The American Journal of Forensic Medicine and Pathology

24(1):83–86, 2003.

©2003 by Lippincott Williams & Wilkins, Inc., Philadelphia

Sudden Death in a 35-Year-Old Man with Occult Malformation
of the Brain and Aseptic Meningitis
Jakob Matschke, M.D., Maria Makrigeorgi-Butera, M.D., and Dimitrios Stavrou, M.D.

A 35-year-old man was found dead by his wife. He was
reported to have had symptoms of a common cold the week
preceding his death. The medicolegal autopsy yielded signs of
central dysregulation (ectasia of the urinary bladder and rectum, dystelectasis of the lungs) together with marked brain
edema and fresh bite marks on the tongue. The cause of death
was presumed to be lethal epileptic seizure. Neuropathologic
examination revealed neuronal nodular heterotopia as well as
discrete lymphocytic meningitis (aseptic meningitis). The death
was most probably caused by the combination of the meningitis
with the occult malformation, leading to a lowered seizure
threshold and subsequent lethal seizure. The morphologic findings of this case are presented, and the probable mechanisms of
death are discussed.
Key Words: Sudden death—Brain malformation—Meningitis—Aseptic—Neuronal heterotopia.

Sudden unexpected death has been defined as death
occurring in a very short interval beginning from the
onset of symptoms, making it impossible for any physician familiar with the patient to certify the cause of death
with reasonable accuracy. The length of the interval has
been given as long as 24 hours by some authors and as
short as 1 hour by others (1,2).
Intracranial pathologic conditions as a cause of sudden
unexpected death are all too familiar to the forensic
practitioner. Intracranial bleeding (intracerebral hemorrhage or spontaneous subarachnoid hemorrhage), infections (bacterial meningitis), sudden unexpected death in
patients with epilepsy (SUDEP), and tumors are among
the most frequent (3).
Neuronal nodular heterotopia, defined as nodules of
gray matter in an inappropriate location (4), are a frequent finding both in patients with intractable epilepsy
and in normal subjects after careful neuropathologic examination.
We present the case of a 35-year-old man with clinically silent and occult nodular heterotopia, in whom an
additional benign lymphocytic meningitis led to death
resulting from epileptic seizure.

CASE REPORT
The 35-year-old man worked as a physician in a hospital. He was reportedly in complete good health, apart
from stress at the job and being a heavy smoker. During
the week preceding his death he experienced a common
cold (fever, headaches, malaise, coughing, sneezing). On
the day of his death, he went to bed at about 11 P.M. and
suddenly sat up in bed, leading to his wife’s “impression
of something being wrong.” She went to another room to
call an ambulance. When she came back, the man had
fallen out of bed and was lying on the floor, pulseless and
breathless. Despite cardiopulmonary resuscitation attempts by the emergency physician who arrived some 5
minutes later at the scene, the man died. A legal autopsy

Manuscript received August 28, 2002; accepted November 14, 2002.
From the Institute of Neuropathology (J.M., M.M.-B., D.S.) and the
Institute of Legal Medicine (J.M.), University Hospital of HamburgEppendorf, Hamburg, Germany.
Address correspondence and reprint requests to Dr. J. Matschke,
Institute of Neuropathology, Martinistrasse 52, D-20246 Hamburg,
Germany; e-mail: matschke@uke.uni-hamburg.de

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J. MATSCHKE ET AL.

was initiated by the local authorities and was performed
36 hours after the death.
Autopsy Findings
The body was that of a 35-year-old obese man (body
weight 102 kg, body length 181 cm). Apart from signs of
cardiopulmonary resuscitation (electrodes, vein cannulas) no external abnormalities could be seen. Signs of
central dysregulation were present, with ectasia of bladder and rectum, pulmonary dysteletasis and edema, and
marked brain edema (fresh brain weight 1720 g). Fresh
bite marks appeared on the tongue. Slight general and
coronary atherosclerosis was seen. Acute infection of the
upper airways was seen, with edema and congestion of
the bronchial mucosa and moderate amount of mucus.
The remaining morphologic findings were completely
unremarkable. Intoxication was ruled out: the blood alcohol concentration was 0.00 mg/ml, and toxicologic
analysis failed to detect any drugs or unusual substances.
Histologic analysis of the internal organs yielded no
pathologic findings, especially no signs of myocarditis or
pneumonia. Death was attributed to epileptic seizure, and
the unsliced brain was fixed in formalin for 3 weeks.
Neuropathologic Findings
Macroscopically, signs of marked brain edema with
flattened gyri, compression of the ventricular system,
and prominent temporal and tonsillar herniation were
seen. Around the occipital horns of the lateral ventricles,
nodules of gray matter were seen bilaterally, bulging into

