Forensic Science International 194 (2010) e21e24

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Forensic Science International

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Case report

CardiomyopathiesMisdiagnosed as Sudden Infant Death Syndrome (SIDS)

R.B. Dettmeyer a,*, R. Kandolf b
a
Institute of Forensic Medicine, University of Giessen, Frankfurter Str. 58, D-35392 Giessen, Germany
b
Department of Molecular Pathology, Institute of Pathology, University Hospital of Tubingen, Liebermeisterstr. 8, D-72076 Tubingen, Germany

A R T I C L E I N F O A B S T R A C T

Article history: Cardiomyopathies are an important and heterogenous group of diseases. With the identication of
Received 6 May 2009 several new disease entities over the past decade, advances in diagnosis and precise causation, some
Received in revised form 30 July 2009 disease denitions have become outdated. The past decade has witnessed a rapid evolution of molecular
Accepted 12 October 2009
genetics in cardiology, e.g. myocardial diseases (Hypertrophic cardiomyopathyHCM, Arrhythmogenic
right ventricular cardiomyopathyARVCM) and channelopathies (Long QT syndromeLQTS, Brugada
Keywords: syndromeBrS, Catecholaminergic Polymorphic Ventricular TachycardiaCPVT and Short QT syn-
Inammatory cardiomyopathy
dromeSQTS) as diseases predisposing to potentially lethal ventricular tachyarrhythmias. Beside the
Left ventricular non-compaction
cardiomyopathy (LVNC)
detection of mutations in several genes, histological and immunohistochemical ndings can point to a
Hypertrophic cardiomyopathy cardiomyopathy as underlying disease. Therefore, previous microscopical investigations of different
Sudden Infant Death Syndrome (SIDS) parts of the myocardium can help to select those cases of suspected Sudden Infant Death Syndrome
(SIDS), where a search for genetic mutations can lead to a diagnosis explaining the sudden and
unexpected death.
2009 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Previous studies revealed cases of virus-induced myocarditis,
misdiagnosed as Sudden Infant Death Syndrome (SIDS) [17]. Such
cases include those with signs of inammation and intramyo-
cardial persistence of cardiotropic viruses, regarded as chronic
myocarditis or cardiomyopathy, inammatory typeaccording to
recently published contemporary denitions and classications of
the cardiomyopathies [8]. Nevertheless, morphological ndings
using histological and immunohistochemical methods can help to
nd out different forms of cardiomyopathies in cases of suspected
SIDS, cardiomyopathies which are known to cause sudden death in
infants, e.g. histiocytoid cardiomyopathy [915]. Also genetic
cardiomyopathies can be identied, if there is an irregular
arrangement of myocardial bers or, e.g. typical signs of left
ventricular non-compaction cardiomyopathy (LVNC) like deep
trabeculations [1623].
2. Case reports
Out of a series of suspected SIDS-cases category IB SIDS and
category II SIDS according a classication published 2004 [24]
without macroscopic abnormalities, postmortem tissue samples
* Corresponding author. Tel.: +49 0 641 99 41410; fax: +49 0 641 99 41419.
E-mail address: reinhard.dettmeyer@forens.med.uni-giessen.de
(R.B. Dettmeyer).
from the heart were obtained from dened locations and
routine histology as well as immunohistochemical investigations
were done.
Eight myocardium samples were taken from the anterior and
posterior part of the right ventricle, two specimens from the
septum interventriculare and the left ventricle, anterior and
posterior wall. All samples had been xed in neutral buffered
formaldehyde (pH 7.0) for a maximum of 48 h. Samples from all
internal organs were investigated with conventional stainings.
A report is given on microscopic ndings in the myocardium of
three cases, pointing to different forms of cardiomyopathies.
2.1. Case No. 1
A 4-month-old male baby was found lifeless in his bed after a
longer sleeping period. Circumstances as far as claried lead to
the opinion of the emergency doctor, that this case should be
attributed to the Sudden Infant Death Syndrome (SIDS). Autopsy
revealed some petechiae subpleural, subepicardial and under the
capsule of the thymus, but no pathological ndings explaining the
sudden death. Histological investigations showed a severe inter-
stitial and especially perivascular brosis (Fig. 1a), together with a
moderate increased number of interstitial cells (Fig. 1b). The
methods applied for immunohistochemistry stainings have been
described in detail elsewhere [4] and the following antibodies were
used: LCA, clones 2B11, PD7/26; CD45R0; CD68, clone PG-M1,
mABs; HLA-DP, DQ, DR, clone CR3/43; CD62E, clone 1.2B6; DAKO
Ltd.). Immunohistochemical stainings from heart tissue samples

