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CORRESPONDENCE

Microvascular Retractor: A New Concept of Retracting


and Repositioning Cerebral Blood Vessels
To the Editor:
We read with great interest the article on a new microvascular retractor (1). The authors describe a very useful selfretaining microvascular retractor for the retraction and repositioning of cerebral blood vessels. They state that this
retractor, with a semicircular tip, remains stable on pulsating
vessels during the procedure and grossly preserves the vessel
diameter.
In our department, we have been using a comparable instrument (Fig. C1). The diameters of the blades are 2, 4, and 6
mm, respectively. However, this microvascular retractor is
hand-held and not self-retaining, as the one described by the
authors. This instrument has been used mainly during microvascular decompression surgery for lifting, manipulating, and
repositioning offending cerebral vessels. It can anchor the
vessel and permit its manipulation during retraction in the vertical and horizontal planes. This handheld retractor is especially
useful when dealing with
larger or elongated vessels
that may easily slip from FIGURE C1. Photograph showing the
the classic suction tips of free-hand microvascular retractor.
The blades are available in diameters
microdissectors.
of 2, 4, and 6 mm, respectively.

Tomas Menovsky
Nijmegen, The Netherlands
Iris van den Hurk
Amsterdam, The Netherlands

1. Youssef AS, van Loveren H: Microvascular retractor: A new concept of


retracting and repositioning cerebral blood vessels. Neurosurgery 57 [Suppl
1]:199202, 2005.

DOI: 10.1227/01.NEU.0000217312.38460.FA

Chronic Traumatic Encephalopathy in a National


Football League Player
To the Editor:
We disagree with the assertion that Omalu et al.s (6) recent
article actually reports a case of chronic traumatic encephalopathy in a National Football League (NFL) player. We base
our opinion on two serious flaws in Omalu et al.s article,
namely a serious misinterpretation of their neuropathological
findings in relation to the tetrad characteristics of chronic
traumatic encephalopathy and a failure to provide an adequate clinical history.

NEUROSURGERY

Neuropathology of Chronic Traumatic Encephalopathy


We disagree with Omalu et al.s statements that the neuropathological findings in this case are consistent with chronic
traumatic encephalopathy and met criteria for chronic traumatic encephalopathy. These statements are based on a complete misunderstanding of the relevant medical literature on
chronic traumatic encephalopathy of boxers (dementia pugilistica). A review of the relevant medical literature, including that
cited by Omalu et al., in the chronological order in which it was
published demonstrates the flaws in Omalu et al.s assertions.
The seminal paper on chronic encephalopathy of boxers was
published by Corsellis et al. (2). In this landmark study,
Corsellis et al. reported a specific pattern of neuropathological
findings in the brains of 15 retired boxers. The results were
based on gross and standard histological examinations of the
autopsy material. Corsellis et al. determined the hallmark
neuropathology of chronic traumatic encephalopathy to be: 1)
abnormalities of the septum pellucidum (cavum, fenestrations); 2) cerebellar scarring on the inferior surface of the
lateral lobes, most marked in the tonsillar region and loss of
Purkinje cells in these areas; 3) degeneration of the substantia
nigra with loss of pigmentation, neurofibrillary changes, and
no Lewy bodies; and 4) widespread neurofibrillary tangles in
the cerebral cortex and brainstem, most prominently in the
medial temporal lobe gray matter, in contrast to the sparsity,
or in most cases, the total absence of senile plaques.
None of the later references cited by Omalu et al. or others
ever argued that the findings reported by Corsellis et al. (2) do
not define chronic traumatic encephalopathy in boxers. The
relevant references suggested a possible qualifier to the fourth
characteristic (widespread neurofibrillary tangles and sparse
or no senile plaques), but never took issue with the first three
characteristics.
Roberts (7) performed immunocytochemical studies on
brain material on eight of Corsellis et al.s 15 cases. He reported that the neurofibrillary tangles in these cases were
stained by a battery of antisera that also stained the neurofibrillary tangles of 15 cases of Alzheimers disease brains.
Roberts thus suggested that head injury and Alzheimers disease may share some pathogenetic factors. Nothing in Roberts
study suggested that Corsellis et al.s original definition of
chronic traumatic encephalopathy was incorrect. In fact, the
material examined in the study by Roberts was defined as
originating in dementia pugilistica brains because it was so
designated by Corsellis in his earlier paper (7).
Adams and Bruton (1) examined the brains of 22 former
boxers and found that 17 of the 22 brains showed histological
evidence of recent or past hemorrhages. Thirteen of these
brains were those originally studied and reported on by
Corsellis et al. (2). Twelve of these brains showed neuropathological evidence of brain damage of the type described in
the punch-drunk state (1). The brains of five additional
retired boxers were examined; three of these showed the
typical stigmata of dementia pugilistica (1). What was the

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CORRESPONDENCE

neuropathological pattern or stigmata that defined the punchdrunk or dementia pugilistica state according to Adams and
Bruton? A tetrad of pathological processes originally described by Corsellis et al. (1). Clearly, Adams and Bruton did
not dispute the fact that Corsellis et al.s criteria defined the
neuropathology of chronic traumatic encephalopathy.
Roberts et al. (9) reported a case of dementia in a punchdrunk wife. The neuropathology of the case revealed a large
fenestrated cavum septum pellucidum, neurofibrillary tangles
on routine staining and immunoreactive tangles and diffuse
plaques on immunocytochemical studies with specific antisera
(9). The authors stated that the brain of this repeatedly battered woman resembled that seen in dementia pugilistica.
Roberts et al. suggested that the immunocytochemical picture
might be a part of this condition, but mainly suggested that
the case provided evidence that head injury can be followed
by Alzheimer type degeneration (9). Roberts et al. (9) cited
Corsellis et als (2) study as the source of his description of
dementia pugilistica. Furthermore, the brain reported by Roberts in this letter had the septal abnormalities on gross examination and neurofibrillary tangles on routine histological
staining that are integral to the neuropathological description
of dementia pugilistica.
Roberts et al. (8) also reported the results of immunocytochemical staining of 20 former boxers necropsy brains with an
antibody to -protein amyloid. Fourteen of the cases were
from Corsellis et al.s (2) original material. One was from a
boxer who died during a bout. The other five consisted of
three additional professional and two amateur boxers. Nineteen of the 20 cases had a cavum septum pellucidum. On
routine staining, 13 had neurofibrillary tangles with minimal
or no plaque formation, four had equal amounts of tangle and
plaque formation, and three had no neurofibrillary tangles.
Thus, most of the cases fit the definition of dementia pugilistica as described by Corsellis et al. (2) and most, in fact, were
from Corsellis original material (8).
Roberts et al. (8) reported that 19 of the cases exhibited substantial numbers of hitherto invisible diffuse -protein immunoreactive plaques on immunocytochemical analysis. They suggested that the present neuropathological description of
dementia pugilistica (tangles, but no plaques) should be altered
to acknowledge the presence of substantial -protein deposition
(plaques). The authors did not indicate that the gross brain
findings or microscopic findings on routine histology reported
by Corsellis et al. (2) were incorrect, but rather offered a qualifier
to the fourth criterion of the tetrad, made possible by the development of new immunocytochemical techniques that were not
available to Corsellis et al. (2).
Dale et al. (3) reported the results of immunocytochemical
staining of 16 former boxers brains with antisera to ubiquitin
(a component of neurofibrillary tangles in Alzheimers disease) and to BF-10 (a component of tangles in Alzheimers
disease and dementia pugilistica). Eleven of these cases had
dementia pugilistica, as defined by the Corsellis et al. (2)
criteria. In fact, 10 of the cases were from Corsellis original
material. Nine of these 10 cases were also included in Roberts

E1003 | VOLUME 58 | NUMBER 5 | MAY 2006

et als (8, 9) study. The results demonstrated that ubiquitin (a


component of Alzheimers disease tangles) is also present in
neurofibrillary tangles in dementia pugilistica and that more
neurofibrillary tangles in dementia pugilistica are stained with
BF-10 than with antiubiquitin.
The authors proposed that Alzheimers disease and dementia pugilistica neurofibrillary tangle formation share many
common features (3). At no point, however, did the authors
imply or state that Corsellis et al.s (2) criteria for dementia
pugilistica were incorrect; and in fact, the authors used
Corsellis criteria to identify the cases of dementia pugilistica
for their study.
Tokuda et al. (10) reexamined eight former boxers brains
using immunohistochemistry with antibodies to amyloid
-protein and -protein. Seven of the eight cases were taken
from Corsellis et al.s (2) original material. Tokuda et al. (10)
reported that the neurofibrillary tangles in dementia pugilistica are similar to those seen in Alzheimers disease. They also
found other -immunoreactive structures (neuropil threads
and degenerating neurites) in the periphery of degenerating
plaques in dementia pugilistica. The authors also found
-protein cerebral amyloid angiopathy in three of the eight
cases. Tokuda et al. (10) did not comment on any of the other
Corsellis et al. criteria, did not indicate any disagreement with
those criteria and in fact used Corsellis et al.s original material
(brains that meet the Corsellis et al. criteria for a diagnosis of
dementia pugilistica) as brains defined as exhibiting dementia
pugilistica.
Geddes et al. (5) reported the autopsy results of a 23-yearold boxer who died in the ring. They found widespread neurofibrillary tangles in all neocortical areas with sparing of the
medial temporal lobe. No Alzheimers disease changes and
none of the other characteristics findings of dementia pugilistica (as defined by Corsellis et al.) were reported (5). The
authors suggested that the development of neurofibrillary
tangles may be the earliest change in the development of
chronic encephalopathy of boxers. Nothing in Geddes study
challenged Corsellis criterion for the diagnosis of dementia
pugilistica (5).
Geddes et al. (4) later reported autopsy results of five young
men who experienced mild chronic head injury. Two were
boxers, one was a soccer player, one was an epileptic who
frequently hit his head during seizures, and one was a developmentally disabled man with a long history of head banging.
Geddes et al. (4) performed routine staining and immunostaining with antisera to -amyloid and -proteins. All of the
cases demonstrated neocortical neurofibrillary tangles and
-positive neuropil threads. There was no abnormal staining
with antisera to -amyloid. No abnormal plaques were seen
(4). The authors concluded that neocortical neurofibrillary
tangle and -positive neuropil thread formation without
-amyloid deposition is the earliest neuropathological finding
in repetitive head injury in young adults. This report is thus
very consistent with Corsellis et al.s original findings and is,
in fact, inconsistent with Omalu et al.s (6) assertions. Omalu
et al.s case demonstrated diffuse amyloid plaques, sparse

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CORRESPONDENCE

neuritic threads, and sparse neurofibrillary tangles which is


the opposite of Geddes et al.s findings of widespread neurofibrillary tangles without -amyloid plaque formation (4, 6).
This chronological review of the development of the neuropathological description of dementia pugilistica indicates the
following: 1) in 1973, Corsellis et al. (2) described the tetrad of
findings that still define the neuropathological picture of dementia pugilistica; 2) this tetrad includes abnormalities of the
septum pellucidum, cerebellar scarring, degeneration of the
substantia nigra, and widespread neurofibrillary tangles with
minimal or no plaque formation on routine histological staining; 3) in the late 1980s and 1990s, the availability of new
techniques of immunocytochemical analysis further described
the nature of neurofibrillary tangles in dementia pugilistica
and revealed that plaques were indeed present when these
new techniques were applied; and 4) a qualifier to Corsellis et
al.s fourth criterion (neurofibrillary tangles without plaques
on routine histological examination) can be added: immunocytochemical studies reveal that plaques are indeed present in
these brains.
None of the references reviewed argued, in any way, that
Corsellis et al.s (2) original tetrad of findings was not correct
or do not define the syndrome of dementia pugilistica. In fact,
all of the more recent studies cite Corsellis et al.s (2) paper,
and many of them actually used brain material from Corsellis
et al.s original subjects (defined as being dementia pugilistica
brains) for their newer analyses. These studies would not have
done so if their authors did not agree that Corsellis et als
description accurately classifies the neuropathology of chronic
traumatic encephalopathy. None of the references reviewed
ever suggested that Corsellis et al.s neuropathological description be abandoned or that immunocytochemical criteria
alone should replace Corsellis et al.s tetrad in defining
chronic traumatic encephalopathy.
This historical review clearly demonstrates the error of
Omalu et al.s (6) statements that their case is consistent with
chronic traumatic encephalopathy and met criteria for
chronic traumatic encephalopathy. The following compares
Omalu et al.s reported case findings with the tetrad neuropathological criteria of Corsellis et al. (2): 1) Omalu et al.s case
did not have a cavum septum pellucidum or a fenestrated
septum pellucidum; 2) Omalu et al.s case did not have scarring of the inferior surface of the cerebellum; 3) Omalu et al.s
case did not have widespread neurofibrillary tangles with
minimal or no plaque formation on routine histological examination; and 4) Omalu et al.s case did have depigmentation of
the substantia nigra.
Omalu et als case demonstrated only one of the four of
Corsellis et al.s (2) tetrad criteria, certainly not enough to be
consistent with or meet criteria for chronic traumatic encephalopathy of boxers. On immunohistochemical staining, Omalu
et al.s case had frequent amyloid plagues, but only sparse
neuritic threads and neurofibrillary tangles. Close review of
the literature indicates that these findings share some similarities to Roberts et al.s (8) results, but are not exactly the same
as those reported by Tokuda et al. (10), who found significant,

NEUROSURGERY

not sparse, neurofibrillary tangles and significant, not sparse,


amounts of neurofibrillary tangles and neuropil threads), or
Geddes et al. (4). Even if one accepts that these immunohistochemical results are similar to those reported in the references (this is not at all certain), this consistency with the
qualifier to Corsellis et al.s fourth criterion is still not enough
to be consistent with a diagnosis of chronic traumatic encephalopathy of boxers.
This detailed review of the relevant literature including that
cited by Omalu et al. shows clearly that Omalu et al.s description of chronic traumatic encephalopathy is completely
wrong. The characteristic neuropathological findings for
chronic traumatic encephalopathy, especially in boxers are
not sparse to many neurofibrillary tangles in the cortex, neuropil threads and neocortical diffuse amyloid plaques as
stated by Omalu et al. (6). It is clear that Omalu et al.s case did
not meet the accepted criteria for chronic traumatic encephalopathy as described by Corsellis et al. (2) with only one
qualification uncovered by newer immunocytochemical techniques in the late 1980s and early 1990s.

Clinical History
The dearth of clinical information seriously compromises
Omalu et al.s (6) assertions that this case is one of chronic
traumatic encephalopathy. The diagnosis of a chronic condition requires a medical history indicating a long-standing
nature of the illness. Clinical information regarding the onset
and course of the illness over time is invaluable in this regard.
Such a history is completely lacking in Omalu et al.s (6)
report.
The diagnosis of encephalopathy requires a detailed neurological history and neurological examination indicating
clear evidence of clinical brain dysfunction. Postmortem telephone interviews with surviving relatives, which reveal a
neuropsychiatric history that resembled a dysthymic disorder do not qualify as an adequate detailed neurologic and/or
psychiatric history and clinical examination. One sentence
indicating a deficit in memory and judgment as well as
Parkinsonian symptoms is too vague and nonspecific. Did
this information also come from postmortem telephone interviews with surviving relatives?
Results of medical-neurological clinical evaluations of the
patient while he was alive are necessary to determine if he had
any brain dysfunction. In the absence of adequate clinical
evidence of any type of brain dysfunction, one cannot make a
diagnosis of encephalopathy.
To state that a condition is traumatic in origin, one needs
to present a history of significant injury (in this case, head
injury) and rule out other possible etiological factors. Omalu et
al. (6) indicate that their subject had a long career in professional football as an offensive lineman. They correctly point
out that offensive linemen have a low incidence of mild traumatic brain injury (MTBI) compared with other position players. In the premortem history of this case, Omalu et al. do not
mention any history of cerebral concussion, MTBI, or removal
from play after a blow to the head.

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In their discussion, Omalu et al. (6) indicate that he sustained numerous episodes of MTBI and/or concussive injury, as evidenced by the histological evidence of remote
hemorrhages. This is circular reasoning. Although there is no
history of head injury, the subject must have had multiple
head injuries because of the autopsy findings.
The absence of an adequate medical history cannot be compensated for by reporting autopsy results. Omalu et al. (6) go
on to state that there was no known history of brain trauma
outside professional football. In fact, there was no known
history of brain trauma inside professional football either.
Omalu et al. also overlooked the patients participation in both
high school and college football, in which head injuries have
been known to occur. Omalu et al. have also ignored other
possible etiologies of brain dysfunction (if there was indeed
brain dysfunction) in this case.
The patient had severe heart disease (atrial fibrillation, coronary artery disease, cardiomyopathy) and obesity. Certainly,
he was a good candidate for hypertension, diabetes, hyperlipidemia, and numerous other metabolic abnormalities. He was
likely on multiple medications for treatment of his medical
conditions. Omalu et al. (6), however, present us with no
information regarding these clinical issues. Furthermore, they
present no information regarding possible alcohol, steroid, or
illicit drug abuse in this subject. All of these substances can
cause brain dysfunction and thus deserve mention, at least
with a simple statement about the presence or absence of such
abuse in the medical history.
For all of these reasons, one cannot state that head trauma
was a primary cause of his purported brain dysfunction. It is
our contention that there is inadequate clinical evidence that
the subject had a chronic neurological condition, a traumatically
induced brain condition or, in fact, a clinical encephalopathy.
The term chronic traumatic encephalopathy thus should not
be applied to their case.
We have demonstrated that Omalu at al.s (6) case does not
meet the clinical or neuropathological criteria of chronic traumatic encephalopathy. We, therefore, urge the authors to retract their paper or sufficiently revise it and its title after more
detailed investigation of this case.
Ira R. Casson
Elliot J. Pellman
David C. Viano
New York, New York

1. Adams CW, Bruton CJ: The cerebral vasculature in dementia pugilistica.


J Neurol Neurosurg Psychiatry 52:600604, 1989.
2. Corsellis JA, Bruton CJ, Freeman-Browne D: The aftermath of boxing.
Psychol Med 3:270303, 1973.
3. Dale GE, Leigh PN, Luthert P, Anderton BH, Roberts GW: Neurofibrillary
tangles in dementia pugilistica are ubiquitinated. J Neurol Neurosurg Psychiatry 54:116118, 1991.
4. Geddes JF, Vowles GH, Nicoll JA, Revesz T: Neuronal cytoskeletal changes
are an early consequence of repetitive head injury. Acta Neuropathol (Berl)
98:171178, 1999.

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5. Geddes JF, Vowles GH, Robinson SF, Sutcliffe JC: Neurofibrillary tangles,
but not Alzheimer-type pathology, in a young boxer. Neuropathol Appl
Neurobiol 22:1216, 1996.
6. Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH:
Chronic traumatic encephalopathy in a National Football League player.
Neurosurgery 57:128134, 2005.
7. Roberts GW: Immunocytochemistry of neurofibrillary tangles in dementia
pugilistica and Alzheimers disease: Evidence for common genesis. Lancet
2:14561458, 1988.
8. Roberts GW, Allsop D, Bruton C: The occult aftermath of boxing. J Neurol
Neurosurg Psychiatry 53:373378, 1990.
9. Roberts GW, Whitwell HL, Acland PR, Bruton CJ: Dementia in a
punchdrunk wife. Lancet 335:918919, 1990.
10. Tokuda T, Ikeda S, Yanagisawa N, Ihara Y, Glenner GG: Re-examination of
ex-boxers brains using immunohistochemistry with antibodies to amyloid
protein and -protein. Acta Neuropathol (Berl) 82:280285, 1991.

In Reply:
We read with great interest the very long and scholarly
letter by Drs. Casson, Pellman, and Viano, of the Mild Traumatic Brain Injury Committee of the NFL [NFL], regarding
our case report of chronic traumatic encephalopathy in a NFL
player (6). They disagree with the diagnosis of chronic traumatic encephalopathy in this report because they feel that the
neuropathological findings in our case do not meet criteria
enumerated in the landmark study of boxers brains (dementia
pugilistica) by Cosellis et al. (2) and because of the lack of
adequate clinical history. They call for the withdrawal of the
article, which we would not consider, for the reasons below.
Corsellis et al. (2) examined some of the most severely affected
cases of dementia pugilistica, and reported fenestrated cavum
septum pellucidi, scarring of the inferior cerebellum, nigral degeneration, and widespread neocortical neurofibrillary tangle
formation. However, he found the complete tetrad in only twothirds of his cases. Casson et al. imply that the lack of a cavum
septum pellucidum (with or without fenestrations) in our case
somehow precludes a diagnosis of chronic traumatic encephalopathy. However, Corsellis et al. (2) and others have never
asserted that this finding is a sine quo non of dementia pugilistica.
Indeed, it is likely that repetitive head injury in boxers is the most
severe form of chronic traumatic encephalopathy and that septal
injury is most likely to be found in this population. A similar
reason can be given for the lack of cerebellar injury in our
non-pugilistic case. Boxers necessarily experience much more
severe head injuries than would be expected in football players,
and it is not unexpected that the pathological changes may not be
as severe in the latter. The physics of brain trauma in boxing are
quite different from those in football, and football players wear
helmets that diffuse the impact. On the other hand, our case
showed degeneration of the substantia nigra and, most importantly, widespread neocortical neurofibrillary tangle formation.
Neurofibrillary tangles, in this case, were found in the frontal,
temporal, parietal, and occipital cortices, as well as in the cingulate gyrus and insular cortex, but were lacking in the hippocampus and entorhinal cortex, where they always appear first, before
cortical deposition, if the diagnosis is Alzheimers disease (1, 9).
Widespread neocortical neurofibrillary tangles without neuritic
plaques in a 50-year-old man are distinctly unusual and clearly

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CORRESPONDENCE

pathological. This pattern of neurofibrillary tangle formation


would cause most neuropathologists to question whether this
patient had a history of boxing and lead them to examine the
clinical history for episodes of repetitive head trauma, regardless
of whether there were clinical manifestations of the neuropathological changes. This last point is an important one because not
all brain injuries necessarily have a clinical correlate. For example, if a neuropathologist examining a brain discovers an old
infarct, he can conclude that the patient suffered a vascular
ischemic event (stroke), regardless of an absence of clinical
history of stroke.
The term encephalopathy, although most commonly used
to indicate a clinical condition, is a nonspecific term and can be
used in the broadest sense to describe any disease of the
brain according to Stedmans Medical dictionary (8).
Literature cited by our report (6) and by Casson et al.
suggest that neocortical neurofibrillary tangle formation may
be the earliest consequence of repetitive head injury in boxers
and others (3) and underscores that neuropathological
changes may precede obvious clinical symptoms. In this case,
we also describe deposits of -A4, which were also seen in 19
of 20 cases of dementia pugilistica (7).
We doubt Casson et al. really feel that NFL offensive linemen do not experience repeated episodes of head trauma. It is
far more likely that the majority of the head trauma in the
NFL, as well as in American football in general, is underreported by the players and the team staff, who accept the
occasionally dazed recovery during the game and postgame
headaches simply as part of the sport, not unlike bruises and
sprains. Although we agree that this head trauma is not as
severe as that experienced by boxers, who wear no protective
helmets, the repetitive trauma experienced during games, especially over many seasons, may be sufficient in some individuals, especially those with longer careers, to result in neuropathological changes. Those changes could, in some cases,
have clinical significance. More clinical detail was not available to us, but the relationship of the subjects football career
to his cognitive status was also reported in the press:
U.S. District Judge William D. Quarles of Baltimore,
where the Bert Bell/Pete Rozelle Disability Plan is headquartered, agreed with the [family], their attorneys, their
doctors and even an NFL-appointed physician that the
17-year veterans frontal-lobe injury was directly related to
football and therefore started the disability benefits clock
upon his retirement in March 1991. . . the Plan likely will
take the case to the next step a federal appeals court in
the Fourth Circuit at Richmond, Va. . . .the case could take
another year to resolve. It was a triumph nevertheless, said
estate attorney Bob Fitzsimmons, and one that could help
ensuing generations of NFL retirees with brain injuries and
degenerative cognitive impairments (4).
The appeal was subsequently denied (5) and the disability
awarded. Of course, the NFL, at least the Disability Plan,
acknowledged the cognitive impairment and its relationship
to his profession.

NEUROSURGERY

Rather than argue over whether this particular case had


sufficiently documented clinical history of encephalopathy
to warrant the use of the term chronic traumatic encephalopathy, it would seem that the Mild Traumatic Brain Injury
Committee of the NFL should seriously consider this case,
with clear neuropathological changes associated with repetitive head trauma, as one which warrants investigation by the
NFL to determine if clinically significant chronic traumatic
encephalopathy is an occupational hazard in the sport. Our
findings in this initial case are further supported by a second
such case that has come to our attention of another NFL player
with similar neuropathological changes.
The neuropathological findings in this case are distinctly
and uniquely the pattern reported in the early stages of repetitive head trauma and can only have come from a chronic, not
acute, condition. The use of the term chronic traumatic encephalopathy should be considered broad enough to include
preclinical cases, as well as those with mild clinical symptoms,
not just those with severe clinical symptoms. In fact, our case
is important primarily because it indicates that there may be
brain damage in NFL players that is currently under-reported,
because of a lack of long-term clinical follow-up focused on
evaluating such a condition. We suggest that the NFL begin
examining the long-term effects of brain injury in its former
players. We would be happy to collaborate with the Mild
Traumatic Brain Injury Committee and the NFL in developing
and implementing an optimal research program that will address these newly emerging issues.
Bennet I. Omalu
Steven T. DeKosky
Ryan L. Minster
M. Ilyas Kamboh
Ronald L. Hamilton
Cyril H. Wecht
Pittsburgh, Pennsylvania

1. Braak H, Braak E: Neuropathological staging of Alzheimer-related changes.


Acta Neuropathol (Berl) 82:239259, 1991.
2. Corsellis JA, Bruton CJ, Freeman-Browne D: The aftermath of boxing.
Psychol Med 3:270303, 1973.
3. Geddes JF, Vowles GH, Nicoll JA, Revesz T: Neuronal cytoskeletal changes
are an early consequence of repetitive head injury. Acta Neuropathol (Berl)
98:171178, 1999.
4. http://www.post-gazette.com/pg/05117/494863.stm. Accessed February
2006.
5. http://www.post-gazette.com/pg/05152/513580.stm. Accessed February
2006.
6. Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH:
Chronic traumatic encephalopathy in a National Football League player.
Neurosurgery 57:128134, 2005.
7. Roberts GW, Allsop D, Bruton C: The occult aftermath of boxing. J Neurol
Neurosurg Psychiatry 53:373378, 1990.
8. Stedman TL: Stedmans medical dictionary. Baltimore, Williams & Wilkins,
1990.
9. Thal DR, Arendt T, Waldmann G, Holzer M, Zedlick D, Rub U, Schober R:
Progression of neurofibrillary changes and PHF- in end-stage Alzheimers
disease is different from plaque and cortical microglial pathology.
Neurobiol Aging 19:517525, 1998.

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CORRESPONDENCE

In Reply:
The letter by Casson et al. shed light and clarification on the
entity of chronic traumatic encephalopathy that was lacking in
the article by Omalu et al. (1). As they note, it was originally
characterized by a tetrad of findings, including abnormalities
of the septum pellucidum, cerebellar scarring, degeneration of
the substantia nigra, and widespread neurofibrillary tangles in
the cerebral cortex and brainstem. They correctly point out
that the case presented by Omalu et al. (1) had only one of
these pathological findings, raising concern as to whether the
individual actually met the criteria for chronic traumatic encephalopathy. Based on these criteria, it would seem not.
Consequently, the authors assertion that the individuals premortem cognitive decline, depression, and Parkinsonian
symptoms where a manifestation of chronic traumatic encephalopathy seems largely unfounded. Unfortunately, as previously noted by several of the reviewers of the original manuscript, there was no evidence presented linking the players
NFL career to his neurocognitive decline or to the neuropathological findings. Furthermore, the player had no documented
concussions during his career and he played mostly as an
offensive linesman which is one of the positions associated
with the lowest frequency of concussion. Ultimately, the authors lack of alternative explanations for the neuropathological findings, the selective and seemingly inappropriate use of
the definition of chronic traumatic encephalopathy, and the
N of 1 nature of this study severely weaken it. Given this
lack of hard evidence and the overly assuming nature linking
the available data together, I agree that retraction or a major
revision by the authors is warranted. Casson et al. are to be
thanked for further educating us about the entity of chronic
traumatic encephalopathy and completing the editorial
process.
Daniel F. Kelly
Los Angeles, California

1. Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH:
Chronic traumatic encephalopathy in a National Football League player.
Neurosurgery 57:128134, 2005.

In Reply:
My review of the first submission from Omalu et al. (1)
identified many of the issues noted in Casson et al.s letter to
the editor. I recommended that Omalu et al. explicitly state the
weaknesses of their case report material. This was combined
with a corresponding recommendation that sweeping generalizations, based upon this single case, be removed. I concluded my review with the statement: . . .this paper raises
more questions than it answers. . . .
Omalu et al. resubmitted a substantially revised and truncated paper, much more modest in scope, and much more
cautious regarding sweeping generalizations. I thought they
had been responsive to my initial review.
The above statements are regarding the last few paragraphs
of the letter by Casson et al.

E1003 | VOLUME 58 | NUMBER 5 | MAY 2006

More important, however, is the issue of the first several


paragraphs of their letter, which consist of repetitious expositions regarding how Omalu et al. incorrectly used diagnostic
nomenclature. They do not dispute his findings, they simply
dispute the name Omalu et al. have given to those findings.
This seems to be an issue that requires brief discussion and
clarification, not relentless table-pounding.
In summary, I see the Casson et al. letter as raising several
valid points regarding the intrinsic limitations of the case
material used in Omalu et al.s study. However, because these
limitations were noted by Omalu et al. in the published version, I do not see the point of publishing a letter reiterating
them. Additionally, and perhaps more importantly, I see no
value in the repetitious initial paragraphs of the letter devoted
entirely to nomenclature.
Lastly, there is the issue of the tone of the letter. Disagreements among clinicians and scientists are important and
should be published, but they need to reflect appropriate
collegial respect.
Joseph Bleiberg
Neuropsychologist
Washington, D.C.

1. Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH:
Chronic traumatic encephalopathy in a National Football League player.
Neurosurgery 57:128134, 2005.

In Reply:
The authors of this letter should be thanked for compiling this
detailed historical review of our understanding of the neuropathology of chronic brain injury. They argue that the structural
findings reported by Omalu et al. (2) are insufficient to meet the
criteria of chronic traumatic encephalopathy as defined by
Corsellis et al. (1) in 1973 and modified by Roberts et al. (3) in
1990. In addition, this letter emphasizes the paucity of information about the medical history of Omalu et al.s patient.
Omalu et al.s report may serve to stimulate interest in the
area of neurodegenerative histological findings in athletes.
However, the bar has clearly been raised. Future studies will
need to use standardized or widely accepted histological criteria in addition to firm and accurate medical histories.
Alex B. Valadka
Houston, Texas

1. Corsellis JA, Bruton CJ, Freeman-Browne D: The aftermath of boxing.


Psychol Med 3:270303, 1973.
2. Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH:
Chronic traumatic encephalopathy in a National Football League player.
Neurosurgery 57:128134, 2005.
3. Roberts GW, Allsop D, Bruton C: The occult aftermath of boxing. J Neurol
Neurosurg Psychiatry 53:373378, 1990.

In Reply:
Drs. Casson, Pellman, and Vianos letter asserts that Omalu
et al.s (1) article in Neurosurgery contains a serious misinter-

www.neurosurgery-online.com

CORRESPONDENCE

pretation of neuropathological findings in relation to the characteristics of chronic traumatic encephalopathy and a failure
to provide an adequate clinical history. These individuals also
state that they have demonstrated that Omalu et al.s case does
not meet the clinical or neuropathological criteria of chronic
traumatic encephalopathy. They then proceed to urge the
authors to retract their article or sufficiently revise it and its
title after more detailed investigation of the case. I respectfully
disagree with many points presented in this letter and I am
concerned about their extreme reaction in urging the authors
to retract the article.
First, they state that they have demonstrated Omalu et al.s
case did not meet the neuropathological criteria of chronic
traumatic encephalopathy. Neuropathology falls outside of
the scope of expertise in neuropsychology. Therefore, I cannot
comment on neuropathological specifics. However, the neuropathological studies referenced by Casson et al. focus on
boxing studies. Although similar, the biomechanics of
football-related head trauma is not fully equivocal. Therefore,
one cannot absolutely state that chronic traumatic encephalopathy in professional football should be identical to that
found in boxing. Because the article in question is the first of
its kind, no data exists in regarding neuropathology and
chronic traumatic encephalopathy in NFL players. Casson et
al. can only provide an opinion that the neuropathological
findings are owing to other factors. Clearly, they have not
demonstrated this.
Secondly, Casson et al.s assertion that an adequate medical
history was not obtained conveniently does not include reference to traumatic brain injury not being systematically assessed or consistently diagnosed in the league at the time this
player was active. At the time this individual played, there
was a dearth of scientific studies of sports-related head injury
in sports. At the time this individual played, neuropsychological assessment was not being used in the league. At the time
this individual played, concussions were not being monitored.
The lack of documented head injuries and lack of neuropsychological tests results do not demonstrate that multiple concussions did not occur in this individual.
Third, before its acceptance, Omalu et al.s report was carefully reviewed by a group of opinion leaders in the field. This
group included three neurosurgeons, two neurologists, and
two neuropsychologists, all of whom have extensive clinical
and research experience in the field of sports-related head
trauma. The reviewers comments were published at the end
of the article and discussed issues of: 1) neuropathology (Drs.
Bailes, Valadka, and Bleiberg), 2) neuropsychological data
(Drs. Marion and Kutner), 3) lack of documented medical
history (Drs. Kutner and Guskiewicz). It is noted that the
published comments by reviewers contained clear discussion
of limitations of the study.
Fourth, Casson et al. conveniently omitted the obvious contribution of this study. Namely, this is a seminal study in the
field.
Fifth, Casson et al.s letter seems to have exceeded the
protocol for scientifically providing an additional opinion for

NEUROSURGERY

a published story. Specifically, they took an extreme stand in


actually urging the authors to retract the article. Their stand is
quite excessive and, in my opinion, inappropriate. Articles
should be considered for retraction if they contain fabricated
data, contamination of data, or allegation of misconduct. It is
my opinion that there is no justification for retracting this
article.
Kenneth C. Kutner
New York, New York

1. Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH:
Chronic traumatic encephalopathy in a National Football League player.
Neurosurgery 57:128134, 2005.

In Reply:
Drs. Casson, Pellman, and Viano have raised concerns
about the autopsy report of a former NFL player published by
Omalu et al. (6). Specifically, they are concerned that Omalu et
al. may have inappropriately applied the term chronic traumatic encephalopathy to this case because, in their opinion,
the case did not meet histolopathological criteria for this diagnosis. The issues raised by Casson et al. deserve careful
consideration, especially because of their intense research focus on head injury in the NFL as manifest by a series of reports
from this group published in Neurosurgery since 2003.
The letter from Casson et al. is extraordinary in the degree
to which it claims definitive answers to difficult questions
about the neuropathological sequelae of playing football. The
basis for their argument is a report of the autopsies of 15
retired boxers published in 1973, and subsequent publications
that, in most cases, reanalyzed the brain tissue of some of these
original 15 cases. Based on his findings, Corsellis concluded
that boxing led to abnormalities of the septum pellucidum
such as a cavum septum, cerebellar scarring, depigmentation
of the substantia nigra, widespread neurofibrillary tangles,
and total absence of senile plaques. Casson et al. argue that
these autopsy findings of boxers should be the histopathological definition of chronic traumatic encephalopathy of any
cause, and the absence of most of these findings (e.g., the
Omalu et al. case) should exclude the diagnosis.
But, it also is possible, and perhaps likely, that the neuropathological sequelae of football injuries differ from those
observed in boxing. Relevant differences between the two
sports include the fact that the objective of professional boxing
is to cause your opponent to have a concussion (knock out),
whereas in football, it is to score a touchdown. Head injuries
in football, although not uncommon, are incidental. As a
result, football has traditionally included the use of rigid
protective head gear, whereas boxing has not. The most common injuries sustained by football players are orthopedic injuries of the extremities, whereas in boxing, 90% of the injuries
sustained are to the head (10). Pellman et al. have examined
the biomechanics of head injuries sustained in football and
determined that the change in head velocity associated with
the injury is, on average, 7.2 meters per second (7). Atha et al.

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CORRESPONDENCE

(1) have reported that the change in head velocity after a


professional boxing punch may be as much as 5.20 meters per
second, and a force of 6320 newtons. Indeed, an argument
could be made that the neuropathological findings of Corsellis
et al. are unique to retired boxers, and most closely associated
with the clinical entity of dementia pugilistica. Others have
noted a high incidence of cavum septum pellucidum in boxers, and suggested that this is a sign of boxers encephalopathy (2).
Regarding the acute and chronic molecular and histological
changes associated with brain injury, there remain far more
questions than answers. Although most clinical epidemiological studies have found that traumatic brain injury is a risk
factor for the development of dementia (5), there is relatively
little data defining the typical histological sequelae of mild
traumatic brain injury, especially in sports other than boxing.
The link between brain injury and the molecular and histological manifestations of Alzheimers disease is particularly
complicated. The molecular and histological hallmarks of Alzheimers disease are increased levels of amyloid--protein,
-amyloid precursor protein, , and apolipoprotein E.
-protein is associated with neurofibrillary tangles, and
-amyloid precursor protein with plaque formation, the two
histological characteristics of Alzheimers disease. Confounding the picture is the fact that neurofibrillary tangles and
plaques are common in normal aging, even in those without
dementia (3). And some patients with a clear premorbid history of dementia have been found at autopsy to have predominant plaques, but few or no neurofibrillary tangles (9).
Recently, a number of investigators have studied the association of acute brain injury with amyloid--protein,
-amyloid precursor protein, apolipoprotein, and , as well as
with plaques and neurofibrillary tangles. After traumatic
brain injury, markedly elevated cerebrospinal levels of
amyloid--protein and -amyloid precursor protein have
been observed (5). Ikonomovic et al. (4) studied the fresh
tissue obtained at surgery from 18 traumatic brain injury
patients, aged 18 to 64 years, who were undergoing decompressive procedures. Diffuse cortical amyloid--protein deposits were observed in 33%, but -positive neurofibrillary
tangles were detected in only two patients, both of whom
were older. Smith et al. (8) compared histopathological
changes in 45 traumatic brain injury patients who died up to
1 month after injury with age-matched controls and found a
subtle increase in immunoreactivity in some of the traumatic
brain injury patients, but not a greater prevalence of neurofibrillary tangles, as compared with controls. Based on these
studies, at least, it is not surprising that Omalu et al. (6) did not
find a predominance of neurofibrillary tangles in the brain of
the football player they examined. It is important to emphasize, however, that these were studies of the acute manifestations of severe traumatic brain injury, and the relevance of
these findings to mild traumatic brain injury is not known.
Subtle cognitive and memory disturbances are well known
sequelae of sports-related concussion and are worse and of
longer duration when there are multiple injuries. Prolonged or

