PDF - Neurosurgery - Neuropathology of Chronic Traumatic Encephalopathy

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Microvascular Retractor: A New Concept of Retractingand Repositioning Cerebral Blood Vessels

To the Editor:We read with great interest the article on a new microvas-

cular retractor (1). The authors describe a very useful self-retaining microvascular retractor for the retraction and repo-sitioning of cerebral blood vessels. They state that thisretractor, with a semicircular tip, remains stable on pulsatingvessels during the procedure and grossly preserves the vesseldiameter.In our department, we have been using a comparable in-

strument (Fig. C1). The diameters of the blades are 2, 4, and 6mm, respectively. However, this microvascular retractor ishand-held and not self-retaining, as the one described by theauthors. This instrument has been used mainly during micro-vascular decompression surgery for lifting, manipulating, andrepositioning offending cerebral vessels. It can anchor thevessel and permit its ma-nipulation during retrac-tion in the vertical and hor-izontal planes. This hand-held retractor is especiallyuseful when dealing withlarger or elongated vesselsthat may easily slip fromthe classic suction tips ofmicrodissectors.

Tomas MenovskyNijmegen, The NetherlandsIris van den HurkAmsterdam, The Netherlands

1. Youssef AS, van Loveren H: Microvascular retractor: A new concept ofretracting and repositioning cerebral blood vessels. Neurosurgery 57 [Suppl1]:199202, 2005.

DOI: 10.1227/01.NEU.0000217312.38460.FA

Chronic Traumatic Encephalopathy in a NationalFootball 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 encepha-lopathy in a National Football League (NFL) player. We baseour opinion on two serious flaws in Omalu et al.s article,namely a serious misinterpretation of their neuropathologicalfindings in relation to the tetrad characteristics of chronictraumatic encephalopathy and a failure to provide an ade-quate clinical history.

Neuropathology of Chronic Traumatic Encephalopathy

We disagree with Omalu et al.s statements that the neuro-pathological findings in this case are consistent with chronictraumatic encephalopathy and met criteria for chronic trau-matic encephalopathy. These statements are based on a com-plete misunderstanding of the relevant medical literature onchronic traumatic encephalopathy of boxers (dementia pugilis-tica). A review of the relevant medical literature, including thatcited by Omalu et al., in the chronological order in which it waspublished 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 neuropathologicalfindings in the brains of 15 retired boxers. The results werebased on gross and standard histological examinations of theautopsy material. Corsellis et al. determined the hallmarkneuropathology of chronic traumatic encephalopathy to be: 1)abnormalities of the septum pellucidum (cavum, fenestra-tions); 2) cerebellar scarring on the inferior surface of thelateral lobes, most marked in the tonsillar region and loss ofPurkinje cells in these areas; 3) degeneration of the substantianigra with loss of pigmentation, neurofibrillary changes, andno Lewy bodies; and 4) widespread neurofibrillary tangles inthe cerebral cortex and brainstem, most prominently in themedial 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) donot define chronic traumatic encephalopathy in boxers. Therelevant references suggested a possible qualifier to the fourthcharacteristic (widespread neurofibrillary tangles and sparseor no senile plaques), but never took issue with the first threecharacteristics.Roberts (7) performed immunocytochemical studies on

brain material on eight of Corsellis et al.s 15 cases. He re-ported that the neurofibrillary tangles in these cases werestained by a battery of antisera that also stained the neurofi-brillary tangles of 15 cases of Alzheimers disease brains.Roberts thus suggested that head injury and Alzheimers dis-ease may share some pathogenetic factors. Nothing in Robertsstudy suggested that Corsellis et al.s original definition ofchronic traumatic encephalopathy was incorrect. In fact, thematerial examined in the study by Roberts was defined asoriginating in dementia pugilistica brains because it was sodesignated 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 histologicalevidence of recent or past hemorrhages. Thirteen of thesebrains were those originally studied and reported on byCorsellis et al. (2). Twelve of these brains showed neuro-pathological evidence of brain damage of the type described inthe punch-drunk state (1). The brains of five additionalretired boxers were examined; three of these showed thetypical stigmata of dementia pugilistica (1). What was the

FIGURE C1. Photograph showing thefree-hand microvascular retractor.The blades are available in diametersof 2, 4, and 6 mm, respectively.

NEUROSURGERY VOLUME 58 | NUMBER 5 | MAY 2006 | E1003

neuropathological pattern or stigmata that defined the punch-drunk or dementia pugilistica state according to Adams andBruton? A tetrad of pathological processes originally de-scribed by Corsellis et al. (1). Clearly, Adams and Bruton didnot dispute the fact that Corsellis et al.s criteria defined theneuropathology of chronic traumatic encephalopathy.Roberts et al. (9) reported a case of dementia in a punch-

drunk wife. The neuropathology of the case revealed a largefenestrated cavum septum pellucidum, neurofibrillary tangleson routine staining and immunoreactive tangles and diffuseplaques on immunocytochemical studies with specific antisera(9). The authors stated that the brain of this repeatedly bat-tered woman resembled that seen in dementia pugilistica.Roberts et al. suggested that the immunocytochemical picturemight be a part of this condition, but mainly suggested thatthe case provided evidence that head injury can be followedby Alzheimer type degeneration (9). Roberts et al. (9) citedCorsellis et als (2) study as the source of his description ofdementia pugilistica. Furthermore, the brain reported by Rob-erts in this letter had the septal abnormalities on gross exam-ination and neurofibrillary tangles on routine histologicalstaining that are integral to the neuropathological descriptionof dementia pugilistica.Roberts et al. (8) also reported the results of immunocyto-

chemical staining of 20 former boxers necropsy brains with anantibody to -protein amyloid. Fourteen of the cases werefrom Corsellis et al.s (2) original material. One was from aboxer who died during a bout. The other five consisted ofthree additional professional and two amateur boxers. Nine-teen of the 20 cases had a cavum septum pellucidum. Onroutine staining, 13 had neurofibrillary tangles with minimalor no plaque formation, four had equal amounts of tangle andplaque formation, and three had no neurofibrillary tangles.Thus, most of the cases fit the definition of dementia pugilis-tica as described by Corsellis et al. (2) and most, in fact, werefrom Corsellis original material (8).Roberts et al. (8) reported that 19 of the cases exhibited sub-

stantial numbers of hitherto invisible diffuse -protein immuno-reactive plaques on immunocytochemical analysis. They sug-gested that the present neuropathological description ofdementia pugilistica (tangles, but no plaques) should be alteredto acknowledge the presence of substantial -protein deposition(plaques). The authors did not indicate that the gross brainfindings or microscopic findings on routine histology reportedby Corsellis et al. (2) were incorrect, but rather offered a qualifierto the fourth criterion of the tetrad, made possible by the devel-opment of new immunocytochemical techniques that were notavailable 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 dis-ease) and to BF-10 (a component of tangles in Alzheimersdisease and dementia pugilistica). Eleven of these cases haddementia pugilistica, as defined by the Corsellis et al. (2)criteria. In fact, 10 of the cases were from Corsellis originalmaterial. Nine of these 10 cases were also included in Roberts

et als (8, 9) study. The results demonstrated that ubiquitin (acomponent of Alzheimers disease tangles) is also present inneurofibrillary tangles in dementia pugilistica and that moreneurofibrillary tangles in dementia pugilistica are stained withBF-10 than with antiubiquitin.The authors proposed that Alzheimers disease and demen-

tia pugilistica neurofibrillary tangle formation share manycommon features (3). At no point, however, did the authorsimply or state that Corsellis et al.s (2) criteria for dementiapugilistica were incorrect; and in fact, the authors usedCorsellis criteria to identify the cases of dementia pugilisticafor 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 takenfrom Corsellis et al.s (2) original material. Tokuda et al. (10)reported that the neurofibrillary tangles in dementia pugilis-tica are similar to those seen in Alzheimers disease. They alsofound other -immunoreactive structures (neuropil threadsand degenerating neurites) in the periphery of degeneratingplaques in dementia pugilistica. The authors also found-protein cerebral amyloid angiopathy in three of the eightcases. Tokuda et al. (10) did not comment on any of the otherCorsellis et al. criteria, did not indicate any disagreement withthose criteria and in fact used Corsellis et al.s original material(brains that meet the Corsellis et al. criteria for a diagnosis ofdementia pugilistica) as brains defined as exhibiting dementiapugilistica.Geddes et al. (5) reported the autopsy results of a 23-year-

old boxer who died in the ring. They found widespread neu-rofibrillary tangles in all neocortical areas with sparing of themedial temporal lobe. No Alzheimers disease changes andnone of the other characteristics findings of dementia pugilis-tica (as defined by Corsellis et al.) were reported (5). Theauthors suggested that the development of neurofibrillarytangles may be the earliest change in the development ofchronic encephalopathy of boxers. Nothing in Geddes studychallenged Corsellis criterion for the diagnosis of dementiapugilistica (5).Geddes et al. (4) later reported autopsy results of five young

men who experienced mild chronic head injury. Two wereboxers, one was a soccer player, one was an epileptic whofrequently hit his head during seizures, and one was a devel-opmentally disabled man with a long history of head banging.Geddes et al. (4) performed routine staining and immuno-

staining with antisera to -amyloid and -proteins. All of thecases demonstrated neocortical neurofibrillary tangles and-positive neuropil threads. There was no abnormal stainingwith antisera to -amyloid. No abnormal plaques were seen(4). The authors concluded that neocortical neurofibrillarytangle and -positive neuropil thread formation without-amyloid deposition is the earliest neuropathological findingin repetitive head injury in young adults. This report is thusvery consistent with Corsellis et al.s original findings and is,in fact, inconsistent with Omalu et al.s (6) assertions. Omaluet al.s case demonstrated diffuse amyloid plaques, sparse

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E1003 | VOLUME 58 | NUMBER 5 | MAY 2006 www.neurosurgery-online.com

neuritic threads, and sparse neurofibrillary tangles which isthe opposite of Geddes et al.s findings of widespread neuro-fibrillary tangles without -amyloid plaque formation (4, 6).This chronological review of the development of the neuro-

pathological description of dementia pugilistica indicates thefollowing: 1) in 1973, Corsellis et al. (2) described the tetrad offindings that still define the neuropathological picture of de-mentia pugilistica; 2) this tetrad includes abnormalities of theseptum pellucidum, cerebellar scarring, degeneration of thesubstantia nigra, and widespread neurofibrillary tangles withminimal or no plaque formation on routine histological stain-ing; 3) in the late 1980s and 1990s, the availability of newtechniques of immunocytochemical analysis further describedthe nature of neurofibrillary tangles in dementia pugilisticaand revealed that plaques were indeed present when thesenew techniques were applied; and 4) a qualifier to Corsellis etal.s fourth criterion (neurofibrillary tangles without plaqueson routine histological examination) can be added: immuno-cytochemical studies reveal that plaques are indeed present inthese brains.None of the references reviewed argued, in any way, that

Corsellis et al.s (2) original tetrad of findings was not corrector 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 Corselliset al.s original subjects (defined as being dementia pugilisticabrains) for their newer analyses. These studies would not havedone so if their authors did not agree that Corsellis et alsdescription accurately classifies the neuropathology of chronictraumatic encephalopathy. None of the references reviewedever suggested that Corsellis et al.s neuropathological de-scription be abandoned or that immunocytochemical criteriaalone should replace Corsellis et al.s tetrad in definingchronic traumatic encephalopathy.This historical review clearly demonstrates the error of

Omalu et al.s (6) statements that their case is consistent withchronic traumatic encephalopathy and met criteria forchronic traumatic encephalopathy. The following comparesOmalu et al.s reported case findings with the tetrad neuro-pathological criteria of Corsellis et al. (2): 1) Omalu et al.s casedid not have a cavum septum pellucidum or a fenestratedseptum pellucidum; 2) Omalu et al.s case did not have scar-ring of the inferior surface of the cerebellum; 3) Omalu et al.scase did not have widespread neurofibrillary tangles withminimal or no plaque formation on routine histological exam-ination; and 4) Omalu et al.s case did have depigmentation ofthe substantia nigra.Omalu et als case demonstrated only one of the four of

Corsellis et al.s (2) tetrad criteria, certainly not enough to beconsistent with or meet criteria for chronic traumatic enceph-alopathy of boxers. On immunohistochemical staining, Omaluet al.s case had frequent amyloid plagues, but only sparseneuritic threads and neurofibrillary tangles. Close review ofthe literature indicates that these findings share some similar-ities to Roberts et al.s (8) results, but are not exactly the sameas those reported by Tokuda et al. (10), who found significant,

not sparse, neurofibrillary tangles and significant, not sparse,amounts of neurofibrillary tangles and neuropil threads), orGeddes et al. (4). Even if one accepts that these immunohis-tochemical results are similar to those reported in the refer-ences (this is not at all certain), this consistency with thequalifier to Corsellis et al.s fourth criterion is still not enoughto be consistent with a diagnosis of chronic traumatic enceph-alopathy of boxers.This detailed review of the relevant literature including that

cited by Omalu et al. shows clearly that Omalu et al.s descrip-tion of chronic traumatic encephalopathy is completelywrong. The characteristic neuropathological findings forchronic traumatic encephalopathy, especially in boxers arenot sparse to many neurofibrillary tangles in the cortex, neu-ropil threads and neocortical diffuse amyloid plaques asstated by Omalu et al. (6). It is clear that Omalu et al.s case didnot meet the accepted criteria for chronic traumatic encepha-lopathy as described by Corsellis et al. (2) with only onequalification uncovered by newer immunocytochemical tech-niques in the late 1980s and early 1990s.

Clinical History

The dearth of clinical information seriously compromisesOmalu et al.s (6) assertions that this case is one of chronictraumatic encephalopathy. The diagnosis of a chronic condi-tion requires a medical history indicating a long-standingnature of the illness. Clinical information regarding the onsetand 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 neu-

rological history and neurological examination indicatingclear evidence of clinical brain dysfunction. Postmortem tele-phone interviews with surviving relatives, which reveal aneuropsychiatric history that resembled a dysthymic disor-der do not qualify as an adequate detailed neurologic and/orpsychiatric history and clinical examination. One sentenceindicating a deficit in memory and judgment as well asParkinsonian symptoms is too vague and nonspecific. Didthis information also come from postmortem telephone inter-views with surviving relatives?Results of medical-neurological clinical evaluations of the

patient while he was alive are necessary to determine if he hadany brain dysfunction. In the absence of adequate clinicalevidence of any type of brain dysfunction, one cannot make adiagnosis of encephalopathy.To state that a condition is traumatic in origin, one needs

to present a history of significant injury (in this case, headinjury) and rule out other possible etiological factors. Omalu etal. (6) indicate that their subject had a long career in profes-sional football as an offensive lineman. They correctly pointout that offensive linemen have a low incidence of mild trau-matic brain injury (MTBI) compared with other position play-ers. In the premortem history of this case, Omalu et al. do notmention any history of cerebral concussion, MTBI, or removalfrom play after a blow to the head.

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In their discussion, Omalu et al. (6) indicate that he sus-tained numerous episodes of MTBI and/or concussive in-jury, as evidenced by the histological evidence of remotehemorrhages. This is circular reasoning. Although there is nohistory of head injury, the subject must have had multiplehead injuries because of the autopsy findings.The absence of an adequate medical history cannot be com-

pensated for by reporting autopsy results. Omalu et al. (6) goon to state that there was no known history of brain traumaoutside professional football. In fact, there was no knownhistory of brain trauma inside professional football either.Omalu et al. also overlooked the patients participation in bothhigh school and college football, in which head injuries havebeen known to occur. Omalu et al. have also ignored otherpossible etiologies of brain dysfunction (if there was indeedbrain dysfunction) in this case.The patient had severe heart disease (atrial fibrillation, cor-

onary artery disease, cardiomyopathy) and obesity. Certainly,he was a good candidate for hypertension, diabetes, hyperlip-idemia, and numerous other metabolic abnormalities. He waslikely on multiple medications for treatment of his medicalconditions. Omalu et al. (6), however, present us with noinformation regarding these clinical issues. Furthermore, theypresent no information regarding possible alcohol, steroid, orillicit drug abuse in this subject. All of these substances cancause brain dysfunction and thus deserve mention, at leastwith a simple statement about the presence or absence of suchabuse 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 isour contention that there is inadequate clinical evidence thatthe subject had a chronic neurological condition, a traumaticallyinduced brain condition or, in fact, a clinical encephalopathy.The term chronic traumatic encephalopathy thus should notbe applied to their case.We have demonstrated that Omalu at al.s (6) case does not

meet the clinical or neuropathological criteria of chronic trau-matic encephalopathy. We, therefore, urge the authors to re-tract their paper or sufficiently revise it and its title after moredetailed investigation of this case.

Ira R. CassonElliot J. PellmanDavid C. VianoNew 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: Neurofibrillarytangles in dementia pugilistica are ubiquitinated. J Neurol Neurosurg Psy-chiatry 54:116118, 1991.

4. Geddes JF, Vowles GH, Nicoll JA, Revesz T: Neuronal cytoskeletal changesare an early consequence of repetitive head injury. Acta Neuropathol (Berl)98:171178, 1999.