0379-0738/$ see front matter 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.forsciint.2009.10.010
e22 R.B. Dettmeyer, R. Kandolf / Forensic Science International 194 (2010) e21e24

epicardial fat tissue and the myocardium (Fig. 1c). Additionally,

molecularpathological investigations, as described elsewhere
[3,4], could demonstrate an infection with enteroviruses, here
coxsackievirus type B3 (CVB3), a virus type which is known to be
cardiotropic. Therefore a cardiomyopathy inammatory type
was diagnosable as cause of death.

2.2. Case No. 2

An 11-month-old female baby was found lifeless by her mother

on the back seat of the car, shortly after having started to sleep.
Resuscitation failed and the emergency doctor regarded the sudden
death of the baby as Sudden Infant Death Syndrome (SIDS). Only
because of a medical history with psychiatric disorders concerning
the mother, the informed prosecuting attorney decided to initiate a
forensic autopsy. This autopsy macroscopically revealed no
pathological ndings, especially the physicians did not describe
deep trabeculations of the myocardium, which are difcult to
identify in a small heart by macroscopy. Tissue samples were taken
for routine histology including samples from the myocardium from
different locations. Histological investigations showed deep trabe-
culations (Fig. 2a) with a spongiform myocardium (Fig. 2b) and
partly an irregular arrangement of myocardial bers in samples from
the left ventricular anterior wall. The deep trabeculations presented
a CD34-positive endothelium. These typical ndings lead to the
diagnosis of a left ventricular non-compaction cardiomyopathy
(LVNC) as cause of sudden death.

Fig. 1. Case No. 1male, 4 months, Cardiomyopathyinammatory type. (a)

Diffuse severe perivascular brosis in the myocardium (EvG, 100). (b) Edema and
moderate increase of myocardial interstitial cells (H&E, 200). (c) Diffuse and
focal inltration of CD68+-macrophages in subepicardial fat tissue and the
myocardium (200).

did not demonstrate an increased number of LCA+-leucocytes,

CD45R0+-T-lymphocytes and CD68+-macrophages within the
myocardium. An enhanced expression of MHC-class-II molecules
was found in the endothelium of myocardial vessels as well as an
expression of E-selectine. LCA+-leucocytes, CD45R0+-T-lympho-
cytes and CD68+-macrophages were counted (20 high power
eldsHPF; magnication 400) and were found in diffuse
distribution patterns. The mean values were not suspicious for
acute myocarditis according to our experience [3]: 9.8 LCA+-
leucocytes, 4.8 CD68+-macrophages and 2.6 CD45R0+-T-lympho- Fig. 2. Case No. 2female, 11 months, left ventricular non-compaction
cytes per high power eld (HPF; 400), although there were cardiomyopathy (LVNC). (a) Deep trabeculation (EvG, 100). (b) Spongy
regions with inltrations of CD68+-macrophages including sub- myocardium with CD34+-endothelium (100) in the left ventricular anterior wall.
 R.B. Dettmeyer, R. Kandolf / Forensic Science International 194 (2010) e21e24
Fig. 3. Case No. 3irregular arrangement of myocardial bers in the left ventricular
anterior wall (H&E, 100).
2.3. Case No. 3
A 6-month-old male baby was found lifeless in a prone
position in the early morning, already presenting livores and
rigor. Autopsy revealed no pathological ndings. Histological
investigations demonstrate an irregular arrangement of myo-
cardial bers (myocardial disarray) outside the interventricular
septum in parts of the left ventricular anterior wall (Fig. 3). The
myocardial bers present y-like formations and differences in
the size of the myocardial bers and nuclei (myocyte
hypertrophy), partly a moderate increased interstitial brosis
was found. As far as ascertainable, these ndings did not involve
the conduction system of the heart. Therefore, the initial phase
of a developing primary Hypertrophic cardiomyopathy was
diagnosed, although there were other regions in the myocar-
dium devoid of these changes.
3. Discussion
Although sudden cardiac death usually happens in older
people, 510% of the affected individuals are young and
apparently healthy. Sudden death in infants is relatively rare,
but up to 7000 asymptomatic children die in the USA each year,
almost half of them without any warning signs of symptoms [25].
Sudden cardiac death is one of the most common causes of death,
especially in the young. Macro- and micromorphological changes
are described concerning adults and children and can lead to the
diagnosis cardiomyopathy. Cardiomyopathies are myocardial
diseases associated with cardiac dysfunction. Concerning cardi-
omyopathies, a familial type of disease with autosomal dominant
inheritance predominates, and mutations in sarcomeric contrac-
tile machinery genes are regarded as the causative factors [26].
Obstructive and non-obstructive hypertrophic cardiomyopathies
are primary diseases of the myocardium, and are characterized by
left and/or right ventricular hypertrophy, may be septal, apical, or
may involve the midventricular wall [27]. In cases of suspected
Sudden Infant Death Syndrome (SIDS), these hypertrophies
usually cannot be identied macroscopically by autopsy. Addi-
tional histological and immunohistochemical investigations can
lead to the diagnosis or help to nd out cases, which should be
investigated genetically. The role of genetic factors in the
pathogenesis of cardiomyopathies has received growing attention
during the past 15 years [25,28]. The presented cases must be
regarded as cardiomyopathyinammatory type (Case No. 1), left
ventricular non-compaction cardiomyopathy (LVNC) (Case No. 2)
according to recent classications of cardiomyopathies from the
United States and Europe [8,29] and also the third case (Case No. 3)
e23
with irregular arrangement of muscular bers points to a genetic
primary cardiomyopathy. Cardiomyopathy, inammatory type, is
characterized by a moderate increased number of inltrating
lymphocytes and macrophages together with interstitial and
perivascular brosis, ndings which are very unusual in babies.
Demonstration of viral genome in myocardial samples is possible
in some cases, here coxackievirus type B3 was found, which is
known as cardiotropic virus.
Left ventricular non-compaction cardiomyopathy (LVNC) also
called spongy myocardium, spongiform cardiomyopathy or
left ventricular hypertrabeculation is a cardiomyopathy
characterized anatomically by deep trabeculations in the ven-
tricular wall, with dene recesses communicating with the main
ventricular chamber. Major clinical correlates include systolic and
diastolic dysfunction, associated at times with arrhythmias and
systemic embolic events. The frequency is not well known. While
the annual incidence of unclassied cardiomyopathies among
children 010 years of age is 0.17 per 100,000 children, LVNC in
this age group can be expected as 0.12 per 100,000. Mechanisms
leading to LVNC are unclear. A genetic basis is generally suggested
and there is evidence for a role of mutations of the following genes:
G4.5, located on Xq28initially described in patients with Barth
Syndrome [23,30,31], alpha-dystrobrevinan autosomal gene rst
identied in a Japanese family with six members affected by LVNC
[24], FRKBP12a gene modulating the release of calcium from the
sarcoplasmic reticulum by the ryanodine receptor 2, deletions in
FKBP12 in mice lead to a feature of non-compaction and congenital
heart defects [30], Lamin A/C (LMNA)mutations have been
reported concerning patients with dilated cardiomyopathy, one
was reported to have features of LVNC [32], 11p15this locus was
suggested by genome-wide linkage analysis in one family with
autosomal dominant LVNC [33].
There is no doubt, that genetic cardiomyopathies play an
important role also in sudden deaths of infants [3436], therefore
histological and immunohistochemical ndings are of great
importance to nd out cases which should be investigated either
by molecularpathological methods to detect viral genome within
the myocardium and leading to inammatory cardiomyopathy
and/or to initiate genetic investigations to clarify, whether a
primary cardiomyopathy can be regarded as possible cause of
death [37]. Histopathological hallmarks can be myocyte hyper-
trophy, myocardial disarray, increased interstitial brosis, deep
trabeculations with CD34+-endothelium and a spongy myocar-
dium as well as small vessel disease or arterial dysplasia [38].
Beside the cases of virus-induced myocarditis [38], more effort
should be taken into further research to nd out the incidence of
genetic cardiomyopathies in cases of suspected Sudden Infant
Death Syndrome (SIDS) as well as in cases of older children, dieing
suddenly and presenting morphological ndings pointing to a
primary genetic cardiomyopathy [36]. Nevertheless, up to now the
frequency of primary arrythmogenic disorders misdiagnosed as
Sudden Infant Death Syndrome (SIDS) is unknown.
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