E1003 | VOLUME 58 | NUMBER 5 | MAY 2006

permanent cognitive deficits can severely disable otherwise


healthy athletes. Yet, because such injuries are rarely fatal,
little is known about the brain histopathology underlying
these disturbances. Excluding autopsy reports of former boxers, there are very few reports of the histopathological changes
in the brains of athletes with a past history of mild traumatic
brain injury. Although the report by Omalu et al. (6) can be
criticized for not providing documentation of specific premorbid episodes of concussion, the likelihood that that individual
sustained one or more concussions during the 17 seasons he
played in the NFL is high. Despite this shortcoming, their
report is important because it is the first to carefully document
the late histopathological changes in a professional football
player. Their findings can reasonably be considered consistent
with chronic traumatic encephalopathy because few others
have clearly described the autopsy findings in such cases. It
should not be assumed that autopsy findings in boxers will be
similar to those seen in other sports, and the only way to
establish the presence or absence of similarities will be
through a large number of reports similar to that from Omalu
et al. (6). The criteria for the diagnosis of chronic traumatic
encephalopathy attributed to Corsellis may, therefore, only be
appropriate for boxers.
As members of the Mild Traumatic Brain Injury Committee
of the NFL, and clinician-scientists that are clearly devoted to
the investigation of sports-related concussion, Drs. Casson,
Pellman, and Viano should welcome the contribution from
Omalu et al. and consider the findings of that report highly
relevant to their own research, rather than recommending
retraction of the article. The need to obtain more details regarding premorbid neuropsychological deficits and specific
episodes of concussion is clearly recognized and stated by
Omalu et al. (6) in their paper, but the histopathological findings are clearly described and consistent with a previous
history of brain injury. Together with subsequent reports of
autopsy results from NFL players, which hopefully will include the important premorbid clinical details, we will begin
to establish a reliable definition of chronic traumatic encephalopathy typical for professional football players.
Donald W. Marion
Boston, Massachusetts

1. Atha J, Yeadon MR, Sandover J, Parsons KC: The damaging punch. Br Med J
(Clin Res Ed) 291:17561757, 1985.
2. Bogdanoff B, Natter HM: Incidence of cavum septum pellucidum in adults:
A sign of boxers encephalopathy. Neurology 39:991992, 1989.
3. Hof PR, Glannakopoulos P, Bouras C: The neuropathological changes associated with normal brain aging. Histol Histopathol 11:10751088, 1996.
4. Ikonomovic MD, Uryu K, Abrahamson EE, Ciallella JR, Trojanowski JQ, Lee
VM, Clark RS, Marion DW, Wisniewski SR, DeKosky ST: Alzheimers
pathology in human temporal cortex surgically excised after severe brain
injury. Exp Neurol 190:192203, 2004.
5. Jellinger KA: Head injury and dementia. Curr Opin Neurol 17:719723,
2004.
6. Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH:
Chronic traumatic encephalopathy in a National Football League player.
Neurosurgery 57:128134, 2005.

www.neurosurgery-online.com

CORRESPONDENCE

7. Pellman EJ, Viano DC, Tucker AM, Casson IR, Waeckerle JF: Concussion in
professional football: Reconstruction of game impacts and injuries.
Neurosurgery 53:799812, 2003.
8. Smith MS, Dyson RJ, Hale T, Janaway L: Development of a boxing dynamometer and its punch force discrimination efficacy. J Sports Sci 18:445
450, 2000.
9. Tiraboschi P, Sabbagh MN, Hansen LA, Salmon DP, Merdes A, Gamst A,
Masliah E, Alford M, Thal LJ, Corey-Bloom J: Alzheimer disease without
neocortical neurofibrillary tangles: A second look. Neurology 62:1141
1147, 2004.
10. Zazryn TR, Finch CF, McCrory P: A 16 year study of injuries to professional
boxers in the state of Victoria, Australia. Br J Sports Med 37:321324, 2003.

DOI: 10.1227/01.NEY.0000217313.15590.C5

Hyperosmolar Agents in Neurosurgical Practice: The


Evolving Role of Hypertonic Saline
To the Editor:
The article by Ogden et al. (1), Hyperosmolar Agents in
Neurosurgical Practice: The Evolving Role of Hypertonic Saline
was interesting, despite the significant negative aspects pointed
out by the commenters. Perhaps it is attributable to the impact of
the electronic library, but it is sad to see pertinent history ignored.
Hopefully, we will not be doomed to repeat old mistakes. Studies
of hyperosmolar agents used to treat increased intracranial pressure can be traced back to the seminal work of Weed and
McKibben (2) in 1919. They reported that hypertonic saline led to
respiratory and cardiac disturbances, but hypertonic glucose was
followed by a significant pressure rebound. Their work led to
studies of hypertonic magnesium sulfate and sodium arabinate,
and the later discovery that hypertonic urea was clinically useful.
At present, our best studied and extremely useful agents for
osmotherapy are hypertonic glycerol (effective when taken by
mouth or gastric tube, very useful for chronic administration, but
currently underused) and mannitol. Hopefully, these agents will
not be abandoned in a rush to use the new glamour treatment
of hypertonic saline (actually nearly a century old) before its
proper role and safety have been adequately defined, as people
rushed to use pressors to increase central nervous system perfusion pressure in preference to mannitol and caused an unknown
number of cases of severe pulmonary damage (3).
Harold A. Wilkinson
Wellesley, Massachusetts

1. Ogden AT, Mayer SA, Connolly ES Jr: Hyperosmolar agents in neurosurgical practice: The evolving role of hypertonic saline. Neurosurgery 57:207
215, 2005.
2. Weed LH, McKibben PS: Pressure changes in cerebrospinal fluid following
intravenous injection of solutions of various concentrations. Am J Physiol
48:512530, 1919.
3. Wilkinson HA: Cerebral perfusion pressure and intracranial pressure.
J Neurosurg 103: 195196, 2005.

In Reply:
We greatly appreciate the comments of Harold A. Wilkinson
regarding our review of hypertonic saline and are pleasantly
surprised that the review has generated so much animated dis-

NEUROSURGERY

cussion (1). Hypertonic saline is not by any means a new treatment, but it is in the middle of a clinical and investigational
renaissance that far postdates the inception of electronic databases. As Dr. Wilkinson points out, the notion of using hypertonic saline to treat cerebral edema was around for 75 years
before it saw any serious clinical application, so we dont agree
that people have felt rushed to use it. That its breadth of
current clinical use is not well-matched by sufficient animal and
clinical research is one of the chief points of our article. Still, it
does seem that if hypertonic saline, as it is used today, carried the
deleterious cardiopulmonary side-effects implied by Dr. Wilkinson, that the myriad studies outlined in our article would have
mentioned some examples of them.
Although outside the scope of our review, glycerol is, of
course, another effective osmotic agent, little used in the
United States compared with Europe and Japan, perhaps because of the perceived inconvenience of enteral administration. When and whether glycerol, mannitol, or hypertonic
saline works better will hopefully be determined in future
clinical trials. Our hope is that the hypertonic saline revival
will lead to a more rigorous examination and comparison of
all hyperosmolar therapies.
Alfred T. Ogden
New York, New York

1. Ogden AT, Mayer SA, Connolly ES Jr: Hyperosmolar agents in neurosurgical practice: the evolving role of hypertonic saline. Neurosurgery 57:207
215, 2005.

DOI: 10.1227/01.NEU.0000217319.53708.BC

Rapid Administration of Antifibrinolytics and Strict


Blood Pressure Control for Intracerebral Hemorrhage
To the Editor:
In a retrospective study, the administration of antifibrinolytics
and strict blood pressure control was reported to prevent hematoma growth in patients with spontaneous intracerebral hemorrhage (37). A combination of tranexamic acid and nicardipine
was given intravenously to 156 patients. One group received a
prolonged infusion of 1 g tranexamic acid over a period of 6
hours and the second group was given a rapid infusion of 2 g
tranexamic acid over a period of 10 minutes. Hematoma growth
was observed in 17.5 % of the 63 patients in the first group and
in 4.3 % of 93 patients in the second group.
The most commonly used synthetic antifibrinolytics are
epsilon-aminocaproic acid (EACA), tranexamic acid (AMCA)
and para-aminobenzoic acid (PAMBA). On a molar basis
AMCA is four to 10 times more potent than EACA and twice
as strong as PAMBA (2, 26, 29, 31, 34). These antifibrinolytics
have been shown to cross the blood-cerebrospinal fluid (CSF)
barrier to reduce or inhibit the increased fibrinolytic activity of
blood or CSF after aneurysmal subarachnoid hemorrhage
(SAH) and to prolong and solidify experimental thrombosis

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CORRESPONDENCE

(12, 15, 16, 30, 35). The therapeutic plasma concentration of


synthetic antifibrinolytic drugs has been estimated to be more
than 130 mg/L for EACA and more than 10 mg/L for AMCA,
which requires an intravenous dosage of 2436 g of EACA and
36 g of AMCA/ 24 hours (3, 14, 28). It is known that antifibrinolytic agents possess sympathomimetic properties and
may, theoretically, induce vasoconstriction, possibly by acting
via the adrenergic nerve terminals and thus deplete the stored
catecholamines (1, 17, 24, 27, 32, 33). There have been several
reports of thrombotic episodes, glomerular microthrombi, myopathy, myoglobinuria and cardiovascular complications following administration of antifibrinolytic drugs (48, 13, 18, 19,
20, 22, 23, 25, 36, 38, 40). Randomized controlled studies using
antifibrinolytics in patients with SAH have shown increased
delayed cerebral ischemic complications (911, 14, 15, 39).
Some authors have suggested the use of antifibrinolytics in
combination with calcium channel blockers (nicardipine, nimodipine) in the hope of reducing rebleeds as well as delayed
cerebral ischemic complications in SAH (21). However, today
the prime rationale for the use of antifibrinolytic drugs in SAH
has disappeared (14).
In the present study, no serious adverse effects were noted
(37). The occurrence of renal dysfunction in three patients and
fatal myocardial infarction in two patients were considered to
have no relationship with the administration of tranexamic
acid. In my opinion, the authors have no basis for this assumption, and they have refrained from documenting the pharmacokinetics, toxicology, and important side effects of the drug.
They simply refer to an attached document from the drug
manufacturer stating that up to 2.5 g of tranexamic acid can be
safely administered in a single dose and, therefore, settled for
an arbitrary dose of 2 g. Patients who required surgery or who
had a bad prognosis were not included, whereas 20 patients
with history of renal disease, angina pectoris, and myocardial
infarction were included. There is no mention of clinical outcomes in the report, and the only thing we learn from the
study is that there was less hematoma growth. Who is the
winner here, the patient or the drug company?
With regard to the potential serious side effects of tranexamic acid as documented in the literature, the therapeutic
regimen for intracerebral hemorrhage described in this limited
study should be disregarded until a carefully designed randomized controlled clinical trial has been conducted.
Harald Fodstad
New York, New York

1. Anden NE, Henning M, Obianwu HO: Effect of epsilon aminocaproic acid


on adrenergic nerve function and tissue monoamine levels. Acta Pharmacol
Toxicol 26:13129, 1968.
2. Andersson L, Nilsson IM, Nilehn JE, Hedner U, Granstrand B, Melander B:
Experimental and clinical studies on AMCA, the antifibrinolytically active
isomer of p-aminomethyl cyclohexane carboxylic acid. Scand J Haematol
2:22302347, 1965.
3. Andersson L, Eriksson O, Hedlund PO, Kjellman H, Lindqvist B: Special
considerations with regard to the dosage of tranexamic acid in patients with
chronic renal disease. Urol Res 2:8388, 1978.

E1003 | VOLUME 58 | NUMBER 5 | MAY 2006

4. Bergin JJ: Complications of therapy with epsilon-aminocaproic acid. Med


Clin North Am 50:16691678, 1966.
5. Biswas CK, Milligan DA, Agte SD, Kenward DH, Tilley PB: Acute renal
failure and myopathy after treatment with aminocaproic acid. Br Med J
281:115116, 1980.
6. Britt CW, Light RR, Peters BH: Rhabdomyolysis during treatment with
epsilon-aminocaproic acid. Arch Neurol 37:187188, 1980.
7. Charytan C, Purtilo D: Glomerular capillary thrombosis and acute renal
failure after epsilon-aminocaproic acid therapy. N Engl J Med 280:1102
1104, 1969.
8. Davies D, Howell DA: Tranexamic acid and arterial thrombosis. Lancet 1:49,
1977.
9. Fodstad H: Tranexamic acid as therapeutic agent in aneurysmal subarachnoid
haemorrhage: Clinical, laboratory and experimental studies. Umea University
Medical Dissertations, New Series No 60:174, 1980.
10. Fodstad H: Antifibrinolytic treatment in subarachnoid haemorrhage:
Present state. Acta Neurochir 63:233244, 1982.
11. Fodstad H, Forssell A, Liliequist B, Schannong M: Antifibrinolysis with
tranexamic acid in aneurysmal subarachnoid hemorrhage: A consecutive
controlled clinical trial. Neurosurgery 8:158165, 1981.
12. Fodstad H, Kok P, Algers G: Fibrinolytic activity of cerebral tissue after
experimental subarachnoid haemorrhage: Inhibitory effect of tranexamic
acid (AMCA). Acta Neurol Scand 64:2946, 1981.
13. Fodstad H, Liliequist B: Spontaneous thrombosis of ruptured intracranial
aneurysms during treatment with tranexamic acid (AMCA). Report of three
cases. Acta Neurochir 49:129144, 1979.
14. Fodstad H, Ljunggren B: Antifibrinolytic drugs in subarachnoid hemorrhage, in Sawaya R (ed): Fibrinolysis and the Central Nervous System. Philadelphia, Hanley & Belfus, 1990, pp 257273.
15. Fodstad H, Nilsson IM: Coagulation and fibrinolysis in blood and cerebrospinal fluid after aneurysmal subarachnoid haemorrhage: Effect of
tranexamic acid (AMCA). Acta Neurochir 56:2538, 1981.
16. Fodstad H, Pilbrant A, Schannong M, Stromberg S: Determination of
tranexamic acid and fibrin/fibrinogen degradation products in cerebrospinal fluid after aneurysmal subarachnoid haemorrhage. Acta Neurochir 58:
113, 1981.
17. Garrett J, Branco D: Indirect sympathomimetic actions of E-amini-caproic
acid (EACA): Role of the adrenal medulla. Arch Int Pharmacodyn Ther
204:253259, 1973.
18. Gilligan BS: Myoglobinuria with muscle weakness associated with epsilonaminocaproic acid therapy, in Kakulas BA (ed): Clinical Studies in Myology.
Part 2. New York, Elsevier, 1973, pp 589593.
19. Gralnick HR, Greipp P: Thrombosis with epsilon aminocaproic acid therapy.
Am J Clin Pathol 56:151154, 1971.
20. Hoffman EA, Koo AH: Cerebral thrombosis associated with Amicar therapy. Radiology 131:687689, 1979.
21. Kassell NF, Haley EC, Torner JC: Antifibrinolytic therapy in the treatment of
aneurysmal subarachnoid hemorrhage. Clin Neurosurg 33:137145, 1986.
22. Kennard C, Henson RA: Myopathy due to epsilon aminocaproic acid. Muscle Nerve 3:202206, 1980.
23. Kato N, Morimatsu M, Tanaka K, Horie A: Effects of trans-4-aminomethylcyclohexane carboxylic acid as an antifibrinolytic agent on arterial wall and
experimental atherosclerotic lesions in rabbits. Thromb Diath Haemorrh
24:8599, 1970.
24. Lippmann W, Wishnick MM: Effects of the administration of epsilon
aminocaproic acid on catecholamine and serotonin levels in the rat and dog.
J Pharmacol Exp Ther 150:196202, 1965.
25. Mackay AR, Hoi Sang U, Weinstein PR: Myopathy associated with epsilonaminocaproic acid (EACA) therapy: Report of two cases. J Neurosurg 49:
597601, 1978.
26. Maki M, Beller FK: Comparative studies of fibrinolytic inhibitors in vitro.
Thromb Diath Haemorrh 16:668686, 1966.
27. Marmo E, Di Nola R, Rossi F: Cardiovascular effects of of antifibrinolytic
drugs. Res Commun Chem Pathol Pharmacol 6:137150, 1973.
28. McNichol GP, Fletcher AP, Alkjaerstig N, Sherry S: The absorption, distribution and excretion of e-aminocaproic acid following oral or intravenous
administration in man. J Lab Clin Med 59:1524, 1962.

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CORRESPONDENCE

29. Melander B, Gliniecki G, Granstrand B, Hansoff G: Biochemistry and toxicology of Amicapron; the antifibrinolytically active isomer of AMCHA. (A
comparative study with e-aminocaproic acid.) Acta Pharmacol Toxicol 22:
340352, 1965.
30. Mihara H, Fuji T, Okamoto S: Fibrinolytic activity of cerebrospinal fluid and
the development of artificial cerebral haemorrhage. Thromb Diath
Haemorrh 21:294303, 1969.
31. Nilsson IM: Clinical pharmacology of aminocaproic and tranexamic acid.
J Clin Pathol 33 [Suppl 14]:4147, 1980.
32. Norrman SR: The sympathomimetic action of trans-4-amino-methyl
cyclohexane carboxylic acid (AMCA, Cyclocapron) in anaesthetized cats.
Data on file, AB Kabi, Stockholm, 1975.
33. Obianwu HO: Disposition of 3 H-epsilon aminocaproic acid and its interaction with adrenergic neurons. Br J Pharmacol 31:244252, 1967.
34. Okamoto S, Oshiba S, Mihara H, Okamoto U: Synthetic inhibitors of fibrinolysis: In vitro and in vivo mode of action. Ann NY Acad Sci 146:414429,
1968.
35. Patterson RH, Harpel P: The effect of epsilon-aminocaproic acid and
tranexamic acid on thrombus size and strength in a simulated arterial
aneurysm. J Neurosurg 34:365371, 1971.
36. Rydin E, Lundberg PO: Tranexamic acid and intracranial thrombosis. Lancet
2:49, 1976.
37. Sorimachi T, Fujii Y, Morita K, Tanaka R: Rapid administration of
antifibrinolytics and strict blood pressure control for intracerebral hemorrhage. Neurosurgery 57:837844, 2005.
38. Vanneste JA, van Wijngaarden GK: Epsilon-aminocaproic acid myopathy:
Report of a case and literature review. Eur Neurol 21:242248, 1982.
39. Vermeulen M, Lindsay KW, Murray GD, Cheah H, Hijdra A, Muizelaar JP,
Schannong M, Teasdale GM, van Crevel H, van Gijn J: Antifibrinolytic
treatment in subarachnoid hemorrhage. N Engl J Med 311:432437, 1984.
40. Yamaura A, Nakamura T, Makino H: Cerebral complication of
antifibrinolytic therapy in the treatment of ruptured intracranial aneurysm.
Eur Neurol 19:7784, 1980.

In Reply:

Methods of Antifibrinolytics Administration and their


Side Effects
Continuous administration of tranexamic acid (616 g/day)
has been reported to reduce the frequency of rebleeding after
aneurysmal subarachnoid hemorrhage (SAH), but to increase
the risk of delayed cerebral ischemia owing to vasospasm
(1113, 20). Antifibrinolytics therapy is not used for SAH
nowadays because overall outcome does not improve (11, 13).
In our study for intracerebral hemorrhage (ICH), the total dose
of tranexamic acid, which was 2 g (17), is far smaller than
those for SAH. To obtain hemostasis of ICH at the beginning
of the treatment, an initial loading of sufficient amount of
tranexamic acid makes the clot firm. Once the clot is stabilized,
strict control of blood pressure maintains the hemostasis.
Then, we did not use tranexamic acid continuously.
In all of the case reports on side effects of antifibrinolytics
referred by Dr. Fodstad, a large amount of antifibrinolytics
was administered continuously (16, 8, 9, 14, 19). The side
effects were observed during continuous administration of
epsilon-amino caproic acid (2336 g/day) or tranexamic acid
(36 g/day). Myopathy was induced by continuous administration of antifibrinolytics for 4 weeks or longer (1, 2, 8, 9, 19).
Cerebral infarct not related to vasospasm after SAH occurred
during continuous medication with antifibrinolytics for 1 year
or longer (4, 14). Reduction or disappearance of cerebral an-

NEUROSURGERY

eurysms was observed during continuous administration of


antifibrinolytics for 3 weeks or longer (5). On the other hand,
in two case reports renal failure was induced in the early
phase of treatment with continuous administration of epsilonamino caproic acid when the patients were in a serious condition with hypotension (3, 6).
Thromboembolic complication rates related to continuous administration of tranexamic acid have not been reported so high.
Vermeulen et al. (20) reported their randomized control study on
SAH using continuous administration of tranexamic acid (6
g/day) for 1 week or longer. In their study deep-vein thrombosis
was evident in 21 of 241 patients at 3 months, and there was no
difference in incidence between the study groups. Roos et al. (12)
reported randomized study on SAH using continuous administration of tranexamic acid (6 g/day) for up to 3 weeks. A serious
adverse drug reaction observed in their study was pulmonary
embolism, and it was found in only four of 229 patients. On the
other hand, a relative small amount of tranexamic acid was
administered continuously in two studies on SAH. In one study,
tranexamic acid (1.5 g/day) was given for 5 to 25 days (18), and,
in another, 5 g/day for up to 3 days (7). In these studies, there
were no indications of increased risk of either cerebral ischemia
owing to vasospasm or thromboembolic complications that
could be linked to tranexamic acid treatment. In our study, 2 g of
tranexamic acid was administered for only one time, and, to our
knowledge, no serious adverse effect has been reported with this
dose of tranexamic acid.
Tranexamic acid has been used for about 40 years, and approximately 1,240,000 g of tranexamic acid was supplied in 2004.
According to the attached document of tranexamic acid, a limited number of clinical cases of renal dysfunction, cerebral ischemia, cardiac ischemia, and venous thrombosis were reported as
serious side effects, and these side effects should be carefully
checked during treatment with tranexamic acid. However, these
side effects could be regarded as rare, considering the large
amount of tranexamic acid consumption. The half-life of 1g of
intravenously administered tranexamic acid was 1.9 hours, and
94.8% of it was excreted into urine within 2 days (16). The
thromboembolic complications in the rapid administration of
antifibrinolytics (RAF) group of our study occurred 4 to 45 days
after administration of tranexamic acid (17), while the tranexamic
acid was already excreted. However, the possibility cannot be
eliminated that tranexamic acid became a trigger to proceed the
thromboembolic complications.
Table 1 shows thromboembolic complications in the prolonged infusion of antifibrinolytics (PAF) group and the RAF
group of our study. The PAF group was used as a control in
this study, because PAF has been used in many Japanese
hospitals. Thromboembolic complications in the RAF group
were described (17). In the PAF group, either a history or
presence of renal dysfunction was present in eight patients at
admission, and, in one of them, renal function was worsening.
Newly developed renal dysfunction after admission was observed in two patients. These renal dysfunctions improved
after conservative treatment. A history of ischemic heart disease was found in two patients in the PAF group. None of

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CORRESPONDENCE

TABLE 1. Complications in patients treated with prolonged


infusion of antifibrinolytics and rapid administration
of antifibrinolyticsa

TABLE 2. Clinical outcome in patients treated with prolonged


infusion of antifibrinolytics and rapid administration
of antifibrinolyticsa

PAF group
(n 63)

RAF group
(n 93)

Renal dysfunction

3 (4.8%)

3 (3.2%)

0, 1

Ischemic heart disease

3 (4.8%)

2 (2.2%)

Cerebral infarct

1 (1.6%)

Deep vein thrombosis

0 (0%)

Complication

PAF group
(n 63)

RAF group
(n 93)

2 (3.2%)

15 (16.1%)

10 (15.9%)

10 (10.8%)

0 (0%)

13 (20.6%)

13 (14%)

0 (0%)

15 (23.8%)

35 (37.6%)

18 (28.6%)

16 (17.2%)

5 (7.9%)

4 (4.3%)

PAF, prolonged infusion of antifibrinolytics; RAF, rapid administration of


antifibrinolytics.

mRSb

Dead
a

them showed a recurrence during their hospital treatment.


Two patients without history of ischemic heart disease experienced angina pectoris and one patient, who died 50 days
after admission, sustained acute myocardial infarction. Five
patients in the PAF group had a history of cerebral infarction.
None of them sustained cerebral infarction. Newly developed
cerebral infarction was observed in one patient. In the PAF
group, these complications also seem to have no relationship
with the administration of tranexamic acid, because of the
interval (3-50 d) between the administration and the occurrence of the symptoms. No significant difference was observed in occurrence of thromoboembolic complications between the PAF group (11.1%) and the RAF group (5.4%) (P
0.19, 2 analysis). During and after the treatment with tranexamic acid, adverse effects should be carefully monitored.
When a patient has a history of renal dysfunction, dose reduction of tranexamic acid and/or mild blood pressure control
might be better to preserve renal function. In all patients
treated with this method, careful check of urine volume and
renal function should be recommended.

Clinical Outcome
Table 2 shows modified Rankin Scale (mRS) at 1 month
after the onset or at discharge. In patients with good outcome (mRS 0, 1, or 2), no significant difference was
observed between the PAF group (19.1%) and the RAF
group (26.9%) (P 0.26, 2 analysis). On the other hand,
more patients had serious outcome (mRS 5, dead) significantly in the PAF group (36.5%) than those in the RAF
group (21.5%) (P 0.04, 2 analysis). Table 3 shows mRS in
patients with hematoma enlargement. In patients without
hematoma enlargement, no significant difference was observed in serious outcome (mRS 5, dead) between the
PAF group (34.6%) and the RAF group (20.2%) (P 0.06, 2
analysis). Considering the small number of hematoma enlargement in both groups, we cannot conclude that clinical
outcome improved in the RAF group by reduction of hematoma enlargement in this study. On the other hand, in all
of the patients with hematoma enlargement in this study,

E1003 | VOLUME 58 | NUMBER 5 | MAY 2006

mRS, modified Rankin Scale; PAF, prolonged infusion of antifibrinolytics;


RAF, rapid administration of antifibrinolytics.
b
mRS at 30 days or at discharge.

TABLE 3. Clinical outcome in patients with


hematoma enlargementa
mRSb

PAF groupc
(n 11)

RAF groupd
(n 4)

0, 1

0 (0%)

0 (0%)

0 (0%)

0 (0%)

4 (36.4%)

0 (0%)

2 (18.2%)

2 (50%)

4 (36.4%)

2 (50%)

Dead

1 (9.1%)

0 (0%)

PAF, prolonged infusion of antifibrinolytics; RAF, rapid administration of


antifibrinolytics.
b
mRS at 30 days or at discharge.
c
Patients treated with PAF and strict blood pressure control.
d
Patients treated with RAF and strict blood pressure control.

consciousness level, and/or severity of paresis became


worse in the day after admission than those at admission.
Furthermore, no patients with hematoma enlargement
showed good outcome (mRS 0, 1, or 2). Therefore, we
considered that hematoma enlargement resulted in worsening of clinical state.

Who is the winner?


The authors are not related to the drug company, and did
not receive any assistance from the drug company. Tranexamic acid costs about $3.00 for 2 g in Japan. Therefore, the
drug company is not considered the winner. We think that the
winners are the patients without hematoma enlargement
treated with this low-cost method. The prolonged infusion of

www.neurosurgery-online.com

CORRESPONDENCE

tranexamic acid has been used for ICH in many Japanese


hospitals because tranexamic acid is regarded as a relatively
safe drug. ICH occurred more frequently in Japan compared
with the United States and Europe (15). More than one-fifth of
stroke patients treated in our cerebrovascular center experience ICH. ICH is the least treatable form of stroke and is
associated with higher morbidity and greater disability than
ischemic stroke or SAH (15). Intervention with hemostatic
therapy might improve a patients disability after ICH by
arresting ongoing bleeding and minimizing increases in the
volume of the hematoma (10). A well-designed, randomized,
control study is needed to confirm our results, and to determine the appropriate dose of tranexamic acid. Side effects,
including renal dysfunction, should be carefully monitored
during and after the treatment.
Takatoshi Sorimachi
Tokyo, Japan

1. Biswas CK, Milligan DA, Agte SD, Kenward DH, Tilley PB: Acute renal
failure and myopathy after treatment with aminocaproic acid. Br Med J
281:115116, 1980.
2. Britt CW, Light RR, Peters BH: Rhabdomyolysis during treatment with
epsilon-aminocaproic acid. Arch Neurol 37:187188, 1980.
3. Charytan C, Purtilo D: Clomerular capillary thrombosis and acute renal
failure after epsilon-aminocaproic acid therarpy. N Engl J Med 280:1102
1104, 1969.
4. Davies D, Howell DA: Tranexamic acid and arterial thrombosis. Lancet 1:49,
1977.
5. Fodstad H, Liliequist B: Spontaneous thrombosis of ruptured intracranial
aneurysms during treatment with tranexamic acid (AMCA). Report of three
cases. Acta Neurochir 49:129144, 1979.
6. Gralnick HR, Greipp P: Thrombosis with epsilon aminocaproic acid therapy.
Am J Clin Pathol 56:151154, 1971.
7. Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE:
Immediate administration of tranexamic acid and reduced incidence of early
rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 97:771778, 2002.
8. Kennard C, Henson RA: Myopathy due to epsilon aminocaproic acid. Muscle Nerve 3:202206, 1980.
9. Mackay AR, Hoi Sang U, Weinstein PR: Myopathy associated with epsilonaminocaproic acid therapy: Report of two cases. J Neurosurg 49:597601,
1978.
10. Mayer SA: Rapid hemostatic therapy for intracerebral hemorrhage. Stroke
34:224229, 2003.
11. Roos Y, Rinkel G, Vermeulen M, Algra A, van Gijn J: Antifibrinolytic
therapy for aneurysmal subarachnoid hemorrhage. A major update of a
Cochrane review. Stroke 34:23082309, 2003.
12. Roos Y, the Star Study Group: Antifibrinolytic treatment in subarachnoid
hemorrhage. A randomized placebo-controlled trial. Neurology 54:7782,
2000.
13. Roos Y, Vermeulen M, Rinkel GJ, Algra A, van Gijn J, Algra A: Systematic
review of antifibrinolytics treatment in aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 65:942943, 1998.
14. Rydin E, Lundberg PO: Tranexamic acid and intracranial thrombosis. Lancet 2:49, 1976.
15. Sacco RL, Mayer SA: Epidemiology of intracerebral hemorrhage, in
Feldmann E (ed): Intracerebral Hemorrhage. Armonk, Futura Publishing Co,
1994, pp 323.
16. Sano M, Hakusui H, Kojima C, Akimoto T: Absorption and excretion of
tranexamic acid following intravenous, intramuscular and oral administrations in healthy volunteers [in Japanese]. Clin Pharmacol Ther 7:375382,
1976.

NEUROSURGERY

17. Sorimachi T, Fujii Y, Morita K, Tanaka R: Rapid administration of


antifibrinolytics and strict blood pressure control for intracerebral hemorrhage. Neurosurgery 57:837844, 2005.
18. Stroobandt G, Lambert O, Menard E: The association of tranexamic acid and
nimodipine in the pre-operative treatment of ruptured intracranial aneurysms. Acta Neurochir (Wien) 140:148160, 1998.
19. Vanneste JA, van Wijingaarden GK: Epsilon-aminocarproic acid myopathy:
Report of a case and literature review. Eur Neurol 21 242248, 1982.
20. Vermeulen M, Lindsay KW, Murray GD, Cheah F, Muizelaar JP, Schannong
M, Teasdale GM, van Greavel H, van Gijn J: Antifibrinolytic treatment in
subarachnoid hemorrhage. N Engl J Med 311:432437, 1984.

DOI: 10.1227/01.NEU.0000217321.47870.6A

Visualizing the Dynamics of Cerebral Aneurysms with


Four-Dimensional Computed Tomographic Angiography
To the Editor:
We read with great interest the article written by Ishida et
al. (1). In this article, the authors reported that fourdimensional computed tomographic (4D-CT) angiography
detected the pulsating blebs in nine of 28 saccular ruptured
aneurysms. And, in two with ruptured aneurysms, the pulsating blebs were confirmed as the ruptured points during
the surgical procedure. Certainly, this method seems to be
a new and promising technique for the demonstration of the
hemodynamics of the aneurysmal wall. We have performed
the same procedure for the cerebral aneurysms. Initially, we
expected the method would be a novel technique to detect
a portion of wall thinning of cerebral aneurysms, allowing
us to predict the rupture risk of the aneurysms. As the
authors results, our study demonstrated the movement of
the aneurysm with an electrocardiograph cycle. We compared the findings of the 4D-CT movie with the intraoperative findings of the aneurysm. However, there was a big
discrepancy between them (2). If readers look at the figures
and online digital video, they will see that the movement of
aneurysm, the surrounding normal arteries, veins, and bone
is displayed. During operation, the pulsating movement of
major arteries is always observed, but the vein and cranium
do not have any movement.
Nevertheless, the movement of the vein and bone exhibited
on the 4D-CT angiography (14). We have never seen the
pulsating blebs and the aneurysmal wall motion during surgery. We cannot fully explain what induces the movement on
the 4D-CT angiography. We speculate the following factors:
rotating x-ray beam (Helical scanning), heterogeneous concentration of contrast medium in the vessels, and the movement
of the artery itself with cardiac cycle. We studied the movement of the subject using phantom (Fig C2). As you can see,
the artifacts owing to scanning were demonstrated. The plastic
model does not have the movement caused by the cardiac
cycle and heterogeneous concentration of the contrast medium. However, the bleb-like structures were demonstrated.
The authors should indicate the definition to decide the abnormal findings. Figure 7 in the article suggests that this
technique is unreliable, because the phases showing the pulsating bleb are not consistent.

VOLUME 58 | NUMBER 5 | MAY 2006 | E1003

CORRESPONDENCE

2. Matsumoto M, Sato T, Oinuma M,


Sato M, Suzuki K, Sasaki T, Kodama
N, Murakami K, Suzuki K, Katakura
T, Shishido F: ECG triggered 3
dimensional-CT angiography for cerebral aneurysms using multislice helical CT [in Japanese]. Prog Comput
Imaging 23:133138, 2001.
3. Hayakawa M, Katada K, Anno H,
Imizu S, Hayashi J, Irie Keiko,
Negoro M, Kato Y, Kanno T, Sano H:
CT angiography with electrocardiographically gated reconstruction for
visualizing pulsation of intracranial
aneurysms: Identification of aneurysmal protuberance presumably associated with wall thinning. AJNR
Am J Neuroradiol 26:13661369,
2005.
4. Fujita S, Kawaguchi T: Detection of
thin regions of unruptured cerebral
aneurysms by ECG synchronous reconstruction 3D-CT angiography(4DCTA) using 16 slices per rotation CT
[in Japanese]. Prog Comput Imaging
26: 93100, 2004.

In Reply:
We thank Matsumoto et al.
FIGURE C2. The plastic models left arm was 5 mm in size, which is compatible to the regular-sized aneurysms.
The images of 20, 30, 40, and 80% phases demonstrated bleb like protrusions (arrows). The scan was performed for their comments on our article regarding visualizing the dyusing a MDCT scanner with 64 detectors.
namics of cerebral aneurysms
with 4D-CT angiography. They
The authors also described that the 4D-CT movie revealed
pointed out discrepant findings on the aneurysm surface bethe pulsating line that indicated the dissecting cavity and
tween the 4D-CT angiography and intraoperative fields. However, their comments depend on assumptions that may be
intimal flap (1). The initial flap line should be confirmed on the
debated. The fine morphology of the aneurysmal wall may
original image. Moreover, the magnetic resonance imaging
well be different between the condition under the atmospheric
and/or magnetic resonance angiography should be added to
air pressure at surgery and the computed tomographic ansupport the findings.
giography performed under the intracranial pressure within
Fujita and Kawaguchi (4) reported that 4D-CT angiography
the closed-head cavity. In addition, perianeurysmal environwas likely to become indispensable in deciding whether to
ments (2), including arachnoid trabecula, cranial nerves, dura
operate or observe. To apply this technique for the clinical
mater, and adjacent brain pharencyma, may be moved and
examination, however, the further improvement is necessary.
dislocated from their normal setting during surgical proceFor the present, the findings of the 4D-CTA should not be
dures. Direct visual comparison of the contours of the aneuused for making the decision whether the operation should be
rysm may be difficult between the morphological findings
performed in the patients with unruptured cerebral
observed in surgery and flow dynamics obtained by 4D-CT
aneurysms.
angiography. The concept and purpose of the 4D-CT angiography are different from that of Matsumoto in the respect that
Masato Matsumoto
the information obtained by 4D-CT angiography is based not
Tatsuya Sasaki
on the outer shape of aneurysm, but rather on the intraKyouichi Suzuki
aneurysm flow dynamics.
Jun Sakuma
To date, the application of 4D-CT angiography to assess
Yuji Endo
aneurysmal flow dynamics has had certain limitations, as
Namio Kodama
Matsumoto et al. suggest, and there is a need to refine the
Fukushima, Japan
imaging technique. Pulsating blebs and walls on the aneurysmal dome may not be consistent with pulsations on the exposed dome bleb identified during surgery. From our research
1. Ishida F, Ogawa H, Simizu T, Kojima T, Taki W: Visualizing the dynamics
findings, the pulsating changes on 4D-CT angiography may be
of cerebral aneurysms with four-dimensional computed tomographic anclassified into two groups: one is a pulsative movement
giography. Neurosurgery 57:460471, 2005.

E1003 | VOLUME 58 | NUMBER 5 | MAY 2006

www.neurosurgery-online.com

CORRESPONDENCE

caused by motions or other artifacts and the other is a real


pulsation of the aneurysmal wall corresponding to the hemodynamics within the vessels. The protrusive change displayed
by Matsumoto in Figure C2 was considered not a motion
artifact, but a bulge on the surface of the plastic figure model.
False positive findings of 4D-CT movies with smooth surface
models, such as a titanium clip, would be better suited for the
evaluation of the artifacts of 4D-CT angiography. Quantitative
or qualitative analyses of the pulsative changes on 4D-CT
movies are required to rule out such artifacts, and now we are
designing experimental and computational models which will
allow a new protocol for 4D-CT angiography.
In conclusion, we think that 4D-CT angiography reveals not
the morphologic configuration of the aneurysm, but the intraaneurysmal flow hemodynamics, which is shown as pulsatile
movement. Although it is difficult at this point to elucidate the
precise significance of 4D-CT findings for clinical setting and
to define the abnormal findings, 4D-CT angiography should
be a great help to understand the pathological and morpho-

NEUROSURGERY

logical features of cerebral aneurysms (1). More work is required to validate the utility of 4D-CT angiography and to
clarify the significance of visualizing the dynamics of cerebral
aneurysms, and we see this work as a step along that path.
Fujimaro Ishida
Tsu, Japan

1. Kato Y, Hayakawa M, Sano H, Sunil MV, Imizu S, Yoneda M, Watanabe S, Abe M,


Kanno T: Prediction of impending rupture in aneurysms using 4D-CTA: Histopathological verification of a real-time minimally invasive tool in unruptured
aneurysms. Minim Invasive Neurosurg 47:131135, 2004.
2. Satoh T, Omi M, Ohsako C, Katsumata A, Yoshimoto Y, Tsuchimoto S,
Onoda K, Tokunaga K, Sugiu K, Date I: Influence of perianeurysmal environment on the deformation and bleb formation of the unruptured cerebral
aneurysm: Assessment with fusion imaging of 3D MR cisternography and
3D MR angiography. AJNR Am J Neuroradiol 26:20102018, 2005.

DOI: 10.1227/01.NEU.0000217323.32623.F7

VOLUME 58 | NUMBER 5 | MAY 2006 | E1003