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1. The negative autopsy:
Sudden cardiac death or other?
Stephen D. Cohlea,
*, Barbara A. Sampsonb
a
Spectrum Health-Blodgett Campus, MC 444, 1840 Wealthy Street, Southeast, Grand Rapids, MI 49506, USA
b
Office of the Chief Medical Examiner of the City of New York, New York, NY 10016, USA
Received 31 July 2001; accepted 2 August 2001
Abstract
One of the most frustrating challenges faced by the forensic pathologist is the inability to determine the cause of death in a young person
previously thought healthy. The four steps in the investigation of a sudden death include obtaining the history and scene information,
performing a gross and microscopic autopsy, performing appropriate laboratory tests, and making the diagnosis. When examining the heart
grossly it is important to preserve the anatomic landmarks, section the coronary arteries closely, and recognize lethal abnormalities such as
anomalous origin of the coronary arteries. Specimens useful for toxicologic analysis include whole blood, serum, vitreous humor, gastric
contents, bile, urine a purple top tube of blood, and frozen myocardium and spleen. Lethal cardiac diseases with minimal or no anatomic
findings include Brugada and Garg’s syndromes, the long QT syndrome, and Wolff–Parkinson–White (WPW) syndrome. Consultation with
other experts, including cardiac pathologists, cardiologists, electrophysiologists, and molecular biologists, may be helpful in determining a
cause of death. D 2001 Elsevier Science Inc. All rights reserved.
Keywords: Death sudden; Pathology; Long QT syndrome; Wolff–Parkinson–White syndrome
1. Introduction
Few challenges in the practice of forensic pathology
are so frustrating as the failure to determine a cause of
death, particularly in a previously healthy young person
who has died suddenly and unexpectedly. We define
sudden unexpected death as death within 6 hours of
symptoms (e.g., syncope or chest pain) in a person
thought to be previously healthy. In a typical medical
examiner practice, approximately 50% of the deaths are
natural, 5–10% are unexplained after a gross autopsy, and
1–5% are negative after completion of the gross and
microscopic autopsy and other laboratory tests [1]. Upon
determination that an autopsy is grossly negative, the
forensic pathologist should review the history and labor-
atory tests to determine whether additional history needs
to be obtained or studies need to be performed. Because
some subtle causes of sudden, unexpected natural death
may be hereditary, a special effort to determine the cause
of death is necessary to prevent death in relatives. It is
also important to make a maximal effort to determine
cause of death in order to assist the relatives of the
deceased to deal with the death and proceed with the
grieving process.
2. The approach to the investigation of sudden
unexpected death
There are four steps in death investigation: (1) history
and scene examination, (2) autopsy (gross and microscopic),
(3) laboratory tests, and (4) making the diagnosis.
3. History and scene investigation
It is important to determine a history of syncopal epi-
sodes, chest pain, dizziness, prior electrocardiograms
(whether positive or negative), a family history of sudden
death/lethal heart disease, a history of allergies, epilepsy,
and diabetes mellitus. In some cases, such a review may
1054-8807/01/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved.
PII: S1054-8807(01)00093-X
* Corresponding author. Tel.: +1-616-774-7499; fax: +1-616-774-
5280.
E-mail address: sdcohle@aol.com (S.D. Cohle).
Cardiovascular Pathology 10 (2001) 219–222
2. provide the cause of death, for example, an electrocardio-
gram indicating a potentially fatal disease such as long QT
syndrome or Wolff–Parkinson–White (WPW) disease.
Even if a specific cause of death is not elicited from the
history, at least symptoms such as described above may be a
strong indicator of a cardiac cause of death. In cases of
noncardiac sudden death, a history of allergies, epilepsy, or
diabetes may be critical in determining cause of death. The
scene investigation is frequently the best way to separate
cardiac from noncardiac causes of death. Important aspects
of the scene investigation include determining the presence
of cardiac medications, illicit drugs, asthma inhalers, and
prescriptions. Clothing should also be searched for drugs. It
is important to note the position of the body when first
found since positional asphyxia (such as the hyperflexion of
the neck from collapse in the corner of a room) may leave
no anatomic findings. Suffocation by the placing of a plastic
bag over the head can cause asphyxia in the absence of
anatomic findings.
A specific description of the events immediately preced-
ing death may indicate a death of cardiac origin. The
activities of the deceased at the time of collapse may suggest
sudden cardiac death. Those that often precede sudden
cardiac death include exercise, emotional stress, sleep (par-
ticularly collapse during a nightmare), and a game or
altercation in which the victim received a blow to the chest
(commotio cordis) [2]. Such deaths may be accidents or
homicides. The initial heart rhythm after the person is
discovered unresponsive may be helpful in the investigation.
Detailed investigation of deaths that occur at work are
particularly important because of insurance implications.
Detecting workplace hazards, such as the potential for
low-voltage electrocution or asphyxia (positional or by
noxious gases) may reward the investigator with a cause
of death.
4. The autopsy
On the external examination of the autopsy, it is particu-
larly important to examine the body for needle punctures or
needle track scars (suggestive of intravenous drug abuse)
and therapeutic transdermal patches, such as for nitrogly-
cerin and fentanyl. In a low-voltage electrocution, the soles
of the feet or the clothing may have electrical burns that can
easily be missed.
When examining the heart, the coronary arteries should
be sectioned every 2–3 mm. It is generally not necessary to
fix the heart first. If the coronary arteries are severely
calcified, decalcification before sectioning may simplify
the identification of narrowed areas. Severe atherosclerotic
narrowing or coronary dissection may be very focal and can
be missed if the vessels are not sectioned sufficiently
closely. Examine both ends of the cut vessel. Histologically
normal myocardium may contain infarct that is too early to
detect or may be free of infarct. In the latter case, ischemia
from the coronary artery narrowing may be the source of the
lethal arrhythmia.
When the base of the heart is opened along the direction
of flow, preserve the landmarks. An incision connecting
the inferior and superior vena cavae may distort such
important internal landmarks as the crista terminalis.
Instead, when opening the right atrium, make a separate
incision parallel to the right atrioventricular groove, ter-
minating in the right atrial appendage. Similarly, the
pulmonary veins should be left intact with a separate cut
in the posterior inferior left atrium terminating in the left
atrial appendage.
If the gross autopsy is negative, save the entire heart
other than the initial microscopic sections of the myocar-
dium. The following coronary artery anomalies may not be
recognized as being lethal but in fact may provide the
cause of death with an otherwise negative autopsy/drug
screen: anomalous coronary arteries (for example, origin of
the left coronary artery from the right sinus of Valsalva,
the right coronary artery from the left sinus of Valsalva,
etc., a slit-like take off of the coronary artery, an origin of
the coronary artery from a pulmonary artery) [3]. Similarly,
ostial stenosis may result either from aortitis, a congen-
itally narrowed coronary ostium, or atherosclerosis, and
this may be the only site of narrowing in the coronary
system [3]. Coronary artery bridging, an extremely com-
mon finding at autopsy, is seldom fatal, and the cause of
death should not be attributed to this in the vast majority
of cases [3].
On examining the myocardium, it is our opinion that a
minimum of 10 sections of working myocardium, including
the left and right both ventricles and interventricular septum,
be studied if the autopsy is otherwise negative. Myocarditis
or sarcoidosis can be extremely focal. Examination of the
cardiac conducting tissue occasionally yields a cause of
death. In a recent study of the cardiac conduction system in
100 otherwise negative deaths, we [4] found AV node
tumors and fibromuscular hyperplasia of the atrioventricular
node artery in 11 cases and fibrosis of the AV node in an
infant whose mother had systemic lupus erythematosus in
one case. A knowledge of the normal variations in the
cardiac conduction tissue is important in order to avoid
mistakenly attributing a cause of death to a variation of
normal [5].
5. Laboratory tests
A comprehensive drug screen should be performed on
every case of sudden, unexpected death, especially those
without significant anatomic findings. However, although a
‘‘comprehensive’’ drug screen should include most pre-
scribed and illicit drugs, it cannot detect every lethal drug
or toxin. For example, digoxin, thioxanthenes, insulin,
volatiles (e.g., Freon, toluene), etc. are not detected on most
routine drug screens. In addition, heavy metals such as
S.D. Cohle, B.A. Sampson / Cardiovascular Pathology 10 (2001) 219–222
220
3. arsenic, thallium, lead, and mercury must be tested for
separately. It is important to remember that with carbon
monoxide and cyanide poisoning not everyone shows the
classic cherry red discoloration.
Tryptase is useful to detect anaphylactic reactions [6]
since it is released when mast cells degranulate. If a specific
allergen is elevated, venom-specific IgE antibodies may be
detected as well. The most common substances causing
anaphylaxis are food, drugs, and insect stings [7]. The
vitreous humor glucose, electrolytes, and ketones should
be assayed.
6. Making the diagnosis
Specimens that can be useful for additional study if
necessary include whole blood, serum, vitreous humor,
gastric contents (at least a representative sample of 50–
100 ml), bile, portions of organs such as liver, urine, a purple
top tube of blood, and frozen myocardium and spleen.
Causes of cardiac death with minimal or negative find-
ings include commotio cordis, cardiac conduction abnor-
malities, and coronary artery spasm. Noncardiac causes of
death with negative or minimal autopsy findings include
anaphylactic reactions, drug overdosage, sniffing or huffing
(inhaling aerosols sprayed into a paper bag) of volatile
substances, low voltage electrocution, drowning, epilepsy,
asphyxia (some cases), diabetic ketoacidosis [8], and rarely,
hyperinsulinemia causing profound hypoglycemia [9]
(Tables 1 and 2).
There are several electrocardiographic abnormalities that
may cause ventricular fibrillation in anatomically normal
hearts. The Brugada syndrome is characterized by right
bundle branch and ST elevations in V1–V3 [10]. Garg et al.
[11] has described terminal QRS deflection (termed the J
wave) in the inferior leads in patients with a history of
idiopathic ventricular fibrillation and a family history of
sudden death at a young age. The long QT syndrome has
been recognized for years as having a high incidence of
ventricular fibrillation. The WPW syndrome, characterized
as a short PR interval with a characteristic Delta wave on
the electrocardiogram, also may be complicated by vent-
ricular fibrillation. Although WPW is caused by anomalous
atrioventricular connections [12], these are extremely dif-
ficult to find.
7. Conclusion
Chugh et al. [13] recently showed the utility of an in-
depth investigation in cases with a negative autopsy. In a
study of sudden cardiac death covering a 13-year period
involving 270 hearts, they identified 14 cases in which the
heart was structurally normal. Analysis of these cases
revealed two cases of preexcitation (WPW syndrome), one
case with atrial fibrillation with a rapid ventricular response,
two with a history of seizures, two morbidly obese patients,
and benzoyl ecgonine (the major metabolite of cocaine) in
one case. In addition, one patient had a family history of
sudden death and six had had antemortem symptoms
suggestive of heart disease including syncope, palpitations,
and chest pain.
If after initial studies the death remains unexplained,
reinterviewing the family may reveal useful information not
discovered in the initial investigation. Consultation with
other experts, including cardiac pathologists, cardiologists,
electrophysiologists, and molecular biologists may be use-
ful. In particular, when anticipating the need for genetic/
molecular studies in the case of a negative autopsy, it is
advisable to save a purple top tube of blood and to freeze a
sample of myocardium and sample of spleen.
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Table 1
Noncardiac causes of death with minimal findings
Anaphylaxis
Drug overdose
Inhalation of volatiles
Low-voltage electrocution
Drowning
Epilepsy
Asphyxia (especially positional)
Diabetic ketoacidosis
Asthma
Table 2
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Commotio cordis
Coronary artery spasm
Cardiac conduction abnormalities
Long QT syndrome
Brugada syndrome
Garg syndrome
WPW syndrome
Certain types of hypertrophic cardiomyopathy
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