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Cardiac pathology in status epilepticus.

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Cardiac Pathology in
Status Epilepticus
Edward M. Manno, MD,1 Eric A. Pfeifer, MD,2
Gregory D. Cascino, MD,1 Katherine H. Noe, MD,1
and Eelco F. M. Wijdicks, MD1
Massive catecholamine release resulting in the formation
of cardiac contraction bands may represent the cause of
death in status epilepticus (SE). We reviewed the cardiac
pathology of patients who died during SE to asses for
contraction bands. Eight of 11 patients who died during
SE had identifiable myocardial contraction bands compared with 5 of 22 control patients (p < 0.05, Fisher’s
exact t test). These findings delineate a pathological substrate and provide compelling evidence that excessive catecholamine release is the mechanism responsible for
death in SE.
Ann Neurol 2005;58:954 –957
Status epilepticus (SE) is an emergency associated with
significant morbidity and mortality.1 Death secondary
to SE is primarily due to cardiac decompensation, although the exact mechanism as to how this occurs is
unknown.2 It has been proposed that patients die in
SE due to cardiac dysrhythmias and global decompensation attributed to excessive endogenous epinephrine
release.3,4 Cardiac contraction band necrosis (CBN) is
a marker for this phenomenon.5,6 This study is an attempt to examine and quantify the amount of cardiac
damage that occurs in patients who die in SE. The
purpose of this is to determine whether patients with
SE have a significantly greater rate of CBN than a control population.
Subjects and Methods
Medical records from the Mayo Foundation (Rochester,
MN) identified 54 patients between January 1975 and December 2003 who were coded for SE (Hospital Adaptation
of the International Classification of Diseases [HICDA] code
3452-21) and either had full autopsy reports (HICDA code
7969-14-1) or were obtained by direct comparison with lists
obtained from the Department of Pathology. Medical and
From the Departments of 1Neurology and 2Pathology, Mayo Clinic
College of Medicine, Rochester, MN.
Received Apr 21, 2005, and in revised form Aug 16. Accepted for
publication Aug 23, 2005.
Published online Oct 20, 2005 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20677
Address correspondence to Dr Manno, Mayo Clinic College of
Medicine, Division of Critical Care Neurology, Department of
Neurology, W8B, 200 First Street SW, Rochester, MN 55905.
E-mail: manno.edward@mayo.edu
954
pathological records were reviewed for demographic variables, clinical course, cause of death, and electroencephalogram (EEG) reports. Generalized tonic-clonic SE was verified
through chart review of clinical notes from a neurologist,
treating physician, nurse, or EEG reports and was defined
using criteria established by the Epilepsy Foundation of
America.7 Nonconvulsive SE was verified by EEG monitoring.
Patients were grouped into two categories determined by
their immediate cause of death. Group 1 was composed of
patients who died during an episode of SE. Group 2 patients
had a recent bout or remote history of SE but did not die
directly as a result of SE.
A pathologist (E.A.P.) blinded to the clinical history and
pathological reports reviewed the original cardiac pathological slides made from pieces of formalin-fixed myocardium
embedded in paraffin and sectioned to approximately 4 to
5␮m in thickness. Slides were reviewed for evidence of
CBN, ischemia, and other cardiac pathology. Myocardial
contraction bands were identified on hematoxylin and eosin
sections and were graded on a semiquantitative scale based
on the number and density of cells with contraction bands:
grade 0 ⫽ no contraction bands; grade 1 ⫽ contraction
bands found in 1 high-powered microscopic field; grade
2 ⫽ contraction bands found in 2 to 5 high-power fields;
grade 3 ⫽ 6 to 10 high-power fields; and grade 4 ⫽ greater
than 10 high-power fields. Only true contraction bands associated with frank coagulative necrosis or with early nuclear/cytoplasmic changes were reported. Contraction bands
at the peripheral edges of the tissue sections were not included.
Pathological results from the above groups were compared
with 22 control patients. Demographic data were compared
using a t test for continuous variables or a Fisher’s exact t test
for noncontinuous variables. The incidence of CBN was
compared among groups using a Fisher’s exact t test or ␹2
test. To assess for sampling bias, we compared the proportion of slides with CBN for each group using Fisher’s exact
t test or ␹2 test.
A p value of less than 0.05 was considered significant.
This study was approved by the Mayo Foundation Institutional Review Board.
Results
Twenty-six patients were excluded for diagnostic miscoding or unavailability of cardiac pathology. Eleven
Group 1 patients were identified. Demographics, clinical histories, and pathology of this group are documented in Table 1. In this group, five patients had
continual seizure activity that was not treated at family
request. One patient died in the emergency department
before treatment could be initiated. Five patients had
aggressive medical management of seizure activity including three patients who had resuscitative efforts after cardiac arrest.
Seventeen Group 2 patients were identified with either a remote history of SE (two patients) or a bout of
SE during their hospitalization but died later of a secondary illness.
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Table 1. Clinical History and Cardiac Pathology of Patients Who Died during Status Epilepticus
EEG
Report
SE Type
No. of
Slides
COPD, CAD, dementia found in SE, no treatment started
Mental retardation, seizure history, recalcitrant SE
CAD, bladder CA, became septic developed SE
CVA, CAD, CML developed SE
Yes
GTCS
11
No
No
No
GTCS
GTCS
GTCS
1
5
6
No
No
Yes
GTCS
GTCS
GTCS
2
2
1
9/M
4/M
DM, HTN had ICH after bowel surgery then SE
Microcephaly seizures developed SE died in ER
Head trauma, mental retardation developed SE
after frontal lobe resection
VSD, ASD, developed SE after cardiac surgery
CVA after Fontan procedure then SE
1⫹ CBN
1⫹ CBN
2⫹ CBN, old
ischemia
Normal
1⫹ CBN
1⫹ CBN
No
Yes
6
6
3⫹ CBN
Normal
58/F
Lung CA, brain mets became unresponsive
Yes
GTCS
Focal to
GTCS
NCS
4
23/M
Encephalitis
Yes
NCS
1
2⫹ CBN, old
ischemia
Normal
Age/Sex
89/F
84/M
86/M
86/M
44/M
38/F
32/M
Clinical History
Pathology
2⫹ CBN
ASD ⫽ atrial septal defect; CA ⫽ cancer; CAD ⫽ coronary artery disease; CBN ⫽ contraction band necrosis; CML ⫽ chronic myelogenous
leukemia; COPD ⫽ chronic obstructive pulmonary disease; CVA ⫽ cerebrovascular accident; DM ⫽ diabetes mellitus; EEG ⫽ electroencephalography; ER ⫽ emergency room; GTCS ⫽ generalized tonic-clonic status; HTN ⫽ hypertension; ICH ⫽ intracerebral hemorrhage;
NCS ⫽ nonconvulsive status; SE ⫽ status epilepticus; VSD ⫽ ventricular septal defect.
Twenty-two control patients had cardiac slides reviewed for CBN. Demographics, clinical history, and
pathology for this group are documented in Table 2.
There were no significant demographic differences be-
tween Group 1, Group 2, or combined Groups 1 and
2 compared with the control group.
Eight of the 11 patients who died directly as a result
of SE (Group 1) had identifiable CBN compared with
Table 2. Clinical History and Cardiac Pathology of Control Patients
Age/Sex
85/M
30/M
81/M
50/F
15/F
76/F
75/M
70/M
70/M
64/M
83/F
52/M
50/F
93/M
62/M
69/F
72/F
35/F
79/F
78/M
81/M
72/F
Clinical History
No. of Slides
Pathology
Afib, CAD, died of aspiration
C6 quadriplegic patient died of sepsis from decubitus
HTN, CVA, died of an acute MI
Lymphoma developed a SDH, seizures died of DIC
Died of head body trauma in MVA
DM, breast CA, schizophrenia unknown cause of death
PVD, AS, died of MI
ESRD, CAD died after renal transplant
Metastatic liver Ca, hepatic encephalopathy died of liver failure
DM, CHF, cirrhosis, dilated cardiomyopathy, schizophrenia
died of hypotension, hypoglycemia in ER
Lymphoma, died of pneumonia
CAD, COPD, died of lung CA
ESRD, died after third transplant from hemorrhage
CHF, HTN, CRI, Afib, died from MI
MI, lung CA, died of Vfib arrest in the hospital
CAD, HTN, died from CVA
Esophageal CA
IV drug abuse died of overdose of heroin
CHF, HTN, CAD, Afib, COPD died from a PE
Esophageal CA died of aspiration pneumonia
Afib, MI, died after mitral valve surgery
DM, breast CA, dementia died after care withdrawn
3
2
4
1
1
3
3
4
4
5
Old fibrosis
Normal
1⫹ CBN
Normal
Normal
Normal
Old ischemia
Acute ischemia
Normal
Old MI, old
ischemia
Normal
Normal
Old scar
1⫹ CBN
2⫹ CBN
Normal
Normal
Normal
Normal
1⫹ CBN
3⫹ CBN
Normal
3
2
2
5
4
4
2
4
2
5
4
3
AComm ⫽ anterior communicating artery; Afib ⫽ atrial fibrillation; AS ⫽ aortic stenosis; CA ⫽ cancer; CAD ⫽ coronary artery disease;
CBN ⫽ contraction band necrosis; COPD ⫽ chronic obstructive pulmonary disease; C6 ⫽ cervical spine level 6; CVA ⫽ cerebrovascular
accident; DIC ⫽ disseminated intravascular coagulopathy; DM ⫽ diabetes mellitus; ER ⫽ emergency room; ESRD ⫽ end-stage renal disease;
HTN ⫽ hypertension; IV ⫽ intravenous; MI ⫽ myocardial infarction; MVA ⫽ motor vehicle accident; PE ⫽ pulmonary embolus; PVD ⫽
peripheral vascular disease; SDH ⫽ subdural hematoma; Vfib ⫽ ventricular fibrillation.
Manno et al: Cardiac Path in SE
955
Fig. Hematoxylin and eosin section of an 86-year-old man who died during status epilepticus. High-power field magnification of
myocytes exhibiting contraction bands (arrows) that are perpendicular to the long axis of the muscle. Original magnification ⫻400.
5 of 22 control patients ( p ⬍ 0.01, Fisher’s exact t
test) (Fig). This was identified on 8 of 45 slides in the
SE group compared with 5 of 70 of the control slides
( p ⬍ 0.15, Fisher’s exact t test).
Three of 17 Group 2 patients had evidence for CBN
compared with 5 of 22 control patients (not significant, Fisher’s exact t test). Results of combining
Groups 1 and 2 for CBN and comparing with control
patients also were not significant.
Discussion
Cardiac contraction bands were found in a majority of
our patients who died directly as a result of SE. These
findings provide presumptive evidence that excessive
catecholamine release during SE is the mechanism for
cardiac decompensation and death during SE. Contraction bands have been reported previously but poorly
described in SE.4 This study represents the largest
pathological analysis of this population and delineates a
pathological substrate for patients dying directly as a
consequence of uncontrolled seizure activity.
The mechanism of cardiac deterioration during SE is
largely speculative. Boggs and colleagues3 described
two mechanisms for cardiac deterioration and death
during SE. A gradual decline in blood pressure and
cardiac function described in an older population was
contrasted with sudden cardiac death reported in
younger patients. These two mechanisms may repre-
956
Annals of Neurology
Vol 58
No 6
December 2005
sent an imbalance between parasympathetic and sympathetic autonomic activity during SE. Autonomic
control of cardiac function appears to represent a balance between the right and left insular cortices, with
the right insula believed to mediate cardiac sympathetic
activity.8,9 Two of our patients with SE and EEG
monitoring had seizures originating from a right temporal focus, a third patient had seizures originating adjacent to a frontal lobe resection in an area previously
known to exert cardiorespiratory effects.10 We speculate that in these patients increased sympathetic activity
may have led to the development of cardiac arrhythmias and CBN. Unfortunately, cardiac enzyme, electrographic, and intensive care monitoring data at the
time of death were not available for review.
Contraction bands have been described in several
acute neurological injuries.5,6,11–13 The pathological
features of CBN differ from ischemic necrosis. In
CBN, myocardium dies in a hypercontracted state, resulting in the formation of contraction bands.11 These
features are located in the myocardium adjacent to the
insertion of the sympathetic end plates, suggesting that
massive catecholamine release is the mechanism of
CBN.12 Sympathetic innervation to the heart approximates the cardiac conductive system, probably accounting for previously described electrocardiographic
changes and cardiac arrhythmias.11 Myovascular spasm
or direct myocyte injury have been hypothesized to account for myocardial stunning.13
It is possible that selection bias played a role in our
study. Several cases were excluded on chart review because SE could not be identified. However, most of
our patients exhibited generalized and continual seizure
activity, thus making a misdiagnosis of SE improbable.
Similarly, sample bias was accounted for and was unlikely to have accounted for our findings.
A review of the individual histories may account for
why CBN was found in some patients and not in others. CBN represents reperfusion injury after temporary
coronary ischemia and is found surrounding areas of
myocardial infarction.14 Myocardial infarctions were
present in all but one of the control patients with CBN
and in only one Group 1 patient. Similarly, some of
our patients may not have been able to develop CBN.
Two control and one Group 1 patient had longstanding diabetes and may have had an autonomic
neuropathy. Another control patient was a C6 quadriplegic and most likely lost autonomic control of cardiac function.
This review of individual patients suggests that our
comparisons may be somewhat artifactual. In fact, if
the above patients are eliminated from consideration,
then the combined Groups 1 and 2 do have a statistically significant increased incidence of CBN compared
with the remaining control patients. Despite this there
appears to be a difference between those who died in
SE and those with only a history of SE. We speculate
that the quantity of catecholamines released into the
myocardium may be affected by the duration or the
intensity of SE or that some ill-defined period of stress
may be required for the development of CBN.
We doubt that exogenous catecholamines or cardiac
arrhythmias account for our pathological findings. Exogenous catecholamines were given in three patients
who underwent prolonged cardiac arrest; however, only
one of these patients exhibited CBN. Similarly, only
one SE patient was maintained on exogenous vasopressors and did not exhibit CBN. These findings support
the concept that catecholamines released directly from
nerve terminals into the myocardium are more likely to
be responsible for cardiac damage than exogenously administered or endogenously released catecholamines.
Our findings should be verified by future prospective pathological studies and may suggest that in selected patients with refractory SE, a short-acting
␤-blocker could provide some cardiac protection and
prevent cardiac decompensation. We do not think we
can extend these conclusions to sudden death in epilepsy15 but suggest that similar pathological studies in
this condition be undertaken.
References
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12. Greenhout JH, Reichenbach DD. Cardiac injury and subarachnoid hemorrhage. A clinical, pathological, and physiological
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Amati-Bonneau et al: OPA1 Mutation in ADOAD
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