The Sphenoparietal Sinus

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VOLUME 62 | NUMBER 6 | JUNE 2008 | E1384
CORRESPONDENCE
Single Nucleotide Polymorphisms of Tissue Inhibitors of
Metalloproteinase Genes in Familial Moyamoya Disease
To the Editor:
We read with great interest the article by Kang et al. (2). The
authors investigated polymorphisms of the tissue inhibitor of
metalloproteinase-2 (TIMP2) and -4 (TIMP4) genes in patients
diagnosed as having familial moyamoya disease (MMD), to
determine whether sequence variations of these genes were
related to familial MMD. The study was based on familial
MMD gene mapping linkage analysis. TIMP2 and TIMP4 genes
span known MMD loci. Moreover, down-regulation of TIMP
genes may cause matrix metalloproteinase (MMP) overactivity.
In their work, the authors found that a polymorphism in the
promoter region of the TIMP2 gene was significantly associated
with familial MMD (2). In particular, a G/C heterozygous
genotype in the TIMP2 gene at position 2418 was present in
nine of 11 familial MMD patients, resulting in a modification of
the “motif” that recognizes the transcription factor Sp1. The
frequency of the G/C genotype at position 2418 in familial
MMD cases differed significantly from its frequency in normal
controls and in nonfamilial MMD cases.
To explain this finding, Kang et al. hypothesized that the
deregulation of TIMPs can disrupt the balance between MMPs
and TIMPs, resulting in erroneous smooth muscle cell (SMC)
dynamics, leading to the MMD phenotype. Such a theory is
intriguing, because it is potentially linked to the process of vas-
cular remodeling present in MMD at the molecular level (i.e.,
the “vascular injury repair model”). In fact, although currently
there is no definitive explanation for the pathogenesis of MMD,
the final common pathway seems to be represented by exces-
sive SMC migration toward the intima.
In 1999, we reported the first Caucasian monozygotic twins
affected by MMD (1). The incidence rate of MMD in monozy-
gotic twins is 80%, markedly higher than in siblings (3). To
date, 12 pairs of monozygotic twins have been reported as hav-
ing the disease, and all of them, including ours, were female
(1). To provide additional evidence to the model of Kang et al.,
we investigated the role of TIMP genes in our monozygotic
twins. In genomic deoxyribonucleic acid (DNA) samples taken
from our monozygotic twins, we amplified 1) the promoter
region, 2) the exon regions, and 3) the intron-exon junctions of
TIMP2 and TIMP4 genes.
In our patients, the sequence analysis of exon 3 of the TIMP2
gene indicated the presence of the well-characterized polymor-
phism G/A at position +853. However, to our surprise, we did
not find the G/C heterozygous genotype at position 2418 in the
promoter region of the TIMP2 gene, as described by Kang et al.
(2). MMD in Caucasians can present with a more benign form
of the disease, as compared with the disease in Asians (4). This
milder form, as well as other specific features, may be the
expression of different gene mutations.
In conclusion, despite the presence of a single nucleotide
polymorphism, our study did not provide any further evidence
to support the model proposed by Kang et al.
Vincenzo Andreone
Simona Scala
Celeste Tucci
Daniele Di Napoli
Italo Linfante
Andrea Tessitore
Antonio Faiella
Naples, Italy
1. Andreone V, Ciarmiello A, Fusco C, Ambrosanio G, Florio C, Linfante I:
Moyamoya disease in Italian monozygotic twins. Neurology 53:1332–1335,
1999.
2. Kang HS, Kim SK, Cho BK, Kim YY, Hwang YS, Wang KC: Single nucleotide
polymorphisms of tissue inhibitor of metalloproteinase genes in familial
moyamoya disease. Neurosurgery 58:1074–1080, 2006.
3. Yamauchi T, Houkin K, Tada M, Abe H: Familial occurrence of moyamoya
disease. Clin Neurol Neurosurg 2 [Suppl]:S162–S167, 1997.
4. Yilmaz EY, Pritz MB, Bruno A, Lopez-Yunez A, Biller J: Moyamoya: Indiana
University Medical Center experience. Arch Neurol 58:1274–1278, 2001.
DOI: 10.1227/01.NEU.0000315874.49577.99
In Reply:
We greatly appreciate the interest in our article (5). In the
pair of monozygotic twins diagnosed as having MMD, as pre-
sented by Andreone et al., the sequence analysis of the TIMP2
gene showed the presence of the polymorphism G/A at posi-
tion +853 in exon 3 and the absence of the G/C heterozygous
genotype at position 2418 in the promoter region. In our
study, the G/A genotype at position +853 was present in six
of 11 patients with familial MMD (5). However, no signifi-
cant difference was found between the frequency of the G/A
heterozygous genotype at position +853 in familial MMD
patients versus normal control participants or versus nonfa-
milial MMD participants. This polymorphism would produce
change in the third nucleotide of the 101st codon of TIMP2
from TCG to TCA, resulting in serine in both instances, and
thus it is a silent variant.