FIG. 2. Subarachnoid space between two adjacent gyri
showing moderate lymphocytic infiltrates H & E; original
magnification 10⫻.

the ventricular lumen, raising the suspicion of subependymal nodular heterotopia (Fig. 1).
Microscopically, the heterotopia consisted of clusters
of disorderly arranged neurons and glia lining the ventricular wall. The overlying cerebral cortex appeared
normal. Furthermore, there were scanty to moderate lymphocytic infiltrates in the subarachnoid space and in the
perivascular spaces surrounding some of the superficial
cortical blood vessels (Fig. 2). Immunohistochemically,
these infiltrates consisted mainly of T lymphocytes intermingled with some B lymphocytes. Further immunohistochemical studies failed to reveal antigens of herpes
simplex virus type I and II, cytomegalovirus, EpsteinBarr virus, varicella zoster virus, mumps virus, or human
immunodeficiency virus. No other abnormalities could
be found, in particular no indications of epileptic scars
(hippocampal sclerosis) or other malformations.
DISCUSSION

FIG. 1. Occipitomedial right with nodular mass of ectopic
grey substance (white arrowhead) bulging into the ventricular lumen (Elastica-van-Gieson).
Am J Forensic Med Pathol, Vol. 24, No. 1, March 2003

According to most recent advances in the research of
cerebral cortical development, this extremely complex
process can be subdivided into three general and overlapping steps: (1) cell proliferation, which includes neuronal and glial proliferation and apoptosis, (2) neuronal
migration, and (3) cortical organization (5). These milestones of cerebral cortical development provide a framework of both known and yet undescribed malformations,
given that each of the steps has its own unique set of
characteristic malformations.
Disorders of neuronal migration, for example, may
interrupt any of the many complex and interacting processes that lead the immature neuron through the developing hemisphere until it reaches the proper layer of the
mature cerebral cortex (5).

OCCULT MALFORMATION OF THE BRAIN AND ASEPTIC MENINGITIS
Neuronal heterotopias are malformations that result
from disorders of neuronal migration, allowing multiplication of neuroblasts but preventing or arresting their
migration from the periventricular region into the later
cerebral cortex (6). They consist of aggregates of neurons and glia that form a nodular, bandlike or ribbonlike
mass of gray matter in an appropriate location (4 – 6).
Heterotopias may be single or multiple, unilateral or
bilateral. They can be located just beneath the ventricular
lumen (subependymal), in the deep white matter (subcortical), or even in the arachnoid (marginal glioneuronal) (5). They can be associated with accompanying
malformations of the overlying, corresponding cortex.
The genetic basis of some rare familial forms of heterotopias have been elucidated (7–9); however, most cases
appear to be sporadic (6). In animal models of heterotopia, orthodromic and antidromic neuronal connections
between the heterotopia and overlying neocortex and
hippocampus can be found. Furthermore, both the heterotopia and the overlying cortex show altered excitatory
and inhibitory neurotransmitter receptor units, an increase in intrinsically bursting neurons, and prolonged
depolarization potentials (10), findings that help explain
the fact that heterotopias can produce epilepsy in animal
models and in humans.
The term “aseptic meningitis” was coined long ago to
describe a clinical syndrome of meningeal inflammation,
in which common bacterial agents could not be identified
in the cerebrospinal fluid (11). With newer and more
sophisticated techniques, many pathogens, mostly viral,
have been associated with this syndrome. Nowadays, the
term is used to describe a syndrome of fever, headache,
and meningeal irritation together with moderate lymphocytic pleocytosis in the cerebrospinal fluid. Implicit in
the definition is the absence of signs of involvement of
the brain (encephalitis) or spinal cord (myelitis), which
in turn underlies the benignity of the illness in the overwhelming number of cases (11). Depending on the
amount and sophistication of diagnostic methods used,
members of the family of enteroviruses can be detected
in 75% to 90% of all cases with aseptic meningitis
(12,13).
According to the morphologic findings in our case, this
35-year-old man had both bilateral subependymal nodular
heterotopia and benign lymphocytic (aseptic) meningitis.
The cause of the meningitis could not be elucidated, but
because most of the rarer forms of aseptic meningitis (herpes simplex virus type I and II, cytomegalovirus, EpsteinBarr virus, varicella zoster virus, mumps virus, and human
immunodeficiency virus (11)) could be ruled out by immunohistochemistry, the infectious agent in our case could
well have been a member of the family of enteroviruses (for
which no antibody exists).
Seizures are not considered as part of the clinical
spectrum in lymphocytic meningitis without involve-

85

ment of the brain proper (no encephalitis). As for the
necessary lowering of seizure thresholds, the gray matter
has to be affected by the inflammatory process (14,15).
Heterotopias are a relatively frequent finding in unselected patients with epilepsy, e.g. 10% in the series of
Meencke and Veith (16), and epilepsy is a rather common symptom in patients with symptomatic heterotopias,
e.g. 82% in the series of Dubeau et al. (6)). Therefore, it
seems justified to conclude that the clinically silent heterotopias in our case might very well have lowered the seizure
threshold to a point at which any other disturbance in the
dynamics of the neuronal network (14) led to the terminal
lowering of the threshold that did indeed cause the lethal
seizure. All findings in this case strongly suggest the meningitis as being this additional disturbance.
In our opinion, the patient in this case could not be
classified as a SUDEP case, because in all definitions the
diagnosis of epilepsy, meaning recurrent unprovoked
seizures, is mandatory (17,18). In the history of this man
there were no indications of recurrent seizures, and it
seems reasonable to assume that he himself, as a doctor,
would have easily recognized the symptoms of a seizure.
Retrospectively, we believe that the man in our case
experienced a provoked or acute symptomatic seizure
because it occurred in close temporal relationship with
an acute meningitis. Judging from the history given by
the wife, a registered nurse, who witnessed the man
sitting up in bed and giving her the impression of “something being wrong,” the seizure could at least initially
have been a partial one (given that no tonic and/or clonic
movements were noted by her). Finally, the partial seizure obviously generalized secondarily, with the fresh
tongue bites as the strongest indicator for this event.
The issue concerning the actual terminal cause of
death resulting from seizure has not yet been solved.
Central apnea is known to occur in seizures (19,20), and
this would very well explain the signs of central dysregulation in our case. Other theories draw attention to
the arrhythmogenic epileptic death, because seizures are
known to potentially induce malignant cardiac arrhythmias (21,22).
Our case cannot contribute further to this debate, but
it underlines once more the importance of meticulous
investigation and analysis of unexplained deaths. This is
especially true for neuropathologic studies, which we recommend be done in all cases of unexplained death with a
suspected intracranial cause, because only the analysis of
the formalin-fixed brain by an experienced neuropathologist is capable of detecting even the slightest morphologic
cause of sudden unexplained death (23,24).
REFERENCES
1. DiMaio VJ, DiMaio D. Sudden, unexpected natural death. In
DiMaio VJ, DiMaio D. Forensic pathology. 2nd ed. Boca
Raton, FL: CRC Press, 2001:6 –9.
Am J Forensic Med Pathol, Vol. 24, No. 1, March 2003

86

J. MATSCHKE ET AL.

2. Knight B. The pathology of sudden death. In Knight B. Forensic pathology. 2nd ed. London: Arnold, 1996:487–515.
3. Black M, Graham DI. Sudden unexplained death in adults
caused by intracranial pathology. J Clin Pathol 2002;55:44–50.
4. Porter BE, Brooks-Kayal A, Golden JA. Disorders of cortical
development and epilepsy. Arch Neurol 2002;59:361–5.
5. Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R,
Dobyns WB. Classification system for malformations of cortical development. Update 2001. Neurology 2001;57:2168 –78.
6. Dubeau F, Tampieri D, Lee N, et al. Periventricular and
subcortical nodular heterotopia: a study of 33 patients. Brain
1995;118:1273– 87.
7. Gleeson JG, Allen KM, Fox JW, et al. Doublecortin, a brainspecific gene mutated in human X-linked lissencephaly and
double cortex syndrome, encodes a putative signaling protein.
Cell 1998;92:63–72.
8. Des Portes V, Pinard JM, Billuart P, et al. A novel CNS gene
required for neuronal migration and involved in X-linked
subcortical laminar heterotopia and lissencephaly syndrome.
Cell 1998;92:51– 61.
9. Fox JW, Lamperti ED, Eksioglu YZ, et al. Mutations in
filamin 1 prevent migration of cerebral cortical neurons in
human periventricular heterotopia. Neuron 1998;21:1315–25.
10. Sancini G, Franceschetti S, Battaglia G, et al. Dysplastic
neocortex and subcortical heterotopias in methylazoxymethanol-treated rats: an intracellular study of identified pyramidal
neurons. Neurosci Lett 1998;246:181–5.
11. Rotbart HA. Viral meningitis and the aseptic meningitis syndrome. In Scheld WR, Whitley RJ, Durack DT, eds. Infections
of the central nervous system. 2nd ed. Philadelphia: Lippincott-Raven, 1997:23– 46.
12. Rotbart HA. Diagnosis of enteroviral meningitis with the polymerase chain reaction. J Pediatr 1990;117:85–9.

Am J Forensic Med Pathol, Vol. 24, No. 1, March 2003

13. Sawyer MH, Holland D, Aintablian N. Diagnosis of enteroviral central nervous infection by polymerase chain reaction
during a large community outbreak. Pediatr Infect Dis J 1994;
13:177– 82.
14. Lopes da Silva FH, Wadman WJ. Pathophysiology of epilepsy.
In Meinardi H, ed. Handbook of clinical neurology. Vol. 72.
The epilepsies. Part 1. Amsterdam: Elsevier, 1999:39 – 81.
15. De Bittencourt PRM, Sander JW, Mazer S. Viral, bacterial,
fungal and parasitic infections associated with seizure disorders. In Meinardi H, ed. Handbook of clinical neurology. Vol.
72. The epilepsies. Part 1. Amsterdam: Elsevier, 1999:145–74.
16. Meencke HJ, Veith G. Migration disturbances in epilepsy.
Epilepsy Res 1992;(Suppl)9:31– 40.
17. Nashef L. Sudden unexpected death in epilepsy: terminology
and definitions. Epilepsia 1997;38(Suppl 11):S6 –S8.
18. Annegers JF. United States perspective on definitions and
classifications. Epilepsia 1997;38(Suppl 11):S9 –S12.
19. Nashef L, Walker F, Allen P, Sander JWAS, Shorvon SD, Fish
DR. Apnoea and bradycardia during epileptic seizures: relation
to sudden death in epilepsy. J Neurol Neurosurg Psychiatry
1996;60:297–300.
20. So EL, Sam MC, Lagerlund TL. Postictal apnea as a cause of
SUDEP: evidence from near-SUDEP incident. Epilepsia 2000;
41:1494 –7.
21. Reeves AL, Nollet KE, Klass DW, Sharbrough FW, So EL.
The ictal bradycardia syndrome. Epilepsia 1996;37:983–7.
22. Jallon P. Arrhythmogenic seizures. Epilepsia 1997;38(Suppl
11):S43–S47.
23. Rossi L. Bulbo-spinal pathology in neurocardiac sudden death
of adults: a pragmatic approach to a neglected problem. Int J
Legal Med 1999;112:93– 0.
24. Sperhake JP, Matschke J, Orth U, Gal A, Püschel K. Sudden
death due to cerebrotendinous xanthomatosis confirmed by
mutation analysis. Int J Legal Med 2000;113:110 –3.