5. Geddes JF, Vowles GH, Robinson SF, Sutcliffe JC: Neurofibrillary tangles,but not Alzheimer-type pathology, in a young boxer. Neuropathol ApplNeurobiol 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 dementiapugilistica and Alzheimers disease: Evidence for common genesis. Lancet2:14561458, 1988.

8. Roberts GW, Allsop D, Bruton C: The occult aftermath of boxing. J NeurolNeurosurg Psychiatry 53:373378, 1990.

9. Roberts GW, Whitwell HL, Acland PR, Bruton CJ: Dementia in apunchdrunk wife. Lancet 335:918919, 1990.

10. Tokuda T, Ikeda S, Yanagisawa N, Ihara Y, Glenner GG: Re-examination ofex-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 Trau-matic Brain Injury Committee of the NFL [NFL], regardingour case report of chronic traumatic encephalopathy in a NFLplayer (6). They disagree with the diagnosis of chronic trau-matic encephalopathy in this report because they feel that theneuropathological findings in our case do not meet criteriaenumerated in the landmark study of boxers brains (dementiapugilistica) by Cosellis et al. (2) and because of the lack ofadequate clinical history. They call for the withdrawal of thearticle, which we would not consider, for the reasons below.

Corsellis et al. (2) examined some of the most severely affectedcases of dementia pugilistica, and reported fenestrated cavumseptum pellucidi, scarring of the inferior cerebellum, nigral de-generation, and widespread neocortical neurofibrillary tangleformation. However, he found the complete tetrad in only two-thirds of his cases. Casson et al. imply that the lack of a cavumseptum pellucidum (with or without fenestrations) in our casesomehow precludes a diagnosis of chronic traumatic encepha-lopathy. However, Corsellis et al. (2) and others have neverasserted that this finding is a sine quo non of dementia pugilistica.Indeed, it is likely that repetitive head injury in boxers is themostsevere form of chronic traumatic encephalopathy and that septalinjury is most likely to be found in this population. A similarreason can be given for the lack of cerebellar injury in ournon-pugilistic case. Boxers necessarily experience much moresevere head injuries than would be expected in football players,and it is not unexpected that the pathological changesmay not beas severe in the latter. The physics of brain trauma in boxing arequite different from those in football, and football players wearhelmets that diffuse the impact. On the other hand, our caseshowed degeneration of the substantia nigra and, most impor-tantly, 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 cingu-late gyrus and insular cortex, but were lacking in the hippocam-pus and entorhinal cortex, where they always appear first, beforecortical deposition, if the diagnosis is Alzheimers disease (1, 9).Widespread neocortical neurofibrillary tangles without neuriticplaques in a 50-year-old man are distinctly unusual and clearly

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pathological. This pattern of neurofibrillary tangle formationwould cause most neuropathologists to question whether thispatient had a history of boxing and lead them to examine theclinical history for episodes of repetitive head trauma, regardlessof whether there were clinical manifestations of the neuropatho-logical changes. This last point is an important one because notall brain injuries necessarily have a clinical correlate. For exam-ple, if a neuropathologist examining a brain discovers an oldinfarct, he can conclude that the patient suffered a vascularischemic event (stroke), regardless of an absence of clinicalhistory of stroke.The term encephalopathy, although most commonly used

to indicate a clinical condition, is a nonspecific term and can beused in the broadest sense to describe any disease of thebrain according to Stedmans Medical dictionary (8).Literature cited by our report (6) and by Casson et al.

suggest that neocortical neurofibrillary tangle formation maybe the earliest consequence of repetitive head injury in boxersand others (3) and underscores that neuropathologicalchanges may precede obvious clinical symptoms. In this case,we also describe deposits of -A4, which were also seen in 19of 20 cases of dementia pugilistica (7).We doubt Casson et al. really feel that NFL offensive line-

men do not experience repeated episodes of head trauma. It isfar more likely that the majority of the head trauma in theNFL, as well as in American football in general, is under-reported by the players and the team staff, who accept theoccasionally dazed recovery during the game and postgameheadaches simply as part of the sport, not unlike bruises andsprains. Although we agree that this head trauma is not assevere as that experienced by boxers, who wear no protectivehelmets, the repetitive trauma experienced during games, es-pecially over many seasons, may be sufficient in some indi-viduals, especially those with longer careers, to result in neu-ropathological changes. Those changes could, in some cases,have clinical significance. More clinical detail was not avail-able to us, but the relationship of the subjects football careerto 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 head-quartered, agreed with the [family], their attorneys, theirdoctors and even an NFL-appointed physician that the17-year veterans frontal-lobe injury was directly related tofootball and therefore started the disability benefits clockupon his retirement in March 1991. . . the Plan likely willtake the case to the next step a federal appeals court inthe Fourth Circuit at Richmond, Va. . . .the case could takeanother year to resolve. It was a triumph nevertheless, saidestate attorney Bob Fitzsimmons, and one that could helpensuing generations ofNFL retireeswith brain injuries anddegenerative 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 relationshipto his profession.

Rather than argue over whether this particular case hadsufficiently documented clinical history of encephalopathyto warrant the use of the term chronic traumatic encephalop-athy, it would seem that the Mild Traumatic Brain InjuryCommittee of the NFL should seriously consider this case,with clear neuropathological changes associated with repeti-tive head trauma, as one which warrants investigation by theNFL to determine if clinically significant chronic traumaticencephalopathy is an occupational hazard in the sport. Ourfindings in this initial case are further supported by a secondsuch case that has come to our attention of another NFL playerwith similar neuropathological changes.The neuropathological findings in this case are distinctly

and uniquely the pattern reported in the early stages of repet-itive head trauma and can only have come from a chronic, notacute, condition. The use of the term chronic traumatic en-cephalopathy should be considered broad enough to includepreclinical cases, as well as those with mild clinical symptoms,not just those with severe clinical symptoms. In fact, our caseis important primarily because it indicates that there may bebrain damage in NFL players that is currently under-reported,because of a lack of long-term clinical follow-up focused onevaluating such a condition. We suggest that the NFL beginexamining the long-term effects of brain injury in its formerplayers. We would be happy to collaborate with the MildTraumatic Brain Injury Committee and the NFL in developingand implementing an optimal research program that will ad-dress these newly emerging issues.

Bennet I. OmaluSteven T. DeKoskyRyan L. MinsterM. Ilyas KambohRonald L. HamiltonCyril H. WechtPittsburgh, Pennsylvania

1. Braak H, Braak E: Neuropathological staging of Alzheimer-related changes.Acta Neuropathol (Berl) 82:239259, 1991.


3. Geddes JF, Vowles GH, Nicoll JA, Revesz T: Neuronal cytoskeletal changesare an early consequence of repetitive head injury. Acta Neuropathol (Berl)98:171178, 1999.

4. http://www.post-gazette.com/pg/05117/494863.stm. Accessed February2006.

5. http://www.post-gazette.com/pg/05152/513580.stm. Accessed February2006.



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 Alzheimersdisease is different from plaque and cortical microglial pathology.Neurobiol Aging 19:517525, 1998.

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In Reply:The letter by Casson et al. shed light and clarification on the

entity of chronic traumatic encephalopathy that was lacking inthe article by Omalu et al. (1). As they note, it was originallycharacterized by a tetrad of findings, including abnormalitiesof the septum pellucidum, cerebellar scarring, degeneration ofthe substantia nigra, and widespread neurofibrillary tangles inthe cerebral cortex and brainstem. They correctly point outthat the case presented by Omalu et al. (1) had only one ofthese pathological findings, raising concern as to whether theindividual actually met the criteria for chronic traumatic en-cephalopathy. Based on these criteria, it would seem not.Consequently, the authors assertion that the individuals pre-mortem cognitive decline, depression, and Parkinsoniansymptoms where a manifestation of chronic traumatic enceph-alopathy seems largely unfounded. Unfortunately, as previ-ously noted by several of the reviewers of the original manu-script, there was no evidence presented linking the playersNFL career to his neurocognitive decline or to the neuropatho-logical findings. Furthermore, the player had no documentedconcussions during his career and he played mostly as anoffensive linesman which is one of the positions associatedwith the lowest frequency of concussion. Ultimately, the au-thors lack of alternative explanations for the neuropatholog-ical findings, the selective and seemingly inappropriate use ofthe definition of chronic traumatic encephalopathy, and theN of 1 nature of this study severely weaken it. Given thislack of hard evidence and the overly assuming nature linkingthe available data together, I agree that retraction or a majorrevision by the authors is warranted. Casson et al. are to bethanked for further educating us about the entity of chronictraumatic encephalopathy and completing the editorialprocess.

Daniel F. KellyLos Angeles, California


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 tothe editor. I recommended that Omalu et al. explicitly state theweaknesses of their case report material. This was combinedwith a corresponding recommendation that sweeping gener-alizations, based upon this single case, be removed. I con-cluded my review with the statement: . . .this paper raisesmore questions than it answers. . . .Omalu et al. resubmitted a substantially revised and trun-

cated paper, much more modest in scope, and much morecautious regarding sweeping generalizations. I thought theyhad been responsive to my initial review.The above statements are regarding the last few paragraphs

of the letter by Casson et al.

More important, however, is the issue of the first severalparagraphs of their letter, which consist of repetitious exposi-tions regarding how Omalu et al. incorrectly used diagnosticnomenclature. They do not dispute his findings, they simplydispute the name Omalu et al. have given to those findings.This seems to be an issue that requires brief discussion andclarification, not relentless table-pounding.In summary, I see the Casson et al. letter as raising several

valid points regarding the intrinsic limitations of the casematerial used in Omalu et al.s study. However, because theselimitations were noted by Omalu et al. in the published ver-sion, I do not see the point of publishing a letter reiteratingthem. Additionally, and perhaps more importantly, I see novalue in the repetitious initial paragraphs of the letter devotedentirely to nomenclature.Lastly, there is the issue of the tone of the letter. Disagree-

ments among clinicians and scientists are important andshould be published, but they need to reflect appropriatecollegial respect.

Joseph BleibergNeuropsychologistWashington, D.C.


In Reply:The authors of this letter should be thanked for compiling this

detailed historical review of our understanding of the neuropa-thology of chronic brain injury. They argue that the structuralfindings reported by Omalu et al. (2) are insufficient to meet thecriteria of chronic traumatic encephalopathy as defined byCorsellis et al. (1) in 1973 and modified by Roberts et al. (3) in1990. In addition, this letter emphasizes the paucity of informa-tion 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 willneed to use standardized or widely accepted histological cri-teria in addition to firm and accurate medical histories.

Alex B. ValadkaHouston, Texas




In Reply:Drs. Casson, Pellman, and Vianos letter asserts that Omalu

et al.s (1) article in Neurosurgery contains a serious misinter-

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pretation of neuropathological findings in relation to the char-acteristics of chronic traumatic encephalopathy and a failureto provide an adequate clinical history. These individuals alsostate that they have demonstrated that Omalu et al.s case doesnot meet the clinical or neuropathological criteria of chronictraumatic encephalopathy. They then proceed to urge theauthors to retract their article or sufficiently revise it and itstitle after more detailed investigation of the case. I respectfullydisagree with many points presented in this letter and I amconcerned about their extreme reaction in urging the authorsto retract the article.First, they state that they have demonstrated Omalu et al.s

case did not meet the neuropathological criteria of chronictraumatic encephalopathy. Neuropathology falls outside ofthe scope of expertise in neuropsychology. Therefore, I cannotcomment on neuropathological specifics. However, the neu-ropathological studies referenced by Casson et al. focus onboxing studies. Although similar, the biomechanics offootball-related head trauma is not fully equivocal. Therefore,one cannot absolutely state that chronic traumatic encepha-lopathy in professional football should be identical to thatfound in boxing. Because the article in question is the first ofits kind, no data exists in regarding neuropathology andchronic traumatic encephalopathy in NFL players. Casson etal. can only provide an opinion that the neuropathologicalfindings are owing to other factors. Clearly, they have notdemonstrated this.Secondly, Casson et al.s assertion that an adequate medical

history was not obtained conveniently does not include refer-ence to traumatic brain injury not being systematically as-sessed or consistently diagnosed in the league at the time thisplayer was active. At the time this individual played, therewas a dearth of scientific studies of sports-related head injuryin sports. At the time this individual played, neuropsycholog-ical assessment was not being used in the league. At the timethis individual played, concussions were not being monitored.The lack of documented head injuries and lack of neuropsy-chological tests results do not demonstrate that multiple con-cussions did not occur in this individual.Third, before its acceptance, Omalu et al.s report was care-

fully reviewed by a group of opinion leaders in the field. Thisgroup included three neurosurgeons, two neurologists, andtwo neuropsychologists, all of whom have extensive clinicaland research experience in the field of sports-related headtrauma. The reviewers comments were published at the endof the article and discussed issues of: 1) neuropathology (Drs.Bailes, Valadka, and Bleiberg), 2) neuropsychological data(Drs. Marion and Kutner), 3) lack of documented medicalhistory (Drs. Kutner and Guskiewicz). It is noted that thepublished comments by reviewers contained clear discussionof limitations of the study.Fourth, Casson et al. conveniently omitted the obvious con-

tribution of this study. Namely, this is a seminal study in thefield.Fifth, Casson et al.s letter seems to have exceeded the

protocol for scientifically providing an additional opinion for

a published story. Specifically, they took an extreme stand inactually urging the authors to retract the article. Their stand isquite excessive and, in my opinion, inappropriate. Articlesshould be considered for retraction if they contain fabricateddata, contamination of data, or allegation of misconduct. It ismy opinion that there is no justification for retracting thisarticle.

Kenneth C. KutnerNew York, New York


In Reply:Drs. Casson, Pellman, and Viano have raised concerns

about the autopsy report of a former NFL player published byOmalu et al. (6). Specifically, they are concerned that Omalu etal. may have inappropriately applied the term chronic trau-matic encephalopathy to this case because, in their opinion,the case did not meet histolopathological criteria for this di-agnosis. The issues raised by Casson et al. deserve carefulconsideration, especially because of their intense research fo-cus on head injury in the NFL as manifest by a series of reportsfrom 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 questionsabout the neuropathological sequelae of playing football. Thebasis for their argument is a report of the autopsies of 15retired boxers published in 1973, and subsequent publicationsthat, in most cases, reanalyzed the brain tissue of some of theseoriginal 15 cases. Based on his findings, Corsellis concludedthat boxing led to abnormalities of the septum pellucidumsuch as a cavum septum, cerebellar scarring, depigmentationof the substantia nigra, widespread neurofibrillary tangles,and total absence of senile plaques. Casson et al. argue thatthese autopsy findings of boxers should be the histopatholog-ical definition of chronic traumatic encephalopathy of anycause, and the absence of most of these findings (e.g., theOmalu et al. case) should exclude the diagnosis.But, it also is possible, and perhaps likely, that the neuro-

pathological sequelae of football injuries differ from thoseobserved in boxing. Relevant differences between the twosports include the fact that the objective of professional boxingis to cause your opponent to have a concussion (knock out),whereas in football, it is to score a touchdown. Head injuriesin football, although not uncommon, are incidental. As aresult, football has traditionally included the use of rigidprotective head gear, whereas boxing has not. The most com-mon injuries sustained by football players are orthopedic in-juries of the extremities, whereas in boxing, 90% of the injuriessustained are to the head (10). Pellman et al. have examinedthe biomechanics of head injuries sustained in football anddetermined that the change in head velocity associated withthe injury is, on average, 7.2 meters per second (7). Atha et al.

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(1) have reported that the change in head velocity after aprofessional boxing punch may be as much as 5.20 meters persecond, and a force of 6320 newtons. Indeed, an argumentcould be made that the neuropathological findings of Corselliset al. are unique to retired boxers, and most closely associatedwith the clinical entity of dementia pugilistica. Others havenoted a high incidence of cavum septum pellucidum in box-ers, and suggested that this is a sign of boxers encephalop-athy (2).Regarding the acute and chronic molecular and histological

changes associated with brain injury, there remain far morequestions than answers. Although most clinical epidemiolog-ical studies have found that traumatic brain injury is a riskfactor for the development of dementia (5), there is relativelylittle data defining the typical histological sequelae of mildtraumatic brain injury, especially in sports other than boxing.The link between brain injury and the molecular and histo-logical manifestations of Alzheimers disease is particularlycomplicated. The molecular and histological hallmarks of Alz-heimers 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 twohistological characteristics of Alzheimers disease. Confound-ing the picture is the fact that neurofibrillary tangles andplaques are common in normal aging, even in those withoutdementia (3). And some patients with a clear premorbid his-tory of dementia have been found at autopsy to have predom-inant plaques, but few or no neurofibrillary tangles (9).Recently, a number of investigators have studied the asso-

ciation of acute brain injury with amyloid--protein,-amyloid precursor protein, apolipoprotein, and , as well aswith plaques and neurofibrillary tangles. After traumaticbrain injury, markedly elevated cerebrospinal levels ofamyloid--protein and -amyloid precursor protein havebeen observed (5). Ikonomovic et al. (4) studied the freshtissue obtained at surgery from 18 traumatic brain injurypatients, aged 18 to 64 years, who were undergoing decom-pressive procedures. Diffuse cortical amyloid--protein de-posits were observed in 33%, but -positive neurofibrillarytangles were detected in only two patients, both of whomwere older. Smith et al. (8) compared histopathologicalchanges in 45 traumatic brain injury patients who died up to1 month after injury with age-matched controls and found asubtle increase in immunoreactivity in some of the traumaticbrain injury patients, but not a greater prevalence of neurofi-brillary tangles, as compared with controls. Based on thesestudies, at least, it is not surprising that Omalu et al. (6) did notfind a predominance of neurofibrillary tangles in the brain ofthe football player they examined. It is important to empha-size, however, that these were studies of the acute manifesta-tions of severe traumatic brain injury, and the relevance ofthese 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 oflonger duration when there are multiple injuries. Prolonged or

permanent cognitive deficits can severely disable otherwisehealthy athletes. Yet, because such injuries are rarely fatal,little is known about the brain histopathology underlyingthese disturbances. Excluding autopsy reports of former box-ers, there are very few reports of the histopathological changesin the brains of athletes with a past history of mild traumaticbrain injury. Although the report by Omalu et al. (6) can becriticized for not providing documentation of specific premor-bid episodes of concussion, the likelihood that that individualsustained one or more concussions during the 17 seasons heplayed in the NFL is high. Despite this shortcoming, theirreport is important because it is the first to carefully documentthe late histopathological changes in a professional footballplayer. Their findings can reasonably be considered consistentwith chronic traumatic encephalopathy because few othershave clearly described the autopsy findings in such cases. Itshould not be assumed that autopsy findings in boxers will besimilar to those seen in other sports, and the only way toestablish the presence or absence of similarities will bethrough a large number of reports similar to that from Omaluet al. (6). The criteria for the diagnosis of chronic traumaticencephalopathy attributed to Corsellis may, therefore, only beappropriate for boxers.As members of the Mild Traumatic Brain Injury Committee

of the NFL, and clinician-scientists that are clearly devoted tothe investigation of sports-related concussion, Drs. Casson,Pellman, and Viano should welcome the contribution fromOmalu et al. and consider the findings of that report highlyrelevant to their own research, rather than recommendingretraction of the article. The need to obtain more details re-garding premorbid neuropsychological deficits and specificepisodes of concussion is clearly recognized and stated byOmalu et al. (6) in their paper, but the histopathological find-ings are clearly described and consistent with a previoushistory of brain injury. Together with subsequent reports ofautopsy results from NFL players, which hopefully will in-clude the important premorbid clinical details, we will beginto establish a reliable definition of chronic traumatic enceph-alopathy typical for professional football players.

Donald W. MarionBoston, Massachusetts

1. Atha J, YeadonMR, Sandover J, Parsons KC: The damaging punch. BrMed 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 asso-ciated with normal brain aging. Histol Histopathol 11:10751088, 1996.

4. Ikonomovic MD, Uryu K, Abrahamson EE, Ciallella JR, Trojanowski JQ, LeeVM, Clark RS, Marion DW, Wisniewski SR, DeKosky ST: Alzheimerspathology in human temporal cortex surgically excised after severe braininjury. Exp Neurol 190:192203, 2004.

5. Jellinger KA: Head injury and dementia. Curr Opin Neurol 17:719723,2004.


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7. Pellman EJ, Viano DC, Tucker AM, Casson IR, Waeckerle JF: Concussion inprofessional football: Reconstruction of game impacts and injuries.Neurosurgery 53:799812, 2003.

8. Smith MS, Dyson RJ, Hale T, Janaway L: Development of a boxing dyna-mometer and its punch force discrimination efficacy. J Sports Sci 18:445450, 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 withoutneocortical neurofibrillary tangles: A second look. Neurology 62:11411147, 2004.

10. Zazryn TR, Finch CF, McCrory P: A 16 year study of injuries to professionalboxers 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: TheEvolving Role of Hypertonic Saline

To the Editor:The article by Ogden et al. (1), Hyperosmolar Agents in

Neurosurgical Practice: The Evolving Role of Hypertonic Salinewas interesting, despite the significant negative aspects pointedout by the commenters. Perhaps it is attributable to the impact ofthe electronic library, but it is sad to see pertinent history ignored.Hopefully, wewill not be doomed to repeat oldmistakes. Studiesof hyperosmolar agents used to treat increased intracranial pres-sure can be traced back to the seminal work of Weed andMcKibben (2) in 1919. They reported that hypertonic saline led torespiratory and cardiac disturbances, but hypertonic glucose wasfollowed by a significant pressure rebound. Their work led tostudies 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 forosmotherapy are hypertonic glycerol (effective when taken bymouth or gastric tube, very useful for chronic administration, butcurrently underused) and mannitol. Hopefully, these agents willnot be abandoned in a rush to use the new glamour treatmentof hypertonic saline (actually nearly a century old) before itsproper role and safety have been adequately defined, as peoplerushed to use pressors to increase central nervous system perfu-sion pressure in preference to mannitol and caused an unknownnumber of cases of severe pulmonary damage (3).

Harold A. WilkinsonWellesley, Massachusetts

1. Ogden AT, Mayer SA, Connolly ES Jr: Hyperosmolar agents in neurosurgi-cal practice: The evolving role of hypertonic saline. Neurosurgery 57:207215, 2005.

2. Weed LH, McKibben PS: Pressure changes in cerebrospinal fluid followingintravenous injection of solutions of various concentrations. Am J Physiol48:512530, 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 pleasantlysurprised that the review has generated so much animated dis-

cussion (1). Hypertonic saline is not by any means a new treat-ment, but it is in the middle of a clinical and investigationalrenaissance that far postdates the inception of electronic data-bases. As Dr. Wilkinson points out, the notion of using hyper-tonic saline to treat cerebral edema was around for 75 yearsbefore it saw any serious clinical application, so we dont agreethat people have felt rushed to use it. That its breadth ofcurrent clinical use is not well-matched by sufficient animal andclinical research is one of the chief points of our article. Still, itdoes seem that if hypertonic saline, as it is used today, carried thedeleterious cardiopulmonary side-effects implied by Dr. Wilkin-son, that the myriad studies outlined in our article would havementioned some examples of them.Although outside the scope of our review, glycerol is, of

course, another effective osmotic agent, little used in theUnited States compared with Europe and Japan, perhaps be-cause of the perceived inconvenience of enteral administra-tion. When and whether glycerol, mannitol, or hypertonicsaline works better will hopefully be determined in futureclinical trials. Our hope is that the hypertonic saline revivalwill lead to a more rigorous examination and comparison ofall hyperosmolar therapies.

Alfred T. OgdenNew York, New York

1. Ogden AT, Mayer SA, Connolly ES Jr: Hyperosmolar agents in neurosurgi-cal practice: the evolving role of hypertonic saline. Neurosurgery 57:207215, 2005.

DOI: 10.1227/01.NEU.0000217319.53708.BC

Rapid Administration of Antifibrinolytics and StrictBlood 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 hema-toma growth in patients with spontaneous intracerebral hemor-rhage (37). A combination of tranexamic acid and nicardipinewas given intravenously to 156 patients. One group received aprolonged infusion of 1 g tranexamic acid over a period of 6hours and the second group was given a rapid infusion of 2 gtranexamic acid over a period of 10 minutes. Hematoma growthwas observed in 17.5 % of the 63 patients in the first group andin 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 basisAMCA is four to 10 times more potent than EACA and twiceas strong as PAMBA (2, 26, 29, 31, 34). These antifibrinolyticshave been shown to cross the blood-cerebrospinal fluid (CSF)barrier to reduce or inhibit the increased fibrinolytic activity ofblood or CSF after aneurysmal subarachnoid hemorrhage(SAH) and to prolong and solidify experimental thrombosis

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(12, 15, 16, 30, 35). The therapeutic plasma concentration ofsynthetic antifibrinolytic drugs has been estimated to be morethan 130 mg/L for EACA and more than 10 mg/L for AMCA,which requires an intravenous dosage of 2436 g of EACA and36 g of AMCA/ 24 hours (3, 14, 28). It is known that antifi-brinolytic agents possess sympathomimetic properties andmay, theoretically, induce vasoconstriction, possibly by actingvia the adrenergic nerve terminals and thus deplete the storedcatecholamines (1, 17, 24, 27, 32, 33). There have been severalreports of thrombotic episodes, glomerular microthrombi, my-opathy, myoglobinuria and cardiovascular complications fol-lowing administration of antifibrinolytic drugs (48, 13, 18, 19,20, 22, 23, 25, 36, 38, 40). Randomized controlled studies usingantifibrinolytics in patients with SAH have shown increaseddelayed cerebral ischemic complications (911, 14, 15, 39).Some authors have suggested the use of antifibrinolytics incombination with calcium channel blockers (nicardipine, ni-modipine) in the hope of reducing rebleeds as well as delayedcerebral ischemic complications in SAH (21). However, todaythe prime rationale for the use of antifibrinolytic drugs in SAHhas disappeared (14).In the present study, no serious adverse effects were noted

(37). The occurrence of renal dysfunction in three patients andfatal myocardial infarction in two patients were considered tohave no relationship with the administration of tranexamicacid. In my opinion, the authors have no basis for this assump-tion, and they have refrained from documenting the pharma-cokinetics, toxicology, and important side effects of the drug.They simply refer to an attached document from the drugmanufacturer stating that up to 2.5 g of tranexamic acid can besafely administered in a single dose and, therefore, settled foran arbitrary dose of 2 g. Patients who required surgery or whohad a bad prognosis were not included, whereas 20 patientswith history of renal disease, angina pectoris, and myocardialinfarction were included. There is no mention of clinical out-comes in the report, and the only thing we learn from thestudy is that there was less hematoma growth. Who is thewinner here, the patient or the drug company?With regard to the potential serious side effects of tranex-

amic acid as documented in the literature, the therapeuticregimen for intracerebral hemorrhage described in this limitedstudy should be disregarded until a carefully designed ran-domized controlled clinical trial has been conducted.

Harald FodstadNew York, New York

1. Anden NE, Henning M, Obianwu HO: Effect of epsilon aminocaproic acidon adrenergic nerve function and tissue monoamine levels. Acta PharmacolToxicol 26:13129, 1968.

2. Andersson L, Nilsson IM, Nilehn JE, Hedner U, Granstrand B, Melander B:Experimental and clinical studies on AMCA, the antifibrinolytically activeisomer of p-aminomethyl cyclohexane carboxylic acid. Scand J Haematol2:22302347, 1965.

3. Andersson L, Eriksson O, Hedlund PO, Kjellman H, Lindqvist B: Specialconsiderations with regard to the dosage of tranexamic acid in patients withchronic renal disease. Urol Res 2:8388, 1978.

4. Bergin JJ: Complications of therapy with epsilon-aminocaproic acid. MedClin North Am 50:16691678, 1966.

5. Biswas CK, Milligan DA, Agte SD, Kenward DH, Tilley PB: Acute renalfailure and myopathy after treatment with aminocaproic acid. Br Med J281:115116, 1980.

6. Britt CW, Light RR, Peters BH: Rhabdomyolysis during treatment withepsilon-aminocaproic acid. Arch Neurol 37:187188, 1980.

7. Charytan C, Purtilo D: Glomerular capillary thrombosis and acute renalfailure after epsilon-aminocaproic acid therapy. N Engl J Med 280:11021104, 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 subarachnoidhaemorrhage: Clinical, laboratory and experimental studies. Umea UniversityMedical 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 withtranexamic acid in aneurysmal subarachnoid hemorrhage: A consecutivecontrolled clinical trial. Neurosurgery 8:158165, 1981.

12. Fodstad H, Kok P, Algers G: Fibrinolytic activity of cerebral tissue afterexperimental subarachnoid haemorrhage: Inhibitory effect of tranexamicacid (AMCA). Acta Neurol Scand 64:2946, 1981.

13. Fodstad H, Liliequist B: Spontaneous thrombosis of ruptured intracranialaneurysms during treatment with tranexamic acid (AMCA). Report of threecases. Acta Neurochir 49:129144, 1979.

14. Fodstad H, Ljunggren B: Antifibrinolytic drugs in subarachnoid hemor-rhage, in Sawaya R (ed): Fibrinolysis and the Central Nervous System. Phila-delphia, Hanley & Belfus, 1990, pp 257273.

15. Fodstad H, Nilsson IM: Coagulation and fibrinolysis in blood and cerebro-spinal fluid after aneurysmal subarachnoid haemorrhage: Effect oftranexamic acid (AMCA). Acta Neurochir 56:2538, 1981.

16. Fodstad H, Pilbrant A, Schannong M, Stromberg S: Determination oftranexamic acid and fibrin/fibrinogen degradation products in cerebrospi-nal fluid after aneurysmal subarachnoid haemorrhage. Acta Neurochir 58:113, 1981.

17. Garrett J, Branco D: Indirect sympathomimetic actions of E-amini-caproicacid (EACA): Role of the adrenal medulla. Arch Int Pharmacodyn Ther204:253259, 1973.

18. Gilligan BS: Myoglobinuria with muscle weakness associated with epsilon-aminocaproic 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 ther-apy. Radiology 131:687689, 1979.

21. Kassell NF, Haley EC, Torner JC: Antifibrinolytic therapy in the treatment ofaneurysmal subarachnoid hemorrhage. Clin Neurosurg 33:137145, 1986.

22. Kennard C, Henson RA: Myopathy due to epsilon aminocaproic acid.Mus-cle Nerve 3:202206, 1980.

23. Kato N, Morimatsu M, Tanaka K, Horie A: Effects of trans-4-aminomethyl-cyclohexane carboxylic acid as an antifibrinolytic agent on arterial wall andexperimental atherosclerotic lesions in rabbits. Thromb Diath Haemorrh24:8599, 1970.

24. Lippmann W, Wishnick MM: Effects of the administration of epsilonaminocaproic 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 epsilon-aminocaproic 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 antifibrinolyticdrugs. Res Commun Chem Pathol Pharmacol 6:137150, 1973.

28. McNichol GP, Fletcher AP, Alkjaerstig N, Sherry S: The absorption, distri-bution and excretion of e-aminocaproic acid following oral or intravenousadministration in man. J Lab Clin Med 59:1524, 1962.

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29. Melander B, Gliniecki G, Granstrand B, Hansoff G: Biochemistry and toxi-cology of Amicapron; the antifibrinolytically active isomer of AMCHA. (Acomparative study with e-aminocaproic acid.) Acta Pharmacol Toxicol 22:340352, 1965.

30. Mihara H, Fuji T, Okamoto S: Fibrinolytic activity of cerebrospinal fluid andthe development of artificial cerebral haemorrhage. Thromb DiathHaemorrh 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-methylcyclohexane 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 inter-action with adrenergic neurons. Br J Pharmacol 31:244252, 1967.

34. Okamoto S, Oshiba S, Mihara H, Okamoto U: Synthetic inhibitors of fibri-nolysis: 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 andtranexamic acid on thrombus size and strength in a simulated arterialaneurysm. J Neurosurg 34:365371, 1971.

36. Rydin E, Lundberg PO: Tranexamic acid and intracranial thrombosis. Lancet2:49, 1976.

37. Sorimachi T, Fujii Y, Morita K, Tanaka R: Rapid administration ofantifibrinolytics and strict blood pressure control for intracerebral hemor-rhage. 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: Antifibrinolytictreatment in subarachnoid hemorrhage. N Engl J Med 311:432437, 1984.

40. Yamaura A, Nakamura T, Makino H: Cerebral complication ofantifibrinolytic therapy in the treatment of ruptured intracranial aneurysm.Eur Neurol 19:7784, 1980.

In Reply:

Methods of Antifibrinolytics Administration and theirSide Effects

Continuous administration of tranexamic acid (616 g/day)has been reported to reduce the frequency of rebleeding afteraneurysmal subarachnoid hemorrhage (SAH), but to increasethe risk of delayed cerebral ischemia owing to vasospasm(1113, 20). Antifibrinolytics therapy is not used for SAHnowadays because overall outcome does not improve (11, 13).In our study for intracerebral hemorrhage (ICH), the total doseof tranexamic acid, which was 2 g (17), is far smaller thanthose for SAH. To obtain hemostasis of ICH at the beginningof the treatment, an initial loading of sufficient amount oftranexamic 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 antifibrinolyticswas administered continuously (16, 8, 9, 14, 19). The sideeffects were observed during continuous administration ofepsilon-amino caproic acid (2336 g/day) or tranexamic acid(36 g/day). Myopathy was induced by continuous adminis-tration of antifibrinolytics for 4 weeks or longer (1, 2, 8, 9, 19).Cerebral infarct not related to vasospasm after SAH occurredduring continuous medication with antifibrinolytics for 1 yearor longer (4, 14). Reduction or disappearance of cerebral an-

eurysms was observed during continuous administration ofantifibrinolytics for 3 weeks or longer (5). On the other hand,in two case reports renal failure was induced in the earlyphase of treatment with continuous administration of epsilon-amino caproic acid when the patients were in a serious con-dition with hypotension (3, 6).Thromboembolic complication rates related to continuous ad-

ministration of tranexamic acid have not been reported so high.Vermeulen et al. (20) reported their randomized control study onSAH using continuous administration of tranexamic acid (6g/day) for 1 week or longer. In their study deep-vein thrombosiswas evident in 21 of 241 patients at 3 months, and there was nodifference in incidence between the study groups. Roos et al. (12)reported randomized study on SAH using continuous adminis-tration of tranexamic acid (6 g/day) for up to 3 weeks. A seriousadverse drug reaction observed in their study was pulmonaryembolism, and it was found in only four of 229 patients. On theother hand, a relative small amount of tranexamic acid wasadministered 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, therewere no indications of increased risk of either cerebral ischemiaowing to vasospasm or thromboembolic complications thatcould be linked to tranexamic acid treatment. In our study, 2 g oftranexamic acid was administered for only one time, and, to ourknowledge, no serious adverse effect has been reported with thisdose of tranexamic acid.Tranexamic acid has been used for about 40 years, and ap-

proximately 1,240,000 g of tranexamic acid was supplied in 2004.According to the attached document of tranexamic acid, a lim-ited number of clinical cases of renal dysfunction, cerebral isch-emia, cardiac ischemia, and venous thrombosis were reported asserious side effects, and these side effects should be carefullychecked during treatment with tranexamic acid. However, theseside effects could be regarded as rare, considering the largeamount of tranexamic acid consumption. The half-life of 1g ofintravenously administered tranexamic acid was 1.9 hours, and94.8% of it was excreted into urine within 2 days (16). Thethromboembolic complications in the rapid administration ofantifibrinolytics (RAF) group of our study occurred 4 to 45 daysafter administration of tranexamic acid (17), while the tranexamicacid was already excreted. However, the possibility cannot beeliminated that tranexamic acid became a trigger to proceed thethromboembolic complications.Table 1 shows thromboembolic complications in the pro-

longed infusion of antifibrinolytics (PAF) group and the RAFgroup of our study. The PAF group was used as a control inthis study, because PAF has been used in many Japanesehospitals. Thromboembolic complications in the RAF groupwere described (17). In the PAF group, either a history orpresence of renal dysfunction was present in eight patients atadmission, and, in one of them, renal function was worsening.Newly developed renal dysfunction after admission was ob-served in two patients. These renal dysfunctions improvedafter conservative treatment. A history of ischemic heart dis-ease was found in two patients in the PAF group. None of

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them showed a recurrence during their hospital treatment.Two patients without history of ischemic heart disease expe-rienced angina pectoris and one patient, who died 50 daysafter admission, sustained acute myocardial infarction. Fivepatients in the PAF group had a history of cerebral infarction.None of them sustained cerebral infarction. Newly developedcerebral infarction was observed in one patient. In the PAFgroup, these complications also seem to have no relationshipwith the administration of tranexamic acid, because of theinterval (3-50 d) between the administration and the occur-rence of the symptoms. No significant difference was ob-served in occurrence of thromoboembolic complications be-tween the PAF group (11.1%) and the RAF group (5.4%) (P 0.19, 2 analysis). During and after the treatment with tranex-amic acid, adverse effects should be carefully monitored.When a patient has a history of renal dysfunction, dose reduc-tion of tranexamic acid and/or mild blood pressure controlmight be better to preserve renal function. In all patientstreated with this method, careful check of urine volume andrenal function should be recommended.

Clinical Outcome

Table 2 shows modified Rankin Scale (mRS) at 1 monthafter the onset or at discharge. In patients with good out-come (mRS 0, 1, or 2), no significant difference wasobserved between the PAF group (19.1%) and the RAFgroup (26.9%) (P 0.26, 2 analysis). On the other hand,more patients had serious outcome (mRS 5, dead) signif-icantly in the PAF group (36.5%) than those in the RAFgroup (21.5%) (P 0.04, 2 analysis). Table 3 shows mRS inpatients with hematoma enlargement. In patients withouthematoma enlargement, no significant difference was ob-served in serious outcome (mRS 5, dead) between thePAF group (34.6%) and the RAF group (20.2%) (P 0.06, 2

analysis). Considering the small number of hematoma en-largement in both groups, we cannot conclude that clinicaloutcome improved in the RAF group by reduction of he-matoma enlargement in this study. On the other hand, in allof the patients with hematoma enlargement in this study,

consciousness level, and/or severity of paresis becameworse in the day after admission than those at admission.Furthermore, no patients with hematoma enlargementshowed good outcome (mRS 0, 1, or 2). Therefore, weconsidered that hematoma enlargement resulted in worsen-ing of clinical state.

Who is the winner?

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

TABLE 1. Complications in patients treated with prolongedinfusion of antifibrinolytics and rapid administrationof antifibrinolyticsa

ComplicationPAF group(n 63)

RAF group(n 93)

Renal dysfunction 3 (4.8%) 3 (3.2%)

Ischemic heart disease 3 (4.8%) 2 (2.2%)

Cerebral infarct 1 (1.6%) 0 (0%)

Deep vein thrombosis 0 (0%) 0 (0%)

a PAF, prolonged infusion of antifibrinolytics; RAF, rapid administration ofantifibrinolytics.

TABLE 2. Clinical outcome in patients treated with prolongedinfusion of antifibrinolytics and rapid administrationof antifibrinolyticsa

mRSbPAF group(n 63)

RAF group(n 93)

0, 1 2 (3.2%) 15 (16.1%)

2 10 (15.9%) 10 (10.8%)

3 13 (20.6%) 13 (14%)

4 15 (23.8%) 35 (37.6%)

5 18 (28.6%) 16 (17.2%)

Dead 5 (7.9%) 4 (4.3%)

a 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 withhematoma enlargementa

mRSbPAF groupc

(n 11)RAF groupd

(n 4)

0, 1 0 (0%) 0 (0%)

2 0 (0%) 0 (0%)

3 4 (36.4%) 0 (0%)

4 2 (18.2%) 2 (50%)

5 4 (36.4%) 2 (50%)

Dead 1 (9.1%) 0 (0%)

a PAF, prolonged infusion of antifibrinolytics; RAF, rapid administration ofantifibrinolytics.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.

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tranexamic acid has been used for ICH in many Japanesehospitals because tranexamic acid is regarded as a relativelysafe drug. ICH occurred more frequently in Japan comparedwith the United States and Europe (15). More than one-fifth ofstroke patients treated in our cerebrovascular center experi-ence ICH. ICH is the least treatable form of stroke and isassociated with higher morbidity and greater disability thanischemic stroke or SAH (15). Intervention with hemostatictherapy might improve a patients disability after ICH byarresting ongoing bleeding and minimizing increases in thevolume of the hematoma (10). A well-designed, randomized,control study is needed to confirm our results, and to deter-mine the appropriate dose of tranexamic acid. Side effects,including renal dysfunction, should be carefully monitoredduring and after the treatment.

Takatoshi SorimachiTokyo, Japan

1. Biswas CK, Milligan DA, Agte SD, Kenward DH, Tilley PB: Acute renalfailure and myopathy after treatment with aminocaproic acid. Br Med J281:115116, 1980.

2. Britt CW, Light RR, Peters BH: Rhabdomyolysis during treatment withepsilon-aminocaproic acid. Arch Neurol 37:187188, 1980.

3. Charytan C, Purtilo D: Clomerular capillary thrombosis and acute renalfailure after epsilon-aminocaproic acid therarpy. N Engl J Med 280:11021104, 1969.

4. Davies D, Howell DA: Tranexamic acid and arterial thrombosis. Lancet 1:49,1977.

5. Fodstad H, Liliequist B: Spontaneous thrombosis of ruptured intracranialaneurysms during treatment with tranexamic acid (AMCA). Report of threecases. 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 earlyrebleeding after aneurysmal subarachnoid hemorrhage: a prospective ran-domized study. J Neurosurg 97:771778, 2002.

8. Kennard C, Henson RA: Myopathy due to epsilon aminocaproic acid.Mus-cle Nerve 3:202206, 1980.

9. Mackay AR, Hoi Sang U, Weinstein PR: Myopathy associated with epsilon-aminocaproic acid therapy: Report of two cases. J Neurosurg 49:597601,1978.

10. Mayer SA: Rapid hemostatic therapy for intracerebral hemorrhage. Stroke34:224229, 2003.

11. Roos Y, Rinkel G, Vermeulen M, Algra A, van Gijn J: Antifibrinolytictherapy for aneurysmal subarachnoid hemorrhage. A major update of aCochrane review. Stroke 34:23082309, 2003.

12. Roos Y, the Star Study Group: Antifibrinolytic treatment in subarachnoidhemorrhage. A randomized placebo-controlled trial. Neurology 54:7782,2000.

13. Roos Y, Vermeulen M, Rinkel GJ, Algra A, van Gijn J, Algra A: Systematicreview of antifibrinolytics treatment in aneurysmal subarachnoid haemor-rhage. J Neurol Neurosurg Psychiatry 65:942943, 1998.

14. Rydin E, Lundberg PO: Tranexamic acid and intracranial thrombosis. Lan-cet 2:49, 1976.

15. Sacco RL, Mayer SA: Epidemiology of intracerebral hemorrhage, inFeldmann E (ed): Intracerebral Hemorrhage. Armonk, Futura Publishing Co,1994, pp 323.

16. Sano M, Hakusui H, Kojima C, Akimoto T: Absorption and excretion oftranexamic acid following intravenous, intramuscular and oral administra-tions in healthy volunteers [in Japanese]. Clin Pharmacol Ther 7:375382,1976.

17. Sorimachi T, Fujii Y, Morita K, Tanaka R: Rapid administration ofantifibrinolytics and strict blood pressure control for intracerebral hemor-rhage. Neurosurgery 57:837844, 2005.

18. Stroobandt G, Lambert O, Menard E: The association of tranexamic acid andnimodipine in the pre-operative treatment of ruptured intracranial aneu-rysms. 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, SchannongM, Teasdale GM, van Greavel H, van Gijn J: Antifibrinolytic treatment insubarachnoid hemorrhage. N Engl J Med 311:432437, 1984.

DOI: 10.1227/01.NEU.0000217321.47870.6A

Visualizing the Dynamics of Cerebral Aneurysms withFour-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 four-dimensional computed tomographic (4D-CT) angiographydetected the pulsating blebs in nine of 28 saccular rupturedaneurysms. And, in two with ruptured aneurysms, the pul-sating blebs were confirmed as the ruptured points duringthe surgical procedure. Certainly, this method seems to bea new and promising technique for the demonstration of thehemodynamics of the aneurysmal wall. We have performedthe same procedure for the cerebral aneurysms. Initially, weexpected the method would be a novel technique to detecta portion of wall thinning of cerebral aneurysms, allowingus to predict the rupture risk of the aneurysms. As theauthors results, our study demonstrated the movement ofthe aneurysm with an electrocardiograph cycle. We com-pared the findings of the 4D-CT movie with the intraoper-ative findings of the aneurysm. However, there was a bigdiscrepancy between them (2). If readers look at the figuresand online digital video, they will see that the movement ofaneurysm, the surrounding normal arteries, veins, and boneis displayed. During operation, the pulsating movement ofmajor arteries is always observed, but the vein and craniumdo not have any movement.Nevertheless, the movement of the vein and bone exhibited

on the 4D-CT angiography (14). We have never seen thepulsating blebs and the aneurysmal wall motion during sur-gery. We cannot fully explain what induces the movement onthe 4D-CT angiography. We speculate the following factors:rotating x-ray beam (Helical scanning), heterogeneous concen-tration of contrast medium in the vessels, and the movementof the artery itself with cardiac cycle. We studied the move-ment of the subject using phantom (Fig C2). As you can see,the artifacts owing to scanning were demonstrated. The plasticmodel does not have the movement caused by the cardiaccycle and heterogeneous concentration of the contrast me-dium. However, the bleb-like structures were demonstrated.The authors should indicate the definition to decide the ab-normal findings. Figure 7 in the article suggests that thistechnique is unreliable, because the phases showing the pul-sating bleb are not consistent.

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The authors also described that the 4D-CT movie revealedthe pulsating line that indicated the dissecting cavity andintimal flap (1). The initial flap line should be confirmed on theoriginal image. Moreover, the magnetic resonance imagingand/or magnetic resonance angiography should be added tosupport the findings.Fujita and Kawaguchi (4) reported that 4D-CT angiography

was likely to become indispensable in deciding whether tooperate or observe. To apply this technique for the clinicalexamination, however, the further improvement is necessary.For the present, the findings of the 4D-CTA should not beused for making the decision whether the operation should beperformed in the patients with unruptured cerebralaneurysms.

Masato MatsumotoTatsuya SasakiKyouichi SuzukiJun SakumaYuji EndoNamio KodamaFukushima, Japan

1. Ishida F, Ogawa H, Simizu T, Kojima T, Taki W: Visualizing the dynamicsof cerebral aneurysms with four-dimensional computed tomographic an-giography. Neurosurgery 57:460471, 2005.

2. Matsumoto M, Sato T, Oinuma M,Sato M, Suzuki K, Sasaki T, KodamaN, Murakami K, Suzuki K, KatakuraT, Shishido F: ECG triggered 3dimensional-CT angiography for ce-rebral aneurysms using multislice he-lical CT [in Japanese]. Prog ComputImaging 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 electrocardio-graphically gated reconstruction forvisualizing pulsation of intracranialaneurysms: Identification of aneurys-mal protuberance presumably associ-ated with wall thinning. AJNRAm J Neuroradiol 26:13661369,2005.

4. Fujita S, Kawaguchi T: Detection ofthin regions of unruptured cerebralaneurysms by ECG synchronous re-construction 3D-CT angiography(4D-CTA) using 16 slices per rotation CT[in Japanese]. Prog Comput Imaging26: 93100, 2004.

In Reply:We thank Matsumoto et al.

for their comments on our arti-cle regarding visualizing the dy-namics of cerebral aneurysmswith 4D-CT angiography. They

pointed out discrepant findings on the aneurysm surface be-tween the 4D-CT angiography and intraoperative fields. How-ever, their comments depend on assumptions that may bedebated. The fine morphology of the aneurysmal wall maywell be different between the condition under the atmosphericair pressure at surgery and the computed tomographic an-giography performed under the intracranial pressure withinthe closed-head cavity. In addition, perianeurysmal environ-ments (2), including arachnoid trabecula, cranial nerves, duramater, and adjacent brain pharencyma, may be moved anddislocated from their normal setting during surgical proce-dures. Direct visual comparison of the contours of the aneu-rysm may be difficult between the morphological findingsobserved in surgery and flow dynamics obtained by 4D-CTangiography. The concept and purpose of the 4D-CT angiog-raphy are different from that of Matsumoto in the respect thatthe information obtained by 4D-CT angiography is based noton the outer shape of aneurysm, but rather on the intra-aneurysm flow dynamics.To date, the application of 4D-CT angiography to assess

aneurysmal flow dynamics has had certain limitations, asMatsumoto et al. suggest, and there is a need to refine theimaging technique. Pulsating blebs and walls on the aneurys-mal dome may not be consistent with pulsations on the ex-posed dome bleb identified during surgery. From our researchfindings, the pulsating changes on 4D-CT angiography may beclassified into two groups: one is a pulsative movement

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 performedusing a MDCT scanner with 64 detectors.

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caused by motions or other artifacts and the other is a realpulsation of the aneurysmal wall corresponding to the hemo-dynamics within the vessels. The protrusive change displayedby Matsumoto in Figure C2 was considered not a motionartifact, but a bulge on the surface of the plastic figure model.False positive findings of 4D-CT movies with smooth surfacemodels, such as a titanium clip, would be better suited for theevaluation of the artifacts of 4D-CT angiography. Quantitativeor qualitative analyses of the pulsative changes on 4D-CTmovies are required to rule out such artifacts, and now we aredesigning experimental and computational models which willallow 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 intra-aneurysmal flow hemodynamics, which is shown as pulsatilemovement. Although it is difficult at this point to elucidate theprecise significance of 4D-CT findings for clinical setting andto define the abnormal findings, 4D-CT angiography shouldbe a great help to understand the pathological and morpho-

logical features of cerebral aneurysms (1). More work is re-quired to validate the utility of 4D-CT angiography and toclarify the significance of visualizing the dynamics of cerebralaneurysms, and we see this work as a step along that path.

Fujimaro IshidaTsu, Japan

1. Kato Y,HayakawaM, SanoH, SunilMV, Imizu S, YonedaM,Watanabe S, AbeM,Kanno T: Prediction of impending rupture in aneurysms using 4D-CTA: His-topathological verification of a real-time minimally invasive tool in unrupturedaneurysms.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 envi-ronment on the deformation and bleb formation of the unruptured cerebralaneurysm: Assessment with fusion imaging of 3D MR cisternography and3D MR angiography. AJNR Am J Neuroradiol 26:20102018, 2005.

DOI: 10.1227/01.NEU.0000217323.32623.F7

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