In a study by Kanai (4), nine of 10 pairs were concordant for
MMD among monozygotic twins; a genetic study of this pop-
ulation would produce fruitful results for understanding the
pathophysiology of the disease. Thus, it would be valuable to
find genetic causes or predisposing factors among the reported
12 pairs of monozygotic twin cases. As was shown in a previ-
ous report (1), the authors found a 677 C→T mutation
(Ala→Val substitution) of the methylenetetrahydrofolate reduc-
tase-encoding gene in monozygotic twins; it is a presumed risk

factor for arterial steno-occlusive disease. Variable loci related
to familial MMD have been reported (2, 3, 6, 7), and we believe
that various relevant genes in these loci could be investigated
in this special subgroup of patients.
Hyun-Seung Kang
Seung-Ki Kim
Kyu-Chang Wang
Seoul, South Korea
1. Andreone V, Ciarmiello A, Fusco C, Ambrosanio G, Florio C, Linfante I:
Moyamoya disease in Italian monozygotic twins. Neurology 53:1332–1335,
1999.
2. Ikeda H, Sasaki T, Yoshimoto T, Fukui M, Arinami T: Mapping of a familial
moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet
64:533–537, 1999.
3. Inoue TK, Ikezaki K, Sasazuki T, Matsushima T, Fukui M: Linkage analysis of
moyamoya disease on chromosome 6. J Child Neurol 15:179–182, 2000.
4. Kanai N: A genetic study of spontaneous occlusion of the circle of Willis
(moyamoya disease) [in Japanese]. J Tokyo Women Med Univ 62:1227–1258,
1992.
5. Kang HS, Kim SK, Cho BK, Kim YY, Hwang YS, Wang KC: Single nucleotide
polymorphisms of tissue inhibitor of metalloproteinase genes in familial
moyamoya disease. Neurosurgery 58:1074–1080, 2006.
6. Sakurai K, Horiuchi Y, Ikeda H, Ikezaki K, Yoshimoto T, Fukui M, Arinami T:
A novel susceptibility locus for moyamoya disease on chromosome 8q23.
J Hum Genet 49:278–281, 2004.
7. Yamauchi T, Tada M, Houkin K, Tanaka T, Nakamura Y, Kuroda S, Abe H,
Inoue T, Ikezaki K, Matsushima T, Fukui M: Linkage of familial moyamoya
disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25.
Stroke 31:930–935, 2000.
DOI: 10.1227/01.NEU.0000315875.87695.63
Techniques of Posterior C1–C2 Stabilization
To the Editor:
We read with interest the article by Menendez and Wright
(5). Publication of any article in N
EUROSURGERY
has great
implications, as most future references will be based on this
presentation. Articles discussing historical perspectives should
be duly scrutinized so that the material is placed in proper per-
spective for future readers. It is also necessary, in a history-
related article, that all of the relevant references are duly cited
and credits are appropriately given to original contributors. It
is strange that the authors discuss the history of fixation tech-
niques of the atlantoaxial region and conclude that the tech-
nique that they themselves discussed earlier is the safest and
biomechanically strongest.
We previously presented a technique of fixation that involves
screw insertion into the base of the spinous process of the axis
or into the spinolaminar junction (2). One to two screws were
inserted to secure fixation of a plate. The superior end of the
plate was fixed to the occipital bone with either screws or
wires. Our method has similarities with the technique pro-
posed by the authors and deserved to be in the reference list.
We take strong objection, for the second time in this journal
(1), to the naming of our technique as the Harms technique. It
is a “historical” error to give ownership of our several-times-
published technique (3, 4), which predates the authors’ by sev-
eral years, to somebody else just because commercial polyaxial
screws were used instead of monoaxial screws, and rods were
used instead of plates.
Atul Goel
Mumbai, India
1. Goel A: C1–C2 pedicle screw fixation with rigid cantilever beam construct:
Case report and technical note. Neurosurgery 51:853–854, 2002 (letter).
2. Goel A, Kulkarni AG: Screw implantation in spinous process for occipitoax-
ial fixation. J Clin Neurosci 11:735–737, 2004.
3. Goel A, Laheri VK. Plate and screw fixation for atlanto-axial dislocation. Acta
Neurochir (Wien) 129:47–53, 1994.
4. Goel A, Desai K, Muzumdar D: Atlantoaxial fixation using plate and screw
method: A report of 160 treated patients. Neurosurgery 51:1351–1357, 2002.
5. Menendez JA, Wright NM: Techniques of posterior C1–C2 stabilization.
Neurosurgery 60:S103–S111, 2007.
DOI: 10.1227/01.NEU.0000315876.87695.B8
In Reply:
We appreciate Dr. Goel’s comments about our article (9).
Some of his points can be clarified by a careful rereading of the
article.
Dr. Goel’s contributions to the development of atlantoaxial
fixation are significant and were referenced appropriately in the
section on C1–C2 rod-cantilever techniques (2, 3). In the authors’
technique of C1–C2 fixation using crossing C2 laminar screws,
the Harms technique (6) was mentioned in reference to place-
ment of the C1 lateral mass screws. As our technique involves
polyaxial screws in C1 connected via a rod to the C2 screws, the
Harms technique was a more relevant reference than the
monoaxial screw and plate method described by Dr. Goel.
We take issue with the comment by Dr. Goel that we asserted
that our C2 laminar technique was “safest and biomechani-
cally strongest.” A careful reread of our article shows that,
while early biomechanical studies show C2 laminar screws to
be equivalent to other methods of C2 fixation (5, 7), we specif-
ically cautioned the reader that this was a new technique
requiring further study before widespread implementation. We
did, however, suggest that C2 laminar screws are potentially
safer than other C2 screws that require placement near the ver-
tebral artery—an observation borne out in our first 30 patients.
The surgical technique of screw placement into the spinous
process of C2 in constructs of occipital-C2 fixation has,
indeed, been reported by Dr. Goel (1). However, although
both Dr. Goel’s technique and ours involve screw placement
into C2, the method and anatomic location of fixation are sub-
stantially different. Our technique places crossing 30-mm-
length screws into the C2 laminae (8, 10, 11), whereas Dr.
Goel’s technique involves 8- to 12-mm screws placed ven-
trally into the spinous process. We stand by our assertion that
the Wright technique is a novel method of fixation not based
on the technique of Dr. Goel.
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Lastly, by citing Dr. Goel’s articles in our review, we recog-
nized his contribution to the field of atlantoaxial fixation. We
would strongly agree that review articles in any journal should
widely cite relevant literature and be historically accurate. We
commend Dr. Goel for strongly advocating this practice but
were surprised by his recent review article on atlantoaxial fix-
ation (4), in which he cited only one technique other than his
own and failed to mention the Wright technique.
Neill M. Wright
Todd J. Stewart
St. Louis, Missouri
1. Goel A, Kulkarni AG: Screw implantation in spinous process for occipitoax-
ial fixation. J Clin Neurosci 11:735–737, 2004.
2. Goel A, Laheri V: Plate and screw fixation for atlanto-axial subluxation. Acta
Neurochir (Wien) 129:47–53, 1994.
3. Goel A, Desai KI, Muzumdar DP: Atlantoaxial fixation using plate and screw
method: A report of 160 treated patients. Neurosurgery 51:1351–1357, 2002.
4. Goel A, Sharma P, Dange N, Kulkarni AG: Techniques in the treatment of
craniovertebral instability. Neurol India 53:525–533, 2005.
5. Gorek J, Acaroglu E, Berven S, Yousef A, Puttlitz CM: Constructs incorporat-
ing intralaminar C2 screws provide rigid stability for atlantoaxial fixation.
Spine 30:1513–1518, 2005.
6. Harms J, Melcher RP: Posterior C1-C2 fusion with polyaxial screw and rod
fixation. Spine 26:2467–2471, 2001.
7. Lapsiwala SB, Anderson PA, Oza A, Resnick DK: Biomechanical comparison
of four C1 to C2 rigid fixative techniques: Anterior transarticular, posterior
transarticular, C1 to C2 pedicle, and C1 to C2 intralaminar screws.
Neurosurgery 58:516–521, 2006.
8. Leonard JR, Wright NM: Pediatric atlantoaxial fixation with bilateral, cross-
ing C-2 translaminar screws. Technical note. J Neurosurg 104:59–63, 2006.
9. Menendez JA, Wright NM: Techniques of posterior C1–C2 stabilization.
Neurosurgery 60:S103–S111, 2007.
10. Wright NM: Posterior C2 fixation using bilateral, crossing C2 laminar screws:
Case series and technical note. J Spinal Disord Tech 17:158–162, 2004.
11. Wright NM: Translaminar rigid screw fixation of the axis. J Neurosurg Spine
3:409–414, 2005.
DOI: 10.1227/01.NEU.0000315877.95318.B6
Objectifying When to Halt a Boxing Match:
A Video Analysis of Fatalities
To the Editor:
As a former amateur and undefeated professional fighter, I
read with great interest the articles on boxing by Miele and
Bailes (2) and Baird and Levy (1). I would like to offer some
insight and comments with regard to the attempt to establish
greater safety in professional boxing.
It may be apt to say of professional boxing that “…the pri-
mary strategy is to disable an opponent’s central nervous sys-
tem. This is usually performed by striking an adversary with a
force sufficient to render him or her unconscious.” This cannot
be said about amateur boxing, in which fatalities are extraordi-
narily rare. Amateur boxing has a completely different scoring
system that emphasizes finesse and awards no points for the
force of a blow. In fact, a punch that knocks down an opponent
is worth no more than a jab. Technically speaking, there is no
such thing as a knockout (KO) or technical knockout (TKO) in
amateur boxing; rather, the designation “referee stops contest”
(RSC) is used. The scoring system reinforces the philosophy of
amateur boxing that the goal is to outbox and outpoint the
opponent, not to render the opponent unconscious (this is also
the reason why body punching is so much more prevalent in
amateur boxing). Toward that end, numerous other tactics are
used to make neural injury much less likely in amateur boxing,
not the least of which are heavier gloves, use of headgear, and
shorter duration of bouts.
Boxing, in fact, is a full-blown subculture with its own set of
peculiarities, and there have been changes in the sport over
the past several decades that have not all been positive. One
such change that affected boxing in Philadelphia, and the mid-
Atlantic region in general, was the advent of gambling in
Atlantic City, NJ, in the mid-1970s. The frequent shows at the
casinos required more professional fighters to fill the cards; so
instead of a young amateur accumulating two or three hundred
amateur fights before testing the professional ranks, young
fighters instead turned professional when they had much less
experience and ring savvy. The commercialization of the sport
has created countless young “undefeated” and untested boxers
to generate interest. These untested younger fighters often
build impressive records fighting boxers who are less than “up
to the mark” and who, in some cases, make a career of being
traveling opponents. (Variations in state laws regarding boxing
make it advantageous for those seeking loopholes to choose
more lax states as venues.) There is no reason not to establish
a nationwide organization to regulate the sport. There is no
excuse, in the digital age, that prevents tracking fighters so that
they do not embark on a gypsy-like career of becoming profes-
sional opponents. A national organization must be given
“teeth,” if it is to be respected and, thereby, successful.
Another sad issue involves a lack of change, despite tremen-
dous advances in the material sciences. Technological changes
in equipment have been slow in coming and lag substantially
behind other sports. Little has changed in the manufacturing of
boxing gloves and headgear since the use of porous foam
instead of horsehair. The successful reengineering of football
helmets has been a topic in this very publication. It can be
argued that the porous foam headgear worn by amateurs does
little for safety and provides a larger target. The current head-
gear is almost identical to what I wore as an amateur 30 years
ago. I am certain that better materials can be utilized to increase
the efficacy of headgear.
It is very honorable to explore ways to avoid fatalities in
boxing, but the vast majority of neural injuries in boxing are the
result of cumulative trauma, and this occurs with a signifi-
cantly higher incidence in training than it does in actual bouts.
It is rare that fighters are ruined in one fight (examples include
Eugene “Cyclone” Hart, who fell from the ring to a concrete
floor in a bout versus Denny Moyer in 1971, sustaining a closed
head injury, and Meldrick Taylor in his bout against Julio Cesar
Chavez in 1990; neither Hart nor Taylor ever returned to his
prior level of performance). Rather, fighters begin a gradual
slide from their peak (however humble it may be) and continue
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to fight, absorbing and compounding their injuries, which often
lead to full-blown dementia pugilistica, sometimes several
years after they have retired.
There are several things that can be done to improve safety
immediately in professional boxing: Implement a weigh-in sys-
tem, similar to that endorsed by the National Wrestling
Coaches Association, that calculates a participant’s ideal body
weight; the individual then competes at the specified weight
class for the season. Implore manufacturers to design better
equipment and consider the use of heavier gloves. Create a
nationwide regulatory agency with the power to enforce their
decisions. Lastly, give consideration to a scoring system more
in line with that of amateur boxing.
I understand that there is much concern that changes will
diminish the popularity of the sport. Boxing, along with
wrestling and soccer, enjoys a place among the most ancient of
sports. Participation has reached an all-time high in popularity,
but that is, in large part, the result of trendy non-mainstream
participation, as many individuals box to achieve fitness but
are not necessarily viewers of the sport. However, there is an
element of bloodlust in some people, and this is largely being
satiated by pay-per-view events, such as mixed martial arts.
Boxing is unlikely to be outlawed and has managed to survive
through very tough times. Now is a good time to focus on
changing some of the fundamental objectives of professional
boxing to reflect the “sweet science” so it does not degenerate
into the side show of mixed martial arts bouts. Real Pro
Wrestling is a new franchise designed to popularize the great
sport of freestyle wrestling by advocates of amateur wrestling
and give it an identity distinct from that of what was formerly
the World Wrestling Federation. What better time is there to
enact similar changes in boxing?
Richard C. Mendel
Jupiter, Florida
1. Baird LC, Levy ML: The war of the gods. Neurosurgery 60:405–412, 2007.
2. Miele VJ, Bailes JE: Objectifying when to halt a boxing match: A video analy-
sis of fatalities. Neurosurgery 60:307–316, 2007.
DOI: 10.1227/01.NEU.0000315878.72447.74
In Reply:
I appreciate the extremely well-written and informed letter
by Dr. Mendel regarding our article (5). I strongly agree that
amateur boxing is much safer than its professional counter-
part. The two have evolved along differing philosophies to the
point that they are almost incomparable with regard to the risk
of acute and chronic injuries. Amateur boxing’s emphasis has
always been on the safety of the athlete, while the professional
version of the sport has been more concerned with promotion
and economics.
Unfortunately, this lack of focus on safety has been, and will
continue to be, paid for by the athlete who dies or, much more
commonly, is disabled. Although this study addressed acute
neurological injuries in boxing, they are uncommon. It can be
safely stated, however, that this sport is one of the most danger-
ous in terms of chronic injury to the brain. We are facing an epi-
demic of chronic brain injury secondary to cumulative trauma
in all contact sports (2, 6, 7).
I also agree that athletes are at particular risk during
upswings in the popularity of the sport. Similar to the situation
described in the mid-Atlantic region, the recent demand for
experienced female athletes now exceeds the supply, and many
underprepared female boxers move quickly through the ama-
teur and professional ranks—often without developing the
defensive skills needed to avoid serious injury when facing a
more experienced opponent (1).
With regard to equipment changes, one must remember that
the original purpose of headgear and gloves was to prevent
cuts and hand injuries during training. Few adaptations have
been made over the past century. The evolution of safety equip-
ment in the sport has been and is currently hampered by the
unanswered question of which is more dangerous: a fast knock-
out or the continuous accumulation of subconcussive blows for
36 minutes. Many, including myself, feel that the new and
increasingly popular sport of mixed martial arts, which uses no
headgear and much smaller gloves, is actually neurologically
safer than professional boxing, because stoppages and knock-
outs occur much sooner. Until this question is answered, it is
uncertain whether a change in headgear and gloves to absorb
more force would be a detriment to the athlete. Along a similar
line, imagine you are the sideline physician during a football or
hockey game, and a participant receives a blow to the head
resulting in temporary unconsciousness or near unconscious-
ness. Would giving the athlete 8 seconds to recover and return
to competition be appropriate? This occurs so frequently in pro-
fessional boxing that it is incorporated into the rules: the stand-
ing eight count. It is hard to argue that giving an athlete a short
time-out to clear his or her head before resuming being struck
is in the best interest of the athlete. Of course, in amateur box-
ing, which has the goal of scoring points as opposed to knock-
ing out an opponent, safety would be increased by improve-
ments in force-absorbing equipment.
I strongly feel that the most significant change in equip-
ment on the horizon would be the incorporation of force-
measuring devices, such as accelerometers, into the headgear
and mouthpieces of athletes. In a perfect world, the devices
would be worn during both sparring and matches, and a
threshold of punishment to the central nervous system could
be established that, if exceeded, would result in forfeiture of
the match or the end of a career. I agree that weigh-in proto-
cols can significantly affect the vulnerability of the athlete’s
central nervous system and that the immediate implementa-
tion of such a system would benefit boxing. Often, athletes
dehydrate themselves to “make weight” and then rapidly
rehydrate. Studies are currently being conducted in boxers to
analyze the effects of this practice on central nervous system
osmolality and electrolyte balances that could predispose an
athlete to cerebral edema (4).
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As has been eloquently discussed, there are many problems
with boxing that could be easily corrected. A federal commis-
sion that has the oversight and authority to enforce national
and uniform changes is long overdue. Some states, such as
New Jersey, New York, and Nevada, have model programs,
while others, including mine, do not even routinely test for
hepatitis B/C and human immunodeficiency virus in a sport
that often involves the exchange of blood. Because the sharing
of information between states is so important to the safety of
the athletes, such a regulatory agency should create a national
databank for all medical information. Currently, we have only
Fightfax and the Federal Suspension List, whose accuracy relies
heavily on the individual reporting the information (3).
Vincent J. Miele
Morgantown, West Virginia
1. Bailes JE, Miele VJ: Fatal attraction for the ring. New York Times, New York,
5/22/2005, sec 8, p 9.
2. Casson IR, Pellman EJ, Viano DC: Chronic traumatic encephalopathy in a
National Football League player. Neurosurgery 58:E1003; author reply E1003;
discussion E1003, 2006.
3. Goodman M: Ringside Physician and former Chairman of the Medical
Advisory Board of the Nevada State Athletic Commission, in Miele VJ (ed),
2007.
4. Lemons V: in Miele V (ed). Sacramento, CA, 2007.
5. Miele VJ, Bailes JE: Objectifying when to halt a boxing match: A video analy-
sis of fatalities. Neurosurgery 60:307–316, 2007.
6. Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH:
Chronic traumatic encephalopathy in a National Football League player.
Neurosurgery 57:128–134, 2005.
7. Schwenk TL, Gorenflo DW, Dopp RR, Hipple E: Depression and pain in
retired professional football players. Med Sci Sports Exerc 39:599–605, 2007.
DOI: 10.1227/01.NEU.0000315879.80071.7A
The Sphenoparietal Sinus
To the editor:
We read with interest the article by Tubbs et al. (7) and would
like to clarify certain anatomic and embryological concepts on
the basis of our previous work on the sphenoparietal sinus
(SphS) of Breschet (5) and on Padget’s embryology of the cra-
nial venous system (4), which were cited in this publication.
Some of these concepts seem to have been misinterpreted by
the authors, perpetuating the general confusion regarding the
description of the veins of the middle cranial fossa, which is,
unfortunately, widespread in the literature. This confusion usu-
ally arises from the assimilation of the termination of the super-
ficial middle cerebral vein (SMCV) with the SphS. In our expe-
rience, based on classic cadaveric dissection and venous
corrosion cast studies, we have never found any connection
between the SMCV and the so-called SphS (5, 6). Furthermore,
whenever the SMCV drained into the laterosellar region, it gen-
erally directly pierced the dura of the lateral wall of the cav-
ernous sinus (CS). Only rarely was the SMCV attached to the
dura mater underlying the inferior aspect of the lesser sphe-
noid wing. In such cases, it usually maintained the characteris-
tics of an “arachnoid vein,” rather than transforming into a
dural venous sinus, as seems to be the case in Figures 4 and 5in
the publication by Tubbs et al.
Our study also revealed a dural venous channel embedded
in the dura mater underlying the lesser sphenoid wing, which
opened laterally into the anterior branch of the middle
meningeal veins in the region of the pterion, and medially into
the anterior and superior aspects of the cavernous sinus (CS)
(5). Three venous tributaries of this dural venous sinus were
observed: a diploic vein of the orbital roof, a diploic vein of the
greater sphenoid wing, and, on one occasion, an ophthalmo-
meningeal vein of Hyrtl, confirming its function in draining the
neurocranium. This dural venous sinus responds to the
description of Breschet’s SphS, as cited by Cruveilhier: “this
sinus receives several branches from the skull bones, the dura
mater, and the diploic vein of the temporal (bone)” (2), without
mention of any cortical drainage. This view corresponds to
Breschet’s illustrations, which are reproduced in the article by
Tubbs et al., although, unfortunately, it cannot be confirmed in
Breschet’s original monograph on the cranial and spinal venous
system (1), as the text accompanying the illustrations was pub-
lished incompletely (5).
The term “venous sinus of the lesser sphenoid wing” seems
to better describe this channel, which lacks any topographic
relation with the parietal bone (Fig. C1) (5, 8). This term should,
however, not be used to describe the course of the SMCV under
the lesser sphenoid wing, as the article by Tubbs et al. suggests.
Tubbs et al. seem to have confused the SMCV and its termina-
tion for the SphS. Their Figure 6, for instance, shows a venous
channel that originates under the lesser sphenoid wing a short
distance lateral to the anterior clinoid process, which then
courses within the lateral wall of the CS before emptying into
the emissary vein of the middle cranial fossa. This vessel corre-
sponds to a typical laterocavernous sinus. The laterocavernous
sinus was recently described, and it represents the second most
frequent drainage pathway of the SMCV in the middle cranial
fossa (3, 6). It courses within the dural layers of the lateral wall
of the CS and drains into the emissary veins of the middle cra-
nial fossa, the superior petrosal sinus, or the posterior aspect of
the CS. Tubbs et al. mention this type of drainage pathway of
the SMCV, along with the alternative termination of the SMCV
into the paracavernous sinus and the CS, but they seem to have
failed to recognize it in their anatomic preparations.
Having initially hypothesized that the paracavernous sinus,
laterocavernous sinus, and CS terminations of the SMCV rep-
resent variable stages of migration of the primitive tentorial
sinus (of Padget) toward the laterosellar region in late uterine
or early postnatal life (3, 6), we can only agree with the sugges-
tion by Tubbs et al. that the variable drainage patterns of the
SMCV relate to the fate of the primitive tentorial sinus in the
adult. The primitive tentorial sinus is the drainage pathway of
the primitive SMCV and deep middle cerebral vein and of the
future constituents of the basal vein of Rosenthal (4). We dis-
agree, however, with the affirmation by Tubbs et al. (7) that the
portion of the tentorial sinus anterior to the cavernous sinus is
the sphenoparietal sinus. According to Padget (4), the SphS
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derives from the embryonic prootic sinus (the precursor of the
CS, the middle meningeal veins, the inferior petrosal sinus,
and the petrosquamosal sinus), which is found in the outer
(superficial) dural layer and should not be confused with the
primitive tentorial sinus, which lies in the inner (deep) dural
layer. In fact, Padget clearly states that the remnant of the ten-
torial sinus in postnatal stages has been erroneously called
SphS (4).
It remains unclear to us why Tubbs et al. failed to demonstrate
the venous sinus of the lesser sphenoid wing. Their methodology,
however, suggests that they did not specifically look for a sepa-
rate intradural sinus coursing deeply and parallel to the more
obvious SMCV. Indeed, close inspection of their Figure 7 reveals
a possible intradural vascular structure filled with blue latex
coursing along the ridge of the lesser sphenoid wing toward the
CS. This unlabeled structure in Figure 7 could well correspond to
a venous sinus of the lesser sphenoid wing (4).
Diego San Millán Ruíz
Baltimore, Maryland
Jean H.D. Fasel
Geneva, Switzerland
Philippe Gailloud
Baltimore, Maryland
1. Breschet G: Anatomic, Physiological, and Pathological Research on the Venous
System and Especially on the Venous Channels in Bone [in French]. Paris, Villeret
et Rouen, 1829, pp 1–42.
2. Cruveilhier J. Treatise on Descriptive Anatomy: Angiology [in French]. Paris,
Labbé, 1852, ed 3, p 43.
3. Gailloud P, San Millán Ruíz D, Muster M, Murphy KJ, Fasel JHD, Rüfenacht
DA: Angiographic anatomy of the laterocavernous sinus. AJNR Am J
Roentgenol 21:1923–1929, 2000.
4. Padget DH: Development of the cranial venous system in man, from a view-
point of comparative anatomy. Contrib Embryol 36:79–140, 1957.
5. San Millán Ruíz D, Fasel JHD, Rüfenacht DA, Gailloud P: The sphenoparietal
sinus of Breschet, does it exist? An anatomic study. AJNR Am J Neuroradiol
25:112–120, 2004.
6. San Millán Ruíz D, Gailloud P, De Miquel Miquel MA, Muster M, Dolenc VV,
Rüfenacht DA, Fasel JHD: The laterocavernous sinus: An anatomic study.
Anat Rec 254:7–12, 1999.
7. Tubbs RS, Salter EG, Wellons JC 3rd, Blount JP, Oakes WJ: The sphenoparietal
sinus. Neurosurgery 60 [Suppl 1]:ONS9–ONS12, 2007.
8. Wolf BS, Huang YP, Newman CM: The superficial sylvian venous drainage
system. Am J Roentgenol Radium Ther Nucl Med 89:389–410, 1963.
DOI: 10.1227/01.NEU.0000315880.18190.37
In Reply:
We appreciate Dr. San Millán Ruiz’s interest in our article.
We do, however, take issue with his remark that we have per-
petuated the general confusion regarding the description of
the veins of the middle cranial fossa with our anatomic study.
Our study was based on observations of injected cadaveric
specimens, and thus we have no reason to doubt our findings.
Dr. San Millán Ruiz states that his group has never found con-
nections between the superficial sylvian vein and the SphS.
This does not mean that it does not occur, as is vividly seen in
our specimens. Indeed, other reports, such as the classic and
elegant descriptions of the dural venous sinuses by Browder
and Kaplan (1), have stated this. Moreover, the findings of Dr.
Albert Rhoton, one of the most lauded neurosurgeons of our
day, concur with ours, that is, the superficial sylvian vein com-
monly empties into the SphS (5).
Dr. San Millán Ruiz caustically suggests that we confused the
superficial sylvian vein for the SphS. We would counter that he
is confused in his interpretation of our figures, as none of these
demonstrated such. Nowhere in our article do we call the super-
ficial sylvian vein the SphS, or vice versa. These are separate
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FIGURE C1. Computed tomographic three-dimen-
sional reconstruction of a corrosion cast, superior view,
left side. This corrosion illustrates the presence of two
distinct parallel channels under the lesser sphenoid
wing: the superficial middle cerebral vein (SMCV)
(arrows) and the venous sinus of the lesser sphenoid
wing (arrowheads). The venous sinus of the lesser
sphenoid wing drains medially into the anterior por-
tion of the cavernous sinus (CS) over the termination
of the superior ophthalmic vein (SOV). A diploic vein
of the roof of the orbit (double arrowhead) joins the
middle portion of the sinus. In this case, the SMCV
drains into the CS. IPS, inferior petrosal sinus; SS, sig-
moid sinus; PP, pterygoid plexus.

entities. Also, and as clearly stated in our article, we agree with
Wolf et al. (7) that the term “sinus of the lesser sphenoid wing”
may more accurately portray the “sphenoparietal” sinus. Such
terminology is not new and was used by Lindblom in 1936 (3).
Nevertheless, “sphenoparietal sinus” is the current and stan-
dard term used for this venous collection. Embryologically, the
portion of the tentorial sinus anterior to the CS has been
described as giving rise to the SphS, as described by Diamond
(2). Padget (4) actually stated that the SphS is derived from the
embryonic prootic sinus—specifically, from the anteroparietal
meningeal sinus—and that remnants of the tentorial sinus are
incorporated into this structure. When this extends to the region
of the CS, it is properly called the SphS (4).
R. Shane Tubbs
Birmingham, Alabama
1. Browder J, Kaplan HA: Cerebral Dural Sinuses and Their Tributaries. Springfield,
Charles C. Thomas, 1976.
2. Diamond MK: Homology and evolution of the orbitotemporal venous sinuses
of humans. Am J Phys Anthrop 88:211–244, 1992.
3. Lindblom K: A roentgenographic study of the vascular channels of the skull.
Acta Radiol 30:1–146, 1936.
4. Padget DH: The cranial venous system in man in reference to development,
adult configuration, and relation to the arteries. Am J Anat 98:307–355, 1956.
5. Rhoton AL: Rhoton cranial anatomy and surgical approaches. Philadelphia,
Lippincott Williams & Wilkins, 2003.
6. Tubbs RS, Salter EG, Wellons JC 3rd, Blount JP, Oakes WJ: The sphenoparietal
sinus. Neurosurgery 60 [Suppl 1]:ONS9–ONS12, 2007.
7. Wolf BS, Huang YP, Newman CM: The superficial sylvian venous drainage
system. Am J Roentgenol Radium Ther Nucl Med 89:389–410, 1963.
DOI: 10.1227/01.NEU.0000315881.18190.7E
Percutaneous Transforaminal Lumbar Interbody Fusion
for the Treatment of Degenerative Lumbar Instability
To the Editor:
I read the article by Scheufler et al. (1) with great interest.
This article is an excellent addition to the literature, but some
of the terminology used regarding the “mini-open” transforam-
inal lumbar interbody fusion (TLIF) is misleading. The authors
describe a Wiltse muscle-splitting approach and call it
“o-TLIF,” “open TLIF,” and “mini-open TLIF.” They use these
terms interchangeably in their article.
Gerald Rodts and I previously published a description of a
“mini-open TLIF” to describe a Wiltse approach performed via
an expandable tube. It is our impression that a Wiltse approach
done through an expandable tube allows for a relatively
smaller incision and less tissue trauma in patients with deep
lumbar musculature. The “mini-open TLIF” is not the same as
a standard Wiltse TLIF, in my opinion. The authors are to be
commended for their work comparing percutaneous TLIF to
the standard Wiltse TLIF.
Praveen V. Mummaneni
San Francisco, California
1. Scheufler K-M, Dohmen H, Vougioukas VI: Percutaneous transforaminal
lumbar interbody fusion for the treatment of degenerative lumbar instability.
Neurosurgery 60 [Suppl 2]:ONS203–ONS213, 2007.
DOI: 10.1227/01.NEU.0000315882.25813.56
In Reply:
As Dr. Mummaneni correctly points out, precise use of ter-
minology is warranted whenever “standard” and alternative
novel surgical technique are compared. We appreciate and
fully endorse this statement. Indeed, we used the more tradi-
tional “standard” Wiltse approach with a limited midline skin
incision (5 cm/single level), bilateral paramedian fascial inci-
sions, and blunt intermuscular dissection toward the facet
and pedicle entry points. The novel (truly, “mini-open”) para-
median muscle-splitting approach via expandable tubular
retractors described in the recent article by Mummaneni and
Rodts (1) is distinctly different from the traditional Wiltse
approach, is technically similar to our percutaneous technique
(using smaller tubes), and yields clinical results comparable to
those reported in our article (2). We apologize for this lack of
semantic precision.
Kai-Michael Scheufler
Zürich, Switzerland
1. Mummaneni PV, Rodts GE Jr: The mini-open transforaminal lumbar inter-
body fusion. Neurosurgery 57 [Suppl]:256–261, 2005.
2. Scheufler K-M, Dohmen H, Vougioukas VI: Percutaneous transforaminal
lumbar interbody fusion for the treatment of degenerative lumbar instability.
Neurosurgery 60 [Suppl 2]:ONS203–ONS213, 2007.
DOI: 10.1227/01.NEU.0000315883.02943.1E
Detection of Caspase-3, Neuron Specific Enolase, and
High-sensitivity C-reactive Protein Levels in Both
Cerebrospinal Fluid and Serum of Patients after
Aneurysmal Subarachnoid Hemorrhage
To the Editor:
I read with interest the article by Kacira et al. (2) regarding
neuron-specific enolase (NSE) after aneurysmal subarachnoid
hemorrhage (SAH). Two points deserve comment. CSF and
serum levels of NSE were measured by a solid-phase immuno-
assay with a monoclonal antibody raised against γγ- and αγ-
NSE. In the discussion, the authors emphasize that the CSF
levels of NSE showed a trend to increase toward Days 5 and 7,
suggesting that neuronal damage increased, and they also
stressed the finding of higher NSE levels in CSF relative to
serum toward Day 7. Enolase, an essential glycolytic enzyme,
is a dimeric enzyme composed of α, β, and γsubunits. NSE
comprises two isoforms, γγ- and αγ, which are synthesized by
neurons and neuroendocrine tissues. An αγ isoform is abun-
dant in erythrocytes (3).
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One analytical study demonstrated a significant correlation
between the NSE concentration and hemolysis in the sample,
either CSF or serum, owing to the amount of NSE released
from destroyed red blood cells (3). With regard to these data,
the conclusions of the article by Kacira et al. (2) may be differ-
ent. Hemolysis occurs after SAH, and the increase in NSE lev-
els observed on Day 7 may reflect the usual hemolytic process
in the subarachnoid space after SAH, with larger amounts of
NSE released from erythrocytes on Day 7, and not necessarily
caused by neuronal damage. Since no hemolysis was present in
serum, the NSE serum levels remained in a lower range.
In future studies, an index of hemolysis or determinations of
free hemoglobin in CSF would probably be useful to clarify
the interpretation of NSE levels in hemorrhagic CSF samples
and the role of NSE in the pathogenesis and prognosis of
aneurysmal SAH. The use of CSF samples from patients with
normal-pressure hydrocephalus as a control group does not
reflect a normal population, as was recognized by the authors.
Patients undergoing spinal anesthesia for surgical procedures
outside central nervous system served as a control group in a
previous study of NSE in CSF (1).
Jose L. Soto-Hernandez
Tlