybrid MOPP/ABV regimen
showed that the hybrid regimen caused more life-threatening side
6. Dominguez AR, Marquez A, Guma J, Llanos M. Treatment of Stage I and II
Hodgkin’s lymphoma with ABVD chemotherapy: results after 7 years of a prospective
study. Annals of Oncology 15(2004): 1798-1804.
1. Drews, Reed E. Superior Vena Cava Syndrome. Up-To-Date, version 14.2, accessed
September 21, 2006.
2. Macchiarini Paolo, Helmut Ostertag. Uncommon Primary Mediastinal Tumours. The
Lancet 5(2004): 107-18.
3. Strollo DC, Rosado de Christenson ML, Jett JR. Primary Mediastinal Tumors, Part 2:
Tumors of the Middle and Posterior Mediastinum. Chest 112(5): 1344-1357, 1997.
4. Nayak LM, Deschler DG. Lymphomas. Otolaryngologic Clinics of North America
36(2003): 625-646.
5. Thomas RK, Daniel Re, Jurgen Wolf, Volker Diehl. Part I: Hodgkin’s lymphoma –
molecular biology of Hodgkin and Reed-Sternberg cells. The Lancet 5(2004): 11-18.
7. Duggan DB, Petroni GR, Johnson JL, Glick JH. Randomized Comparison of ABVD
and MOPP/ABV Hybrid for the Treatment of Advanced Hodgkin’s Disease: Report
of an Intergroup Trial. Journal of Clinical Oncology 21(4): 607-614, 2003.
8. Meyer RM, Ambinder RF, Stroobants S. Hodgkin’s Lymphoma: Evolving Concepts
with Implications for Practice. American Society of Hematology 2004, 184-202.
Special thanks to Dr. William Kocher of the Department of Pathology
for providing images and guidance.
Case Reports
Neilanjan Nandi MD, Sivakumar Srinivasan MD
Case Presentation
A 62 year-old African American female with past medical history
significant for scleroderma, Raynaud’s phenomenon, and
hypertension presented to the ED with 6 weeks of worsening
fatigue, shortness of breath and a new onset of left sided chest
pressure. Her outpatient medications included metoprolol 50 mg
every 12 hours and nifedipine XR 90 mg once daily. On physical
examination, the patient was noted to have a blood pressure of
189/62 mmHg and a pulse of 44 beats per minute. Her laboratory
data including chemistry panel, complete blood count, and
cardiac enzymes were unremarkable.
EKG was performed and the results are shown (Figures 1 and 2).
In the spectrum of bradyarrhythmias, complete heart block
represents a potentially life threatening condition frequently
resulting in hemodynamic instability and death. Also known as
third degree atrioventricular block (3º AVB), this lethal arrhythmia
is caused by a complete disconnect between the sinoatrial (SA)
and atrioventricular (AV) nodes manifesting in independent atrial
and ventricular rhythms. This dissociation is caused by a
conduction system block at the level of the AV node, the Bundle
of His, or the Purkinje bundle-branch system. Many etiologies
have been identified causing 3ºAVB (Table 1). Careful history
taking and electrocardiographic analysis will allow appropriate
emergent treatments to be intelligently executed.
Approximately 50% of AV block may be caused by conduction
system fibrosis and sclerosis, otherwise known as idiopathic
progressive cardiac conduction disease. Another 40% will be
caused by either acute or chronic ischemic heart disease resulting
in temporary, progressive, or permanent conduction system block.
Table 1. Causes of Complete Heart Block
Idiopathic Progressive Cardiac Conduction Disease
Lenegre’s Disease – Slow progression to 3ºAVB
Lev’s Disease – Sclerosis & calcification of left sided
cardiac tissues
Ischemic Heart Disease
Chronic Ischemic Disease
Acute MI – 20% develop AVB (8% w/1º AVB,
5% w/2º AVB, 6% w/3ºAVB)
Increased Vagal Tone
Valvular/Structural Disease – Aortic or Mitral valve
disease, HOCM
Developmental/Genetic – Congenital, Familial
Infiltrative – Restrictive Processes, Malignancy
Connective Tissue Disease – SLE, Scleroderma,
Infectious – Bacterial Endocarditis, Lyme Disease, Syphilis,
Chagas, Viral
Metabolic/Endocrine – Hyperthyroid, Myxedema,
Hyperkalemia, Hypokalemia
And a myriad of other causes exist that, although rare, should be
considered in diagnosing and management of complete heart
block. Toxicity from cardiac medications such as excess betablockade, calcium channel blockers (verapmil more than
diltiazem), amiodarone, and Class I anti-arrhythmics (quinidine,
procainamide) are not uncommon. Diffuse processes ranging
from restrictive cardiomyopathies such as amyloidosis, sarcoidosis,
and hemochromotosis to infiltrative malignancies such as
Hodgkin’s lymphoma and even multiple myeloma can cause 3o
AVB. Infectious etiologies should not be overlooked as bacterial
endocarditis, Chagas’, and Lyme disease have been documented
before. Electrolyte disturbances such as hyperkalemia and
hormonal disturbances such as hyperthyroidism or myxedema
coma may result in heart block as well. There are also congenital
developmental abnormalities and familial genetic mutations of
sodium channels (i.e. SCN5A , congenital long QT syndrome,
Brugada syndrome) that have been identified. Iatrogenic
complications after ethanol septal reduction or transcatheter
closure of ventricular septal defects have been reported. Other
exotic examples include neurodegenerative diseases, dermatomyositis, Paget’s disease, and cardiac tumors.
Central to the mechanism of autoimmune rheumatic diseases
(ARD) is the concept that these diseases are mediated via a
systemic inflammatory state. Hence, it is not surprising that
ARD’s would contribute and promote atherosclerotic coronary
artery disease. This, in turn, may lead to ischemic disease and
myocardial inflammation creating an excellent substrate for
cardiac arrhythmia and conduction disturbances to occur.
Approximately 25% of patients with systemic sclerosis wre shown
to have antibodies against cardiac tissue. Also, 67% of those with
scleroderma were documented as having ventricular arrhythmias.
About 25-75% had abnormal ECG findings, bundle branch
blocks, fasicular blocks, and less than 2% had 2º or 3º AVB.
Systematic ECG interpretation is always paramount. After
appreciating that the P waves and QRS waves march out
independently of one another on the rhythm strip, it is important
to pay close attention to both the rate and morphology of the QRS
complex. About 20% of 3º AVB are from a lesion at the level of
the AV node and another 20% are within the bundle of His. Both
lesions present with a narrow QRS complex junctional escape
rhythm (~45-60 bpm) and are generally hemodynamically stable.
The remaining 60% of complete heart block are secondary to a
lesion below the Bundle of His and manifest with a wide QRS
escape rhythm (< 45 bpm) with hemodynamic instability.
Although some may be asymptomatic, symptoms may range from
fatigue, light headedness, and dizziness to chest pain, syncopal
event, dyspnea, mental status change, and of course, sudden
cardiac death. Transcutaneous pacing is always indicated and
temporary transvenous pacer may be placed as well. Emergently,
atropine should be administered with caution. A wide QRS
complex suggests infranodal block. Therefore, the anticholinergic
Case Reports
Figure 1: Complete heart block with ventricular escape rate of 44
bpm. Conduction via the left anterior fascicle with left posterior
fascicular block (LPFB) & RBBB.
Figure 2: Obtained approximately 30 minutes after the initial EKG.
Complete heart block with LBBB morphology. Escape rhythm
originates above the Bundle of His bifurcation.
effects of atropine will result in a relative vagolysis with subsequent
unopposed sympathetic stimulation which only serves to increase
the myocardial refractory period. This can dangerously exacerbate
the complete heart block and further decrease the ventricular
depolarizations and contractions leading to further hypotension
and accelerate time to death.
permanent pacemaker was promptly placed. Many etiologies exist
to promote complete heart block. Autoimmune rheumatic
diseases are no exception and may manifest as rhythm and
conduction system disturbances resulting in sudden cardiac death.
Electrocardiographic disturbances in autoimmune rheumatic
diseases such as scleroderma are not insignificant and should be
considered in the differential of complete heart block.
The patient had a transvenous pacer placed emergently. After
waiting a sufficient amount of time to rule out excess betablockade and calcium channel blockade, her heart block persisted
and was attributed to progression of her scleroderma. A
1. Mangrum JM, Dimarco JP. The evaluation and management of bradycardia. NEJM.
2. Seferovic PM, Ristic AD, Maksimovic R, et al. Cardiac arrhythmias and conduction
disturbances in autoimmune rheumatic diseases. Rheum. 2006;45:iv39-iv42.
When It Rains
You ever stand in the rain,
Especially on a hot summers day,
And feel the rain drops drip from the top of your head,
Straight down till it soaks into the seams of your socks,
Do you remember pressing your foot down into your soggy shoe,
And feel bubbles flow between your toes,
And you just couldn’t resist that puddle,
That giant, deep, dark brown, muddy puddle,
You just had to raise your knee high....
Then stomp down on that puddle with a force equal to that of Thor’s
lightning bolt,
You just had to do it,
Just had to,
You just couldn’t waste a good puddle,
You just couldn’t stay indoors,
Had too....just had to play in the rain...
My mother used to tell me the rain was God’s tears,
The rain cooled you,
It played with you, watered you,
It surrounded you...fully,
It fed the trees, and filled the oceans,
You knew you were going to get wet...
You knew you were going to get sick...
You knew your mom was going to yell at you...
And that you were going to track muddy stains all over the floor...
You’re going to get punished...
And it served you right.
You ruined your clothes,
Got yourself sick,
Messed up your hair,
Dirtied the house,
And you rejoiced in God’s tears.
And you also knew.......
That you couldn’t wait till the next rain shower.
Marshall Fleurant, MD
Case Reports
Andra Popescu, MD
Case Presentation
A 70 year-old male presents to his cardiologist’s office with
complaints of feeling fatigued and “lousy”. His past medical
history is significant for HTN and HL, but until a recent hospitalization, he was non-compliant with his outpatient medical
regimen. Of note, he also has a history of heavy alcohol
consumption and a 30 pack-year smoking history. The patient
reports that he was recently discharged after acute myocardial
infarction (AMI) from an outside hospital. At that time, he
underwent a diagnostic cardiac catheterization, but no
intervention was performed secondary to 100% RCA stenosis and
technical difficulties. He was sent home on clopidogrel, aspirin,
metoprolol, lisinopril and simvastatin. He currently appears tired
and anxious, however he has no symptoms of chest pain, dyspnea,
orthopnea, diaphoresis, or lightheadedness; he does report that
his primary symptoms leading him to admission was chest pain
and shortness of breath.
On physical exam, the patient’s blood pressure is 75/56 mmHg
with a heart rate of 89 beats per minute, respiratory rate is 18,
and his room air oxygen saturation is 98%. Cardiac exam revealed
a new apical systolic murmur best heard at the posterior axillary
line radiating towards to the scapula with an S3 present. JVP was
estimated to be 20 cm H2O. Lung exam demonstrated bibasilar
crackles. Peripheral extremities were warm with no lower
extremity edema.
Initial laboratory data include a creatinine of 2.7 mg/dL (baseline
1.3 mg/dL), hemoglobin of 11.8 g/dL, a white blood cell count
of 12,500 cells/mm3 without left shift or band forms, and
troponin of 5.89 ng/mL. EKG revealed a normal sinus rhythm
with ST elevations in leads II, III, aVF and ST depressions
throughout the lateral precordial leads suggesting ongoing
inferolateral ischemia or injury.
The patient was admitted to the Cardiac Care Unit (CCU) for
further medical management. He received fluid boluses for BP
support. Aspirin and statin therapy were continued and
additionally, therapeutic intravenous heparin was initiated.
Clopidogrel was held due to a potential need for surgical
intervention. Beta blocker and ACE inhibitor were discontinued
secondary to hypotension.
Cardiac catheterization reports were obtained from the outside
hospital and demonstrated a 100% RCA stenosis. Additionally,
there was diffuse disease throughout the coronary arteries
including a 50% LAD, 50% LCx, 50% OM1, and 60% D2
stenosis with an ejection fraction of 35%. An echocardiogram
obtained upon admission to this institution visualized a mobile
echodensity attached to the chordal region of the anterior mitral
leaflet suggestive of partial papillary muscle rupture leading to
anterior leaflet prolapse, as well as systolic dysfunction due to
multiple segmental wall motion abnormalities. Doppler
evaluation confirmed severe, posteriorlaterally directed mitral
regurgitation with a “shoulder” sign, suggestive of severe, acute
MR likely secondary to papillary muscle rupture.
Due to the patient’s acute renal failure, RCA angioplasty was not
performed despite persistent ST elevations suggestive of ongoing
ischemia. Right heart catheterization was performed which
demonstrated a RA pressure of 10 mmHg, RV pressure of 43/15
mmHg, PA pressure of 42/23 mmHg, and a pulmonary capillary
wedge pressure of 21 mmHg without significant v-wave. Cardiac
index was measured at 1.5 L/min/m2, consistent with cardiogenic
shock. Intra-aortic balloon counterpulsation was not performed
due to the presence of severe PVD. The patient was started on a
dopamine drip and taken to the operating room for emergent
coronary bypass revascularization and mitral valve replacement.
The post-operative course was complicated by cardiac arrest and
ventricular fibrillation. A trans-esophageal echocardiogram
following resuscitation revealed a new 2 mm inferoseptal VSD.
Multi-system organ failure ensued and the patient expired 9 days
following bypass surgery.
This is an excellent example for a discussion of mechanical
complications following myocardial infarction. Our patient had
two of the three major complications: rupture of the free wall,
rupture of the ventricular septum and mitral regurgitation, each
of which can result in cardiogenic shock.
1. Rupture of the ventricular free wall is a very serious and often
lethal complication which usually occurs within the first 5 days
post MI and has an incidence of less than 1% when all AMI
patients are considered,1 but its incidence is between 14-26%
among patients dying of acute MI.2,3 Risk factors for free wall
rupture were large ischemia territory, lack of collateral blood
flow (no history of previous angina or MI),3 anterior MI, age>
70, and female sex.4,5 Rupture typically occurs in an area that
has been infarcted without successful reperfusion.6 There was
an increased occurrence noted in patients treated with
thrombolytic therapy versus patients who underwent coronary
intervention (3.3% vs. 1.8%).5 Complete rupture of the left
ventricular free wall is suggested by the development of sudden
right heart failure and shock due to hemopericardium with
resultant electromechanical dissociation. Incomplete, or
subacute, rupture occurs when organized thrombus and
pericardium seal the perforation forming a pseudoaneurysm.
Management is with fluids resuscitation, ionotropic and/or
vasopressor support, pericardiocentesis, IABP counterpulsation,
and percutaneous cardiopulmonary bypass. Surgical repair is
indicated for pseudoaneurysm. Prognosis is very poor and
mortality is exceptionally high.
Case Reports
2. Rupture of the interventricular septum typically occurs 3-5
days after an acute MI, however, it may develop within the first
24 hours or as late as two weeks. Risk factors include “wrap
around” LAD covering a large myocardial territory,10,11 extensive
myocardial damage, poor septal collateral circulation, or RV
infarction.7,8,9 Incidence has decreased from 2% in the
conventional therapy era to 0.2% in the reperfusion therapy
era.12,13 Although not a predisposing factor for septal rupture,
thrombolytics may precipitate the occurrence. Rupture
develops at the margin of the necrotic and non-necrotic
myocardium, typically in the apical septum with anterior MI
or near the base of in inferior MI. The size of the defect
determines the magnitude of the left to right shunt, which will
affect the survival. Presentation is acute hemodynamic
compromise with hypotension, biventricular failure and a new,
loud, harsh, holosystolic murmur best heard at the lower left
and right sternal borders. ECG may show persistent ST
elevations for more the 72 hours in those do not undergo
reperfusion. Defects can be visualized by echocardiogram and
confirmed with Swan-Ganz catheterization via the
measurement of a “step-up” in the oxygen saturation right atrial
and ventricular chambers. Patients with HF and shock require
emergent surgical repair, while delayed surgical management is
feasible in patients with HF without shock. Transcatheter
closure of a post-infarction VSD is another potential approach
which may be appropriate for patients who otherwise are not
candidates for other surgical treatments.
3. Acute mitral regurgitation following myocardial infarction is
due to ischemic papillary muscle dysfunction, LV dilatation or
true aneurysm, or papillary muscle/chordal rupture. The degree
of MR may vary from mild (which may be transient during
ischemia) to moderate-severe MR (which may be due to
papillary muscle or chordal rupture).14 Papillary muscle rupture
is seen both in STEMI and NSTEMI,12,14 and accounts for 5%
of deaths seen in AMI. It is usually seen 2-7 days post-MI and
more frequently affects the posteromedial papillary due to its
sole blood supply from the PDA, whereas the anterolateral
papillary muscle has a dual blood supply from LAD and LCx.
Acute MR occurs more frequently in patients presenting with
their first infarction without established collateralization and
up to 50% of these patients may have only single vessel disease.
Presentation is acute onset of hypotension and pulmonary
edema with a hyperactive precordium and a mid-, late- or
holosystolic murmur that has widespread radiation. Intensity
of the murmur does not necessarily correlate with the severity
of the regurgitation. As many as 50% of patients who have
severe MR due to rupture have early equalization of left
ventricular and left atrial pressures resulting in silent MR or a
short, soft, indistinct murmur. Clinical diagnosis is confirmed
by echocardiogram, which may demonstrate a flail segment of
the mitral valve, a severed papillary muscle, or chordae moving
freely within the left ventricular cavity. Swan-Ganz catheterization usually reveals giant v-waves. Medical treatment includes
aggressive reduction of afterload using nitrates, sodium
nitroprusside, diuretics and IABP counterpulsation. Emergent
surgery remains the treatment of choice for papillary muscle
rupture, although operative mortality is high (20-25%).15
Mitral valve repair is superior to replacement and should be
attempted in experienced centers when there is no papillary
necrosis present.14,16
1. Patel, MR, Meine, TJ, Lindblad, L, et al. Cardiac tamponade in the fibrinolytic era:
analysis of >100,000 patients with ST-segment elevation myocardial infarction. Am
Heart J 2006; 151:316.
2. Stevenson, WG, Linssen, GC, Havenith, MG, et al. The spectrum of death after
myocardial infarction: A necropsy study. Am Heart J 1989; 118:1182
3. Pohjola-Sintonen, S, Muller, JE, Stone, PH, et al. Ventricular septal and free wall
rupture complicating acute myocardial infarction: experience in the Multicenter
Investigation of Limitation of Infarct Size. Am Heart J 1989; 117:809
4. Becker, RC, Hochman, JS, Cannon, CP, et al, for the TIMI 9 Investigators. Fatal
cardiac rupture among patients treated with thrombolytic agents and adjunctive
thrombin antagonists. Observations from the Thrombolysis and Thrombin Inhibition
in Myocardial Infarction 9 study. J Am Coll Cardiol 1999; 33:479.
5. Moreno, R, Lopez-Sendon, J, Garcia, E, et al. Primary angioplasty reduces the risk of
left ventricular free wall rupture compared with thrombolysis in patients with acute
myocardial infarction. J Am Coll Cardiol 2002; 39:598
6. Cheriex, EC, de Swart, H, Dijkman, LW, et al. Myocardial rupture after myocardial
infarction is related to the perfusion status of the infarct-related coronary artery. Am
Heart J 1995; 129:644
7. Radford, MJ, Johnson, RA, Daggett, EM Jr, et al. Ventricular septal rupture: A
review of clinical and physiologic features and an analysis of survival. Circulation
1981; 64:545
8. Skehan, JD, Carey, C, Norrell, MS, et al. Patterns of coronary artery disease in postinfarction ventricular septal rupture. Br Heart J 1989; 62:268
9. Pretre, R, Rickli, H, Ye, Q, et al. Frequency of collateral blood flow in the infarctrelated coronary artery in rupture of the ventricular septum after acute myocardial
infarction. Am J Cardiol 2000; 85:497.
10. Hayashi, T, Hirano, Y, Takai, H, et al. Usefulness of ST-segment elevation in the
inferior leads in predicting ventricular septal rupture in patients with anterior wall
acute myocardial infarction. Am J Cardiol 2005; 96:1037
11. Sasaki, K, Yotsukura, M, Sakata, K, et al. Relation of ST-segment changes in inferior
leads during anterior wall acute myocardial infarction to length and occlusion site of
the left anterior descending coronary artery. Am J Cardiol 2001; 87:1340.
12. Reeder, GS. Identification and treatment of complications of myocardial infarction.
Mayo Clin Proc 1995; 70:880
13. Pierli, C, Lisi, G, Mezzacapo, B. Subacute left ventricular free wall rupture. Surgical
repair prompted by echocardiographic diagnosis. Chest 1991; 100:1174.
14. Lavie, CJ, Gersh, BJ. Mechanical and electrical complications of acute myocardial
infarction. Mayo Clin Proc 1990; 65:709.
15. Pasternak, RC, Braunwald, E, Sobel, BE. Acute myocardial infarction. In: Heart
Disease, 4th ed, Braunwald, EB (Ed), Saunders, Philadelphia 1992. p.200.
16. David, TE. Techniques and results of mitral valve repair for ischemic mitral
regurgitation. J Card Surg 1994; 9:274.
Case Reports
Brandy Kaneshiro, MD,1 and Albert Yeung, MD2
Case Presentation
A 35 year-old Caucasian man with Pre-B cell ALL on
day 197 post allogenic stem cell transplant and with a
chest tube for pneumothorax post VATS was admitted
for pain at his chest tube site. Sixteen days into his
admission he developed acute onset of blurry vision.
The patient first noticed some difficulty reading a wall
clock when he woke up in the morning followed by a
subsequent worsening of his visual acuity over the next
eight hours. By late afternoon he could only detect
light. Review of systems was significant only for an
intermittent headache over the preceding week.
The patient had a past medical history of pre-B cell
Figure 1. Non-contrast CT
Figure 2. FLAIR weighted image shows
ALL diagnosed one year prior, allogenic stem cell
high signal intensity in the occipital
transplant six months ago, graft versus host disease,
lobes. This sequence does not
nutrition via provided by home TPN, Adenovirus
discriminate between vasogenic and
infection three months ago status post IVIG and a
cytotoxic edema. PRES is among the
hospitalization one month ago during which VATS was
many causes of increased FLAIR signal.
performed. The pathology from his VATS was
consistent with non-specific interstitial pneumonitis.
His hospitalization post-VATS was complicated by pneumothorax
Radiographic studies
and required chest tube placement which was being cared for at
Figures 1-5 are our patient’s neuroimaging studies performed the
home with the assistance of a visiting nurse.
day he presented with rapid vision loss. While there is no single
pathognomic radiographic finding for PRES, these CT and MRI
On this admission the patient presented to an outside hospital
images demonstrate a series of findings typically suggestive of the
emergency room complaining of pleuritic chest pain and
increasing shortness of breath. Early in his admission he was
empirically started on amphotericin B for suspected fungal
The clinical presentation above confirmed by MRI led to an early
etiology of his pulmonary symptoms. He was also diagnosed with
diagnosis of Posterior Reversible Encephalopathy Syndrome
gastrointestinal graft versus host disease (GVHD) for which he
(PRES) in our patient. The most likely culprit was the
was being treated with steroids and immunosuppressive agents.
cyclosporine he had been taking post stem cell transplant. Both
his cyclosporine and sirolimus were stopped immediately. Our
Medications included cyclosporine, sirolimus, hydrocortisone,
patient’s vision loss persisted four days after the cyclosporine and
Cellcept, Ambisome, Leukine, amikacin, acyclovir, vancomycin,
sirolimus were discontinued. On the fifth day, however, he woke
pentamidine, Dilaudid PCA, acyclovir, Marinol, Nexium, TPN
in the morning reporting a dramatic, complete resolution of his
for nutrition, sliding scale insulin and Zoloft.
visual disturbances.
On physical examination the patient’s temperature was 98.3º F,
respiratory rate was 16, blood pressure was 146/107 mmHg, pulse
Posterior Reversible Encephalopathy Syndrome (PRES)
was 71 and pulse oximetry was 96% on room air. His head, neck,
The classic clinical syndrome includes headache, visual changes,
heart and lung examination were unremarkable. He had a chest
confusion, lethargy and seizures. The headache is typically
tube to water seal. His abdominal exam was significant for an
described as constant, bilateral, moderate and dull in quality. Visual
ileostomy draining brown liquid stool. While he was alert and
changes can progress to complete visual loss or may manifest as
oriented to person, place and time, he was confused and answered
visual hallucinations. Fundoscopic exam is usually normal as was
questions inappropriately. His speech was normal and he did not
seen in our patient. Neurologic exam rarely reveals any focal
have any focal neurologic deficits. His pupils were equal, round
deficits. Seizures usually present as generalized tonic clonic.
and reactive to light, extra ocular movements could not be assessed
secondary to his poor visual acuity and there were no signs of
Little can yet be confirmed about the incidence of or risk factors
increased intracranial pressure by dilated funduscopic exam.
for this syndrome since a significant portion of what is known is
based on published case reports. PRES is most commonly seen as a
Laboratory studies on the day of presentation revealed a complete
complication of hypertensive encephalopathy, eclampsia and
blood count within normal limits. Serum electrolytes and
cytotoxic and immunosuppressant medications (most notably
creatinine were unremarkable. Cyclosporine and sirolimus levels
cyclosporine, tacrolimus and interferon) but there is a long list of
were within the appropriate range.
Thomas Jefferson University Hospital, Philadelphia, PA
Hahnemann University Hospital, Philadelphia, PA
Case Reports
Figure 3. Diffusion weighted image
of the occipital lobes is normal.
Cytotoxic edema secondary to tissue
ischemia is excluded with this
Figure 4. Post-contrast axial T1
weighted image shows patchy
enhancement of the occipital lobes,
consistent with disruption of the blood
brain barrier.
documented etiologies. These varying clinical scenarios are most
clearly unified by the neuroimaging findings seen on CT scanning
and MRI. While cyclosporine is the most common medication
associated with PRES, it is unclear what specific trigger initiates the
syndrome in any particular patient. PRES can develop within days
or many months after exposure and serum levels of cyclosporine
also seem to be a poor predictor of risk for the syndrome.
There are multiple hypotheses concerning the pathogenesis of
PRES but most of the literature describes the syndrome as the
result of impaired cerebral autoregulation and endothelial
dysfunction. The most plausible hypothesis is that, as the body’s
ability to maintain constant cerebral perfusion is impaired or
exceeded, increases in systemic blood pressure could lead to
extravasation of fluid into the surrounding tissue causing vasogenic
edema. Endothelial dysfunction may also contribute since PRES
seems to occur with higher frequency in patients with chronic renal
failure, vasculitis, sepsis and hemolytic uremic syndrome.
Care must be taken to exclude other equally serious diagnoses
such as embolic stroke, venous thrombosis, metabolic
encephalopathy, encephalitis, vasculitis or demyelinating
disorders. This can best be accomplished with neuroimaging
including CT scanning and MRI. Most frequently seen is
symmetrical white matter edema in the parieto-occipital regions
as noted in Figures 1-5.
Appropriate treatment requires discontinuation of the offending
agent or treatment of the underlying disease. Despite optimal care,
some patients sustain permanent vision loss or epilepsy secondary
to PRES. In the majority of cases, however, clinicians can expect
resolution of PRES in days to weeks. Blood pressure should be
Figure 5. Post-contrast sagittal T1
weighted image demonstrates patchy
enhancement of the occipital lobe.
tightly maintained in the normal range with titratable parenteral
agents such as nicardipine or labetalol. Current guidelines for
treating malignant hypertension should be incorporated into the
management of the patient when applicable. Steroids are used in
some settings but are not widely accepted as an appropriate
treatment because of the associated risk of worsening hypertension
and fluid overload. Neuroimaging will also document resolution
of PRES correlating well with the patient’s symptoms. The
offending agent should never be reintroduced to the patient.
The acute development of seizures, visual disturbances, headache
or confusion especially in a patient with hypertension, taking
immunosuppressive or cytotoxic agents or with impaired renal
function should prompt an urgent CT scan and MRI to evaluate
for PRES. This syndrome, while usually reversible in days to weeks
following treatment of the underlying process or withdrawal of
the culprit medication, has the potential to remain permanent
resulting in significant disability if there is a delay in appropriate
diagnosis and treatment.
1. Shin K, Choi HJ, Bae YD, et al. Reversible posterior leukoencephalopathy syndrome
in systemic lupus erythematosus with thrombocytopenia treated with cyclosporine. J
Clin Rheum 2005; 11(3):164-6..
2. Tam CS, Galanos J, Seymour JF, et al. Reversible posterior leukoencephalopathy
syndrome complicating cytotoxic chemotherapy for hematologic malignancies. Am J
Hemat 2004; 77(1):72-6.
3. Mukherjee P, McKinstry RC. Reversible posterior leukoencephalopathy syndrome:
evaluation with diffusion-tensor MR imaging. Radiology 2001; 219(3):756-65.
4. Stott, VL, Hurrell, MA, Anderson, TJ. Reversible posterior leukoencephalopathy
syndrome: a misnomer reviewed. Intern Med J 2005; 35:83.
5. Schwartz, RB, Jones KM, Kalinea, P, et al. Hypertensive encephalopathy: findings on
CT, MR imaging and SPECT imaging in 14 cases. Am J Roentgenol 1992; 159:379.
Case Reports
Saum Shamimi-Noori, MD
Case Presentation
A 78 year-old man with a history of type 2 diabetes mellitus,
hypertension, hyperlipidemia, seizure disorder, dementia, and
alcohol abuse was admitted to the Wilmington VA Medical
Center for treatment of deep vein thrombosis of the lower
extremity. During the hospital course, the patient had a brief
episode of supraventricular tachycardia. An echocardiogram
revealed dilated cardiomyopathy, an ejection fraction of 20%, and
apical and inferolateral akinesis-hypokenesis. On the following
day, the patient developed cardiac arrest with ventricular
fibrillation (VF) that was terminated by electric defibrillation. An
electrocardiogram (Figure 1) obtained immediately after defibrillation demonstrated sinus bradycardia, a prolonged QT interval,
and T-wave alternans. After the cardiac arrest, the patient was
ventilator-dependant, and his family decided to withdraw lifesupporting care.
Since the early 1900s, T-wave alternans (TWA), or repolarization
alternans, has been linked to ventricular arrhythmias. TWA refers
to the alternation of T-wave shape or timing from beat-to-beat on
the electrocardiogram (ECG). TWA may also involve the ST
segment or U wave but ultimately reflects T-wave changes. Note
that this is still in stark contrast to electrical alternans totalis, which
refers to an alternating axis or voltage of all ECG components.
Although the exact pathophysiology of TWA is unknown, it is
most likely caused by a temporal heterogeneity in ventricular
repolarization. This dispersion in ventricular repolarization is an
important mechanism underlying ventricular arrhythmias. In
essence, TWA represents an electrical state of heightened arrhythmogenicity and thus possibly a gateway to VF.
1. Armoundas AA, Tomaselli GF, Esperer HD. Pathophysiological basis and clinical
application of T-wave alternans. J Am Coll Cardiol 2002; 40:207-17.
2. Gehi AK, Stein RH, Metz LD, Gomes JA. Microvolt T-wave alternans for the risk
stratification of ventricular tachyarrhythmic events: a meta-analysis. J Am Coll
Cardiol 2005; 46:75-82.
3. Narayan SM. T-wave alternans and the susceptibility to ventricular arrhythmias. J Am
Coll Cardiol 2006; 47:269-81.
4. Shusterman V, Goldberg A, London B. Upsurge in T-wave alternans and nonalternating repolarization instability precedes spontaneous initiation of ventricular
tachyarrhythmias in humans. Circ 2006; 113:2880-7.
Figure 1. The post-cardiac arrest electrocardiogram demonstrates sinus bradycardia at a heart rate of ~40
beats per minute and a prolonged QT interval. Note the alternating T-wave morphologies most easily
appreciated in leads V2-V5.
Case Reports
Lax Gadde, MD, and Martin Kerrigan, MD
Case Presentation
A 69 year-old male with a past medical history of hyperlipidemia,
GERD, and transitional cell carcinoma of the bladder currently
in remission was admitted to the hospital with increasing fatigue,
arthralgias, and myalgias. He noted that his symptoms began
approximately four weeks prior to admission after working outside
in his yard and on his swimming pool. He stated that one week
later he developed red blotches on his thighs, abdomen and chest
followed by arthralgias and myalgias. He noted there were ticks
where he was working but could not recall a definite tick bite,
nor did he find evidence of one. On further questioning he
revealed that his neighbor had Lyme disease in the past, and his
dog also had Lyme disease. He presented to his primary care
physician three weeks later with myalgias in his arms, shoulders,
elbows, and thighs bilaterally. His outpatient medication include
Niaspan, omeprazole and Lipitor which he had been taking for
the prior two years. Laboratory evaluation revealed a white blood
count of 7000 cells per mm3, hemoglobin of 11.2 g/dL, ESR of
119 mm/hr and a serum creatinine of 1.0 mg/dL. Lyme disease
was considered and serologies were sent but no antibiotics were
started. The Lyme IgM result returned positive 10 days after his
visit to his primary care physician, and the patient was instructed
to come in to the hospital to start treatment. He was still feeling
fatigued. An EKG done upon admission revealed a 2:1 AV Block
(Figure 1) with a heart rate in the 40s and a widened QRS
complex. The patient was admitted to telemetry for lyme carditis
and was started on treatment with ceftriaxone 2 grams once daily
which was continued for 2 weeks. His symptoms resolved and his
repeat EKG showed sinus rhythm with a 1st degree AV Block
with a HR of 78 (Figure 2). The patient’s final diagnosis was Lyme
carditis due to early disseminated Lyme disease.
1. Wormster, GP. Early Lyme disease. NEJM 2006; 354; 2794-801.
2. Steere AC, Sikand VK. The presenting manifestations of Lyme disease and the
outcomes of treatment. NEJM 2003;348:2472-4.
Figure 1.
Figure 2.
Case Reports
Donna Williams, MD
Treatment of Crohn’s disease often involves the use of
immunomodulating drugs. Most trials of these drugs have
excluded patients with coexisting illness by study design. The
purpose of this case report is to describe the treatment of a rare
case of Crohn’s disease in the face of concomitant hepatitis C
and hemophilia.
Case Presentation
The patient is a 37 year-old Caucasian male who has a history of
severe factor IX deficiency complicated by frequent bleeding into
joints, hepatitis C genotype 1b acquired through factor
transfusions, and terminal ileal Crohn’s disease which was
diagnosed by small bowel x-ray in 1985. At that time, he was
treated with azulfidine and corticosteroids with some
improvement. The patient was maintained on 5-ASA and steroids
until 2000, when steroids were tapered in an attempt to prepare
him for treatment of his hepatitis C. By May 2001, the patient
was off all steroids and was maintained on asacol 1200 mg BID.
At that time, liver biopsy revealed liver parenchyma with focal,
mild to moderate macrovesicular steatosis. Portal tracts had mild,
lymphocytic infiltrate and bile ducts were present without
significant epithelial atypia. Due to the benign findings on liver
biopsy, the decision was made to defer treatment of hepatitis C.
In the fall of 2001, the patient began to experience episodes of
bright red blood per rectum, attributed to flares of his Crohn’s
disease, which required treatment with steroid pulses and factor
IX infusions. Ultimately, the patient was placed on daily
alternating doses of prednisone 20 mg and 50 mg. In January
2002, he presented to his hematologist and subsequently to the
ED with hematochezia and hemoglobin of 6.4 g/dL. Colonoscopy
revealed apthous ulcerations in the terminal ileum consistent with
Crohn’s disease. The bleeding was stopped with factor IX
infusions and IV solumedrol. After three days the patient was
discharged on budesonide 9 mg daily, Asacol 3.5 g daily, and was
also receiving daily injections of factor IX. Despite these efforts,
he continued to bleed and required iron infusions for his
profound iron deficiency anemia. Eventually, the patient’s Crohn’s
disease was under control with alternate day prednisone at 30 mg.
The patient was doing well until December of 2003, when he
again began experiencing bright red blood per rectum. He was
started on azathioprine 50 mg, which was soon discontinued
secondary to patient intolerance. Steroids were increased to a daily
dose of prednisone 40 mg with only mild clinical response. In
May 2004, the patient was requiring factor IX infusions
approximately once a month for recurrent GI bleeding. In
October 2004, after discussion with the patient’s hematologist
and Centocor (producers of Remicade), the decision was made to
treat the patient with remicade at the standard dose of 5mg/kg at
weeks 0, 2, and 6 weeks. Initially, the patient responded well with
decreased GI complaints, and he achieved remission of his Crohn’s
disease after the third dose. He no longer had any GI bleeding
and his hemoglobin stabilized at 15.3 g/dL. His prednisone dose
was able to be tapered to 20 mg every other day; further tapering
is in progress. After seeing these results, the patient was continued
on the maintenance dose of 5 mg/kg every 8 weeks.
Review of the literature revealed the absence of reports of patients
with concomitant Crohn’s disease, hemophilia, and hepatitis C.
The literature consists of information about patients who suffer
from hemophilia and hepatitis C as a result of transfusion
acquired disease, but there are no cases also involving
inflammatory bowel disease. Indeed, one study performed by
Thompson, et al.1 showed that the incidence of inflammatory
bowel disease among patients with hemophilia and von
Willebrand’s disease is lower than that found in the general
population. Of 6433 patients with hemophilia and 3129 patients
with von Willebrand’s disease, only 4 cases of Crohn’s disease were
detected while the expected number of cases was 11.97-16.58.
This study suggests that thrombotic events play a role in the
development of inflammatory bowel disease, and therefore,
hemophilia protects against IBD.2
Although there are a large number of patients who have Crohn’s
disease who are also infected with hepatitis B and/or hepatitis C
as a result of frequent endoscopic and surgical procedures, there
are relatively few reported cases of patients with HBV or HCV
who have been treated with infliximab (Remicade, Centocor) for
control of Crohn’s disease.3 Infliximab is a monoclonal antibody
directed against tumor necrosis factor alpha (TNF α), which is a
proinflammatory agent. TNF α is present in abnormally increased
amounts in inflammatory liver diseases such as chronic hepatitis
B and C as well as autoimmune and alcoholic hepatitis. It has
been suggested that up regulation of TNF α may encourage
clearance of hepatitis B virus.4 Therefore, it has been postulated
that treating patients with concomitant hepatitis B or C and
Crohn’s disease with infliximab would increase the amount of
circulating virus and induce reactivation. Even so, the overall
consensus in the literature until recently was that immunomodulating drugs used for the treatment of Crohn’s disease did not alter
the course of patients with coexisting hepatitis B or hepatitis C.5
In 2004, two case reports addressed this issue among four cases of
patients with hepatitis B and Crohn’s disease. These four patients
were treated with infliximab in standard doses of 5 mg/kg, and
two of them experienced acute flare of chronic hepatitis B after
withdraw of infliximab therapy.6-7 One of these patients died as a
result. The two patients who did not experience a flare of hepatitis
B had been treated with lamivudine 100 mg daily during
treatment, which supports its use to prevent reactivation of
hepatitis B. Among three cases of patients with concomitant
Case Reports
hepatitis C and Crohn’s disease who were treated with infliximab
in standard doses, none experienced reactivation of hepatitis C.8-9
After review of the literature and discussion of treatment strategies
with hematology, hepatology, and Centocor, the decision was
made to treat our patient with infliximab due to the frequency
and severity of his Crohn’s disease flares. The patient’s encouraging
response to infliximab has supported the claim that infliximab is
safe in patients with hepatitis C and hemophilia without adverse
effects on either concomitant illness.
3. Biancone L, Pavia M. Del Vecchio Blanco G, et al. Hepatitis B and C virus infection
in Crohn’s disease. Inflammatory Bowel Diseases 2001; 7(4):287-294.
4. Marinos G, Naoumov N, Rossol S, et al. Tumor necrosis factor receptors in patients
with chronic hepatitis B infection. Gastro 1995; 108:1453-1463.
5. Biancone L, Del Vecchio Blanco G, and Pallone F. Immumomodulatory drugs in
Crohn’s disease patients with hepatitis B or C virus infection. Gastro 2002; 122(2):
6. Esteve M, Saro C, Gonzalez-Huix F. Chronic hepatitis B reactivation following
infliximab therapy in Crohn’s disease patients: need for primary prophylaxis. Gut
2004; 53:1363-1365.
7. del Valle Garcia-Sanchez M, Gomez-Camacho F, Poyato-Gonzalez A. Infliximab
therapy in a patient with Crohn’s disease and chronic hepatitis B virus infection.
Inflammatory Bowel Diseases 2004; 10(5): 701-702.
1. Thompson N, Wakefield A, and Pounder R. Inherited disorders of coagulation
appear to protect against inflammatory bowel disease. Gastro 1995; 108:1011-1015.
8. Campbell S and Ghosh S. Infliximab therapy for Crohn’s disease in the presence of
chronic hepatitis C infection. European J of Gastro & Hepatol 2001; 13(2):191-192.
2. Langman M. Can incoagulable blood protect against inflammatory bowel disease?
Gastro 1995; 108: 1305-1307.
9. Holtman M, Galle P and Neurath M. Treatment of patients with Crohn’s disease and
concomitant chronic hepatitis C with a chimeric monoclonal antibody to TNF. Amer
J of Gastro 2003; 98(2):504-505.
Case Reports
Sivakumar Srinivasan, MD, and Sandeep Anreddy, MD
Case Presentation
A 55 yr old male with past medical history significant for end
stage liver disease, intravenous drug abuse and hypertension
presents to the ED with complaints of bright red blood per rectum
for the past 3 days and non-specific chest discomfort. Medications
on admission were amlodipine, valsartan /HCTZ, xanax,
terazosin, and high dose methadone maintenance therapy.
The long QT syndrome is a disorder of myocardial repolarization
characterized by a prolonged QT interval on the electrocardiogram. This syndrome is associated with an increased risk of a
characteristic life threatening cardiac arrhythmia known as
Torsades de pointes. Torsade de pointes is a form of polymorphic
ventricular tachycardia that occurs in the setting of acquired or
congenital QT interval prolongation. Polymorphic ventricular
tachycardia is defined as a ventricular rhythm faster than 100
beats/min with frequent variations of the QRS axis, morphology
or both. The peaks of the QRS complexes appear to twist around
the isoelectric line of recording; the name literally translates to
“twisting of the points.”
On admission, temperature was 98º F, heart rate was 50,
respiratory rate was 18, blood pressure was 122/75, and oxygen
saturation was 99% on room air. Physical examination was
normal. No bright red blood per rectum was noticed and stool
was heme-negative. Initial laboratory values including a complete
blood count and chemistry panel were within normal limits
inclucing a hemoglobin of 14.6, calcium of 9.6, potassium of 3.9,
and magnesium of 1.8. The patient was ruled out for myocardial
infarction with three negative troponins. The admission EKG is
presented below (Figure 1).
While in the ED on the day of admission, the patient was noticed
to have ventricular tachycardia on telemetry. He was
asymptomatic during the episode and his vital signs were stable.
The telemetry strip at that time is shown below (Figure 2).
The patient was given 2 grams magnesium in the and the patient
was admitted to the CCU. QT interval prolongation from high
dose methadone therapy was the most likely cause of his episode
of polymorphic ventricular tachycardia. Electrophysiology
consultation recommended that his methadone dose be decreased
so that his QT interval would be within normal limits. Prior to
discharge, his methadone dose had been lowered without any
symptoms of methadone withdrawal and his EKG on discharge is
shown below (Figure 3).
Figure 1.
The most common causes of acquired long QT interval syndrome
are either medication-induced or electrolyte abnormalities. Some
medications known to cause QT interval prolongation are antiarrhythmics such as quinidine, procainamide, disopyramide,
amiodarone, dofetilide, and ibutilide; antibiotics including
erythromycin, clarithromycin, and fluoroquinolones; antihistamines such as terfinadine and astemizole; the antipsychotic
agents chlorpromazine, haloperidol, and thioridazine; and high
dose methadone. Caution should be used when prescribing a drug
that prolongs QT interval in patients with risk factors; a baseline
EKG and daily EKGs should be obtained during the course of
therapy. There are various risk factors for drug induced torsades
including female sex, hypokalemia, hypomagnesemia,
bradycardia, rapid rate of intravenous infusion with a QT interval
prolonging drug, congestive heart failure, baseline QT interval
prolongation; sub clinical long QT interval prolongation, and ion
channel polymorphisms.
Case Reports
Figure 2.
Figure 3.
QT prolongation and torsade de pointes have been reported in
patients on high doses (100 to 400 mg) of methadone. Methadone
has a long plasma elimination half life and is metabolized by the
CYP3A4 enzyme system in the liver, so any drug which inhibits
the CYP3A4 enzyme system can increase methadone levels in the
blood. CYP3A4 inhibitors include antimicrobials, antifungals,
statins, and acetaminophen. Two mechanisms can explain the
association between methadone and torsade de pointes, synthetic
opoids cause bradycardia and they can inhibit the outward
potassium current during phase 3 of action potential.
In a retrospective analysis of reports of adverse events associated
with methadone from 1969 to 2002 found that out of a total of
5,503 adverse events associated with methadone, 43 (0.78%) were
reported to be torsades de pointes and an additional 16 were noted
to have QT prolongation. The dose reported was 410+/-349
mg/day (median 345 mg, range 29-1680) while only 10 cases
were within the recommended range for methadone maintenance
(60-100mg). Female gender, interacting medications,
hypokalemia, hypomagnesemia and structural heart disease were
found in 44 (75%) cases. Most adverse events required hospitalization (28/59) and death resulted in 5 cases.
1. Roden, DM. Drug induced prolongation of the QT interval. N Engl J Med 2004;
2. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among
methadone users: reports to the FDA spontaneous reporting system.
Pharmacoepidemiol Drug Saf 2005; 14(11):747-53.
3. Moss, AJ. Long QT syndrome. JAMA 2003; 289:2041.
4. Khan, IA. Long QT syndrome: diagnosis and management. Am Heart J 2002; 143:7.
5. Passman, R, Kadish, A. Polymorphic ventricular tachycardia, long Q-T syndrome,
and torsades de pointes. Med Clin North Am 2001; 85:321.
Case Reports
Bonnie Callahan, MD
Case Presentation
A 42 year-old female with a medical history of HIV presented to
the Emergency Department with nausea and vomiting for the past
five days. Six days prior to presentation, she had one week of
symptoms of progressive dyspnea and non-productive cough which
were evaluated by her primary care physician. At that time, blood
work revealed a CD 4 count of 150 cells/mm3 and a chest x-ray
was suggestive of pneumonia. She was given a prescription of
trimethoprim-sulfamethoxazole (TMP/SMX) and guaifenesin
with codeine. Within twenty-four hours of starting the prescribed
medications, she developed nausea and vomiting, and she stopped
taking both medications three days prior to presentation. Although
her cough and shortness-of-breath were much improved, her
nausea and vomiting had not improved with discontinuation of
the TMP/SMX and guaifenesin with codeine. She reported she
was unable to tolerate any solid foods and was only tolerating small
amounts of liquids. She also noted some associated epigastric
“crampiness.” Review of systems was notable for a new headache
that started the morning of presentation to the hospital. The
headache was bilateral, frontal, and “achy, non-throbbing.” She
had no associated photophobia, vision change, or neck-stiffness.
She reported no fever, chills, chest pain, hemoptysis, diarrhea, or
constipation. She had no other complaints.
On review of the patient’s past medical history, she was noted to
have type 2 diabetes, hypertension, “mild” asthma (never
requiring hospitalization or intubation) and HIV/AIDS with a
recent CD4 count of 150 cells/mm3. Her surgical history
included a TAH-BSO and breast biopsy. She was allergic to
penicillin, which caused anaphylaxis. Her medications included
glipizide, amlodipine, losartan, hydrochlorothiazide, and
albuterol. Social history was negative for tobacco, alcohol, or
substance abuse. The patient worked in an office setting and lived
at home with her daughter. She reported no recent sick contacts
and no recent travel. Her family history was significant for type 2
diabetes in her mother, who died from a stroke at age sixty, and
breast cancer in her sister, who died from a stroke in her fifties.
In the ED, the patient was afebrile and her vital signs included a
heart rate of 92 beats per minute, respiratory rate of 16 breaths
per minute, blood pressure of 128/94 mmHg, and an oxygen
saturation of 98% on room air. She was alert and oriented and in
no acute distress. Physical exam revealed oral thrush and scattered
expiratory wheezes in bilateral lungs with decreased breath sounds
at bilateral bases. Her abdomen was diffusely tender, with
normoactive bowel sounds throughout and no rebound or
guarding. No masses or organomegaly were appreciated. The
physical exam was otherwise unremarkable.
The initial evaluation included a chest x-ray which showed “hilar
lymphadenopathy with upper lobe interstitial lung disease” which
was thought to be secondary to infectious etiology. Her urinalysis
was negative for infection, and a complete blood count showed a
normal white blood cell count, a normal platelet count, and mild
anemia with hemoglobin of 12 g/dL. She had an elevated lactate
dehydrogenase of 287 IU/L. Her blood chemistries were normal,
with the exception of a creatinine of 2.0 mg/dL, with a known
baseline of 0.8 mg/dL one year earlier. Blood and sputum cultures
were collected. The patient was diagnosed with communityacquired pneumonia and was started on moxifloxacin in the ED.
She was also started on intravenous TMP/SMX for possible PCP
and fluconazole for her oral thrush. She was admitted to the
hospital and started on intravenous fluid resuscitation.
The first night of the patient’s hospital stay was uneventful. The
following morning she was noted to have acute mental status
change. She appeared awake, but would not answer questions or
follow commands. She had a low grade temperature of 100ºF, was
tachycardic at 110 beats per minute, with a blood pressure of
132/62 mmHg, a respiratory rate of 20 breaths per minute, and
an oxygen saturation of 99% on room air. Her physical exam was
unchanged from the previous day with the exception that she could
not cooperate for the neurologic exam. Her pupils were equal and
reactive to light. She did grimace in reaction to painful stimuli.
Her muscle tone was noted to be normal with no rigidity. She was
spontaneously moving all four extremities, but not on command.
The patient was transferred to the telemetry floor and a full
neurologic evaluation was initiated. A lumbar puncture was
planned, cultures were obtained, and a head CT was unremarkable,
showing no intracranial hemorrhage, acute territorial infarct, or
cerebral edema. Additionally, no mass effect or midline shift was
seen on the CT scan. The patient’s fever increased to 103ºF, and
the infectious disease specialist saw her in consult.
The patient’s condition remained unchanged until 4:45 am the
next morning, when a nurse witnessed the patient having tonicclonic seizure activity. During the seizure the patient foamed at
the mouth and desaturated to 81% on 2L oxygen by nasal canula.
She continued to seize despite 6mg intravenous lorazepam and an
intravenous fosphenytoin load. She was intubated and transferred
to the intensive care unit on the neurology service for
management of status epilepticus. In the intensive care unit she
was given intravenous fosphenytoin and propofol. A lumbar
puncture was performed for suspected encephalitis. Cerebrospinal
fluid analysis, including evaluation for cryptococcus and herpes
simplex virus, revealed no abnormalities. An MRI of her brain
showed no acute abnormalities, and a work-up for an infectious
etiology of her illness was negative. The infectious disease
consultant suspected that the patient’s seizures were a reaction to
the moxifloxacin. It was discontinued and within twenty-four
hours her seizures stopped. An EEG was performed the day after
her seizure activity and intubation. The EEG showed diffuse 2-6
Hertz slowing secondary to sedation. No seizure or epileptiform
abnormalities were seen. Three days after her initial intubation,
she was successfully weaned from the ventilator. Her mental status
quickly returned to baseline. Treatment with azithromycin was
initiated for her respiratory infection, and at the recommendation
of the neurologists, she was maintained on anti-epileptic
Case Reports
medication. Her hospital course was complicated by an upper
extremity DVT during her stay in the intensive care unit. Ten
days after her initial admission she was discharged to her home
with an outpatient enoxaparin bridge to warfarin. She was
instructed to follow-up with her primary care provider, neurology,
and infectious disease as an outpatient.
In the absence of infectious or structural etiologies of the seizures,
they were likely referable to moxifloxacin hydrochloride administration. Moxifloxacin is a normally well-tolerated fluoroquinolone
antibiotic used to treat community-acquired pneumonia, sinusitis,
and other bacterial infections. It does not require dose-modification
for renal or hepatic impairment. Some common side-effects of
moxifloxacin include upset stomach, vomiting, diarrhea, dizziness,
and headache. The product information supplied with Avelox
(brand name for moxifloxacin) notes that seizures are a rare
complication of quinolone use, and have been reported with Avelox.
It reports to “use moxifloxacin with caution in patients with known
or suspected CNS disorders (for example, severe cerebral
arteriosclerosis, epilepsy) or in the presence of other risk factors that
may predispose to seizures or lower the seizure threshold.”1
Moxifloxacin has previously been reported in the literature as
being associated with both seizures and status epilepticus. One
case report described an elderly patient with a past history of
idiopathic seizures who developed status epilepticus four days after
initiating moxifloxacin treatment for a respiratory infection. His
seizures stopped with discontinuation of the drug, but
unfortunately he subsequently died of multiorgan failure
associated with his illness.2 Additionally, an editorial noted that
the WHO Adverse Reactions database contained 53 reports of
convulsions associated with moxifloxacin.2
This report provides further evidence that moxifloxacin should be
avoided, if possible, in patients with a history of seizure disorders.
Furthermore, moxifloxacin should be considered as the possible
cause of new onset seizures in a patient who has initiated
treatment with this drug.
1. Product Information: AVELOX(R) oral tablets, IV injection, moxifloxacin hcl oral
tablets, IV injection. Schering-Plough, Keniloworth, NJ, 2005.
2. Moxifloxacin: First report of status epilepticus in an elderly patient: case report.
Reactions Weekly 2004; 995:11.
Ancient Rooftops,
Seoul, Korea
Photo courtesy of
Eric Choi, MD
Case Reports
Jeffrey Clough, MSIV, and Andrew Rose, MD
Case Presentation
A 20 year-old Caucasian female with a past medical history
significant only for occasional headaches and anemia presents with
a chief complaint of increasing thirst for two weeks. The patient
was in her usual state of health until approximately two weeks
prior to admission when she noted the gradual onset of increasing
thirst and began drinking more and more water over the next few
days. Her thirst increased to the point where she drank an
estimated 18 liters of fluid during the 24 hours prior to admission.
This thirst was accompanied by frequent urination, which would
often awaken her during the night and she noted her urine to be
very clear. These symptoms began within a few days of a vaginal
yeast infection, for which she was treated with one dose of
fluconazole. She denied any other symptoms during this episode.
Her past medical history was significant for occasional non-focal
headaches without aura or specific precipitants. These headaches
had been present for several years and responded well to NSAIDS.
She also reports that she has a history of anemia and occasionally
takes iron supplements. She does not report taking regular
medications and has never had surgery. Her last menstrual period
was approximately three weeks earlier. She is a college student,
works part-time in a pharmacy and lives with her family and
claims to be happy with her life. She is in a monogamous
relationship with her boyfriend and reports no problems. She
denies alcohol, cigarette, or illicit substance use. Her family
history is significant only for hypertension, diabetes mellitus, and
stroke on her maternal side and gastric cancer in her maternal
grandfather. She denies any neurologic, psychiatric, or
autoimmune disease in the family.
On physical examination, the patient appeared comfortable, wellhydrated, and her vital signs were normal. Her examination
revealed no abnormalities, with the exception of hippus of the
pupils. Full neurologic examination was normal including visual
field testing with confrontational visual fields. Initial laboratory
examination revealed a mild microcytic anemia with a
hemoglobin of 11.9 g/dL and a normal chemistry panel including
a serum sodium of 139 meq/dL and creatinine of 0.5 mg/dL.
Differential Diagnosis and Evaluation
The most likely diagnoses given this patient’s history are diabetes
insipidus (DI) or psychogenic polydipsia. DI can be further
classified into nephrogenic or central. Nephrogenic DI is less likely
in this case as it generally occurs either as a genetic disease
presenting early in life in males or as a side effect of medications
such as lithium or demeclocyline. It may also be secondary to
hypercalcemia, which was normal on her laboratory evaluation.
Therefore, central DI and psychogenic polydipsia were the
remaining likely diagnoses. Both of these disorders are common to
the patient’s demographic. Central DI is caused by destruction of
the vasopressin producing cells in the posterior pituitary gland. It
is most often an idiopathic phenomenon likely to be autoimmune,
but other causes include infiltrative disorders such as hemochro-
matosis and sarcoidosis, as well as pituitary neoplasms. Psychogenic
polydipsia is also idiopathic and is thought to be caused by
dysfunction of thirst-regulating nuclei in the hypothalamus. It is
often associated with patients who have a psychiatric disorder but
can occur with infiltrative disorders and in otherwise normal
patients. Psychogenic polydipsia differs from DI in that patients
are driven to drink water and they urinate to compensate for the
increased volume load whereas in DI patients cannot concentrate
their urine and must drink to replace the lost fluids.1
The primary method to distinguish between these three disorders
is the water deprivation test. In this test, the patient remains NPO
and urine osmolarity is measured every hour. Additionally, the
serum osmolarity and sodium level are measured every 2 hours.
The test is stopped if the patient’s urine is concentrated to a level
of 600 mOsm in which case DI is ruled out. If the serum
osmolarity exceeds 295 mOsm or the urine osmolarity is stable
for 2-3 consecutive hours (less than 10% increase) while the serum
osmolarity is rising, DI is the likely diagnosis. At this point, 5 10 mcg of vasopressin is injected subcutaneously and the urine
osmolarity is measured one hour later. If the urine osmolarity
increases by 50% or more, the patient is considered to have central
DI. In many cases of central DI, the disease is only partial and
can be diagnosed if the urine osmolarity increases by 15-50%.1 If
the patient has nephrogenic DI, the urine osmolarity should not
significantly increase.
In addition to water deprivation test, MRI of the brain should be
obtained to rule out any obvious causes of central DI such as a
mass. In idiopathic central DI, the characteristic finding on MRI
is loss of the pituitary bright spot and thickening of the pituitary
stalk. If central DI is determined, a pituitary panel should be
obtained to rule out any other pituitary dysfunction.
The results of the water deprivation test in this patient are shown
in Table 1. The patient was unable to concentrate her urine greater
than 250 mOsm at 6 hours even though her serum osmolarity
rose to 297 mOsm after 4 hours. This indicated that she had
diabetes insipidus rather than psychogenic polydipsia. She was
given 5 mcg of subcutaneous vasopressin and her urine osmolarity
rose to 349 mOsm. Although this did not fulfill the 50% increase
requirement, it did surpass the 15% requirement for partial
central DI. With the high pretest likelihood of central DI rather
than nephrogenic DI, it was felt that she had partial central DI.
Interestingly, the patient reported a complete resolution of her
symptoms of thirst following administration of vasopressin. In
addition, MRI revealed loss of the posterior hypophyseal bright
spot and thickening of the pituitary stalk consistent with central
DI. She was started on 10 mcg of nasal desmopressin twice daily
and discharged the next day with instructions to obtain outpatient
blood work to monitor her electrolytes in one week and follow
up with the endocrinologist in 2 weeks. A pituitary panel was
drawn during the hospital stay with the results to be followed by
her endocrinologist.
Case Reports
Table 1. Water deprivation test
Na (mmol/L)
Serum osmolarity (mOsm)
Urine osmolarity
* 5 mcg vasopressin administered at this time.
Idiopathic DI accounts for 30-50% of cases of central DI.2
Autoimmunity is thought to be an important cause of idiopathic
central DI. Pivonello et al. found that patients with idiopathic
central DI were significantly more likely than control patients to
display antibodies to arginine vasopressin-secreting cells. Age less
than 30, known autoimmune disease, and radiological evidence
of pituitary stalk thickening were all independent risk factors for
having a positive antibody assay. A patient with idiopathic DI and
all of these criteria has a 99% chance of having these antibodies.3
This patient had two of these parameters, which placed her at an
80% chance of having these autoimmune antibodies. While there
is no definitive proof that these antibodies are the cause of central
DI, this is a plausible explanation given our understanding of
To our knowledge, there are no known case reports of an
association between vaginal yeast infections or fluconazole and
central diabetes insipidus. The coincidental timing and likely
autoimmunity of this patient’s disease may suggest either the yeast
infection or fluconazole treatment as a possible trigger for the
disease. Although this represents only one case of central DI
following a vaginal yeast infection with fluconazole treatment,
further such reports might allow researchers to study and
understand this interesting disease.
1. Zerbe RL; Robertson GL A comparison of plasma vasopressin measurements with a
standard indirect test in the differential diagnosis of polyuria. N Engl J Med 1981
Dec 24;305(26):1539-46.
2. Makaryus AN. McFarlane SI. Diabetes insipidus: diagnosis and treatment of a
complex disease. Cleveland Clinic Journal of Medicine. 73(1):65-71, 2006 Jan
3. Pivonello R, De Bellis A, Faggiano A, Di Salle F, Petretta M, Di Somma C, Perrino S,
Altucci P, Bizzarro A, Bellastella A, Lombardi G, Colao A. Central diabetes insipidus
and autoimmunity: relationship between the occurrence of antibodies to arginine
vasopressin-secreting cells and clinical, immunological, and radiological features in a
large cohort of patients with central diabetes insipidus of known and unknown etiology.
4. J Clin Endocrinol Metab. 2003 Apr;88(4):1629-36.
17th Centery Pinjore
Reflecting Pool,
Pinjore, India
Photo courtesy of
Vaibhav Menendiratta, MD
Case Reports
Pamela Cines, MD
Case Presentation
A 44 year-old female with a past medical history significant only
for iron deficiency anemia and syncope presented to an outside
hospital with abdominal pain. The patient initially noted the pain
while shopping; she described it a sharp sensation, regionalized to
the right-epigastric region. When the pain recurred with greater
intensity an hour later now with resulting nausea and right-arm
radiation, she proceeded to her nearest ED.
Cardiac troponins are regulatory proteins controlling the
interaction between actin and myosin mediated by calcium. In
most normal subjects, cardiac troponins are completely
undetectable. Troponin levels will begin to rise in 4 to 6 hours
after an acute insult to cardiac tissue—usually related to lack of
blood flow—and will remain elevated for up to 10 days,
permitting late diagnosis.
Her medical history was significant for iron deficiency anemia,
which with she was diagnosed during pregnancy. She had a recent
hospitalization for syncope and reported positive cardiac enzymes,
however she had a normal cardiac stress test. Surgical history was
significant for an uncomplicated caesarian section. She reports
having no allergies to medicines and her only medications are a
daily aspirin and ibuprofen as needed. Social history was notable
only for a five pack-year history of smoking; she quit
approximately five years prior to admission.
In Western Medicine, and especially in Emergency Medicine, any
level of detectable troponin is typically regarded as the sine qua non
of an acute coronary syndrome. Indeed, according to the ACC/ESC
consensus document, “any amount of myocardial damage implies
an impaired clinical outcome for the patient” and that there is “no
discernible threshold below which an elevated value of cardiac
troponin would be deemed harmless. The ACC/AHA guidelines
do indicate that myocardial necrosis as reflected by elevated
troponin levels may not be due to coronary artery disease; and thus
a diagnosis of myocardial ischemia, or infarction, should be
supported by additional clinical and electrocardiographic evidence.
At the OSH, physical examination was reported to be
unremarkable. Her laboratory data showed a hemoglobin level of
9 g/dL, a normal chemistry panel and a troponin of 1.46 ng/mL.
EKG demonstrated normal sinus rhythm without any ischemic
changes. CT scan and ultrasound of her abdomen were performed
and were unrevealing. The patient was transferred to TJUH for
further evaluation of her troponin elevation.
On admission to TJUH, the patient was afebrile with a heart rate
of 58, a blood pressure of 96/31 mmHg without evidence of
orthostasis, respirations of 16, and oxygen saturation of 98% on
room air. She was oriented and in no distress. Physical exam was
pertinent for clear lungs on pulmonary auscultation; no jugular
venous distension, pedal edema, diminished pulses, or extra heart
sounds on cardiovascular examination; minimal tenderness in the
right upper quadrant, a well-healed caesarean section scar, but
otherwise a benign abdominal examination. Hemoccult
examination of the stool was negative. The EKG performed on
admission to TJUH again demonstrated normal sinus rhythm,
heart rate 55, without evidence of ST-T wave abnormalities.
Laboratory evaluation again showed a microcytic anemia with an
iron saturation of 4% and a troponin of 1.48 ng/mL.
Transthoracic echocardiogram demonstrated an ejection fraction
of 65% with no contraction abnormalities or evidence of valvular
disease. Cardiac catheterization was performed revealing no
evidence of occlusive coronary artery disease. Gastroenterology
consult was obtained for evaluation of her abdominal pain. The
patient underwent a right upper quadrant ultrasound and upper
endoscopy, both of which were normal.
The patient remained symptom-free throughout her three-day
hospitalization at TJUH, she was discharged to home in stable
condition. Curiously, her troponin level on day of discharge
remained elevated at 1.48 ng/mL.
While myocardial ischemia may imply elevated troponin levels,
the converse is not always true. Disease states such as sepsis, atrial
fibrillation, CHF exacerbation, pulmonary embolism,
myocarditis, myocardial contusion, and renal failure are also
associated with detectable troponin.
In 2002 Bakshi et al enrolled 21 consecutive patients with elevated
troponin who had either normal coronary angiography or stenosis
of less than 50% without complex features or thrombus. Among
the enrollees troponin elevations ranged from 0.21 to 54.79.
Following unrevealing angiography, patients were classified as to
the likely cause of their elevated troponin. Eleven of the 21 patients
had tachycardia, strenuous exercise, CHF, and pericarditis ascribed
to the cause of their elevated troponins. For the remaining 10
patients, however, no clear precipitating event could be identified.
More importantly, a study by Ng et al reviewed 1000 consecutive
patients presenting to a large, suburban hospital ED. One
hundred and twelve of these patients had elevated troponin levels,
but amazingly, 45% of them had a final diagnosis other than acute
coronary syndrome. These statistics suggest that measuring
troponin is a highly sensitive—but not a highly specific—test in
settings of a low pretest probability.
This case review will discuss the differential diagnoses of elevated
cardiac troponin when acute coronary syndrome has been excluded.
1. Demand ischemia refers to a mismatch between myocardial
oxygen demand and supply. Myocardial oxygen demand
increases in the setting of tachycardia, increased afterload,
systemic inflammatory response syndrome (SIRS), sepsis, and
septic shock. Decreased oxygen delivery can occur in tachycardia,
hypotension, and hypovolemia. Each of these conditions is either
Case Reports
caused by, or leads to, tachycardia, a situation in which
myocardial oxygen demand increases and supply decreases. In
tachycardia the myocardium requires more oxygen to maintain
its increased contractile rate; however, diastolic time also
shortens, which has a net effect of limiting blood flow to the
coronary arteries, thereby limiting oxygen supply. In the case of
hypovolemia or hypotension, there is reduced perfusion pressure
during systole, also leading to decreased oxygen supply to the
myocardium. This set of circumstances can result in the release
of cardiac troponin into circulation.
2. Sepsis is another clinical situation in which physicians often
detect elevations of cardiac troponin. Amman et al studied 20
septic ICU patients, 17 of whom were noted to have elevated
troponin levels. Troponin measurements ranged from 0.17 to
15.4. Ten of these patients had no history of coronary artery
disease (CAD). Of the five patients who subsequently expired,
eighty percent had no demonstrable CAD on post mortem.
This study suggests that elevations of cardiac troponin in the
setting of sepsis is not uncommon, and may occur in patients
who otherwise show no evidence of CAD. The mechanism of
troponin release in the setting of sepsis has not been completely
elucidated. Endotoxin release from gram-negative organisms
has been shown to lead to ventricular dilatation and myocardial
depression. However, in Amman’s study the majority of patients
had gram-positive sepsis. It has been postulated that troponin
release in sepsis may be due to increased membrane
permeability. One possibility is that cytokines and interleukins
released during sepsis cause the degradation of troponin to
smaller, low molecular weight forms which are release through
a more permeable membrane.
3. Left ventricular hypertrophy is also on the differential for
elevated troponin. Hamwi et al measured troponin levels in
207 consecutive patients referred for echocardiogram. After
excluding 124 on the basis of acute coronary syndrome and 29
on the basis of suboptimal echocardiogram, Hamwi’s group
determined that 8 of 74 patients had troponins out of the
normal range. These 8 patients had a significantly higher mean
left ventricular mass as compared to those with normal
troponin levels. One hypothesis proposed in the article
suggested that increased muscle mass would invariably result in
increased oxygen demands. Furthermore, the increased muscle
mass would potentially lead to decreased flow reserve secondary
to “remodeled coronary microcirculation.” Although
intriguing, this article represents, at best, a correlation between
enlarged muscle mass and troponin elevation, and is far from a
rigorous proof of causality. Indeed, as Hamwi’s group itself
concludes, “[w]hether patients with combined troponin-I
elevation and LV hypertrophy represent a subgroup with a
higher risk of adverse cardiovascular outcome needs to be
further determined.”
4. Myocardial strain results when the myocardium is subjected to
volume or pressure overload as in the case of congestive heart
failure, damage to myofibrils may occur. A correlation has been
demonstrated between elevated troponin and BNP levels in this
setting as well as between myocardial stretch and apoptosis.
Increased wall stress may also lead to decreased subendothelial
perfusion, resulting in troponin release and decreased left
ventricular function. Elevation of troponin tends to be
associated with worse outcomes. In chronic heart failure,
activation the sympathetic nervous system and inflammatory
cytokines by the renin-angiotensin system may lead to myocyte
injury and death, thus explaining elevated troponin levels in this
setting. It is worth noting that troponin elevation is evident in
up to 50% of people with a diagnosis of acute pulmonary
embolism. Although not useful for diagnosis, the presence of an
elevated troponin level in the setting of pulmonary embolism
does portend a worse prognosis, as it suggests a significant clot
burden against which the heart is unable to pump.
5. Other causes include vasospasm, trauma, pericarditis,
myocarditis and renal failure. Vasospasm, or Prinzmetal’s
angina, can produce prolonged periods of ischemia, leading to
the release of troponin in the absence of myocardial necrosis.
Similarly, vasospasm has been offered as a possible explanation
for elevated troponin in normal subjects following extended
periods of exercise. Troponin rise has also been documented in
cases of ischemic strokes and subarachnoid hemorrhage.
Additionally, troponin is released in a significant number of
people who incur blunt thoracic trauma. Hasdamir et al
measured cardiac troponins in 35 patients who were
hospitalized following ICD shocks. They demonstrated that
troponin levels are elevated in the majority of patients who
receive multiple shocks from their ICD, but only a small
percentage of the elevations are due to an acute coronary
syndrome. Elevation of troponin can also be seen in acute
pericarditis and myocarditis as well as chronic renal failure.
In this patient none of the aforementioned causes could sufficiently
explain her persistent elevation of troponin. It is clear, though, that
given the multiple potential causes of troponin elevations outside
of acute coronary syndrome, an individual’s clinical presentation
needs to considered thoroughly before patients are subjected to
expensive—and potentially risky—diagnostic studies.
Jeremias A, Gibson MC. Narrative review: alternative causes for elevated cardiac troponin levels when
acute coronary syndromes are excluded. Annals of Internal Medicine 2005; 142: 786-791.
Bakshi TK, Choo MK, Edwards CC et al. Causes of elevated troponin I with a normal coronary
angiogram. Internal Medicine Journal 2002; 32:520.
Ammann P, Fehr T, Minder EI et al. Elevation of troponin I in sepsis and septic shock. Intensive Care
Medicine 2001; 27: 965-969.
Hamwi, SM, Sharma, AK, Weissman, NJ et al. Troponin-I elevation in patients with increased left
ventricular mass. American Journal of Cardiology 2003; 92:88-90.
Ng SM, Krishnaswamy P, Morrisey R, et al. Mitigation of the clinical significance of spurious elevations
of cardiac troponin I in settings of coronary ischemia using serial testing of multiple cardiac markers.
American Journal of Cardiology 2001; 87:994-999.
Case Reports
Sivakumar Srinivasan, MD, and Sandeep Anreddy, MD
Case Presentation
A 56 year-old male with past medical history
significant for diabetes and obesity presented for
an elective diagnostic cardiac catheterization.
The catheterization films are shown below
(Figures 1 and 2).
Adult coronary anomalies are not very common
and are usually casual findings of diagnostic
angiographic studies. The incidence of these
anomalies has been reported to be between 0.291.34%. Although coronary artery anomalies are
far less common than acquired coronary artery
Figure 1.
disease, their impact on premature cardiac
morbidity and mortality among young adults is
not trivial. In a study of 126 nontraumatic sudden deaths in
young adults, cardiac abnormality was found in 64 cases(51%),
with coronary artery abnormalities being the most common
cardiac abnormality(61%).
Coronary artery anomalies can be classified as hemodynamically
significant or insignificant. Hemodynamically significant
anomalies of the coronary arteries are characterized by
abnormalities of myocardial perfusion, which lead to an increased
risk of myocardial ischemia or sudden death. These anomalies
include an anomalous origin of either the LCA or the RCA from
the pulmonary artery, an anomalous course between the
pulmonary artery and the aorta (interarterial) of either the RCA
arising from the left sinus of valsalva or the LCA arising from the
right sinus of valsalva, occasional myocardial bridging, and
congenital coronary artery fisula.
Anomalous origin of the coronary artery from the pulmonary
artery (ALCAPA) is one of the most serious congenital coronary
artery anomalies. It has an estimated prevalence of one in 300,000
live births. Most affected patients show symptoms in infancy and
early childhood. Approximately 90%of untreated infants die in
the 1st year of life, and only a few patients survive to adulthood.
In the most common form of this disease, the LCA arises from
the pulmonary artery and the RCA arises normally from the aorta
(Bland-White-Garland syndrome).
The four recognized patterns of an anomalous origin of a coronary
artery from the opposite or noncoronary sinus are (a) the RCA
arising from the left coronary sinus, (b) the LCA arising from the
right coronary sinus, (c) the LCx or LAD artery arising from the
right coronary sinus, and (d) the LCA or RCA (or a branch of either
artery) arising from the noncoronary sinus. A coronary artery arising
from the opposite or noncoronary sinus can take any of four
common courses, depending on the anatomic relationship of the
anomalous vessel to the aorta and the pulmonary trunk:
(a)interarterial (ie, between the aorta and the pulmonary artery),
Figure 2.
(b) retroaortic, (c) prepulmonic, or (d) septal (subpulmonic). It is of
great clinical importance which course is taken, an interarterial
course carries a high risk for sudden cardiac death. The most
common course of an anomalous RCA arising from the left sinus of
Valsalva is interarterial; this variant can be associated with sudden
cardiac death in up to 30% of patients. It has been postulated that,
when dilation of the aorta occurs during exercise, the anomalous
slit-like ostium for the RCA in the left sinus becomes narrower,
possibly limiting coronary blood flow and resulting in myocardial
infarction. The LCA arises from the right sinus of valsalva in
0.09%–0.11% of patients who undergo angiography, an interarterial
course may be seen in up to 75% of patients with this anomaly.
Anomalous origin of the Left circumflex artery (LCx) from the
proximal right coronary artery (RCA) is one of the most common
forms of coronary artery anomalies. It has been reported in
0.17%-0.4% of patients undergoing coronary angiography. In
almost all cases where the LCx arises from the proximal RCA the
course is retroaortic. Results from the coronary artery surgery
study showed that anomalous circumflex coronary arteries had a
significant greater degree of stenosis when compared to nonanomalous arteries (p=0.02) though there was no significant
difference in survival by location or degree of stenosis in the
anomalous artery at 7 years.
1. Wilkins CE, Betancourt B, Mathur VS, et al. Coronary artery anomalies: A review of
more than 10,000 patients from the Clayton Cardiovascular Laboratories. Tex Heart
Inst J 1988; 15:166–173.
2. Yamanaka O, Hobbs RE. Coronary artery anomalies in 126,595 patients undergoing
coronary arteriography. Cathet Cardiovascular Diagn 1990;21:28–40.
3. Eckart RE, Scoville SL, Campbell CL, et al. Sudden death in young adults: a 25-year
review of autopsies in military recruits. Ann Intern Med 2004; 141:829–834.
4. Reagan K, Boxt LM, Katz J. Introduction to coronary arteriography. Radiol Clin
North Am 1994; 32:419–433.
5. So Yeon Kim, Joon Beom Seo et al. Coronary Artery Anomalies: Classification and
ECG-gated Multi–Detector Row CT Findings with Angiographic Correlation.
RadioGraphics, Mar 2006; 26: 317 - 333
Cover Art : A Montage of International Experience
Eric Choi, MD, Michael Manolas, MD, Vaibhav Mehendiratta, MD, Andrew Rose, MD
Scott Fertels, MD
Ryan Madanick, MD
David Brandt, MD
Matthew Smith, MD
Candido Rivera, MD
Jackeline Iacovella, MD
Barry Ziring, MD
Qingping Wang, MD
Christina Michael, MD
Michael Steinberg, MD
Susan P. Abraham, MD
We would like to sincerely thank those who made donations towards the
publication of the Jefferson Forum. Without your support, it would be
impossible to produce our journal; we dedicate our efforts to yours.
Thank you to Lisa Graf for her patience and expertise in the graphic design
of The Forum.
JG 07.1934
Advanced Medicine.
Superior Care.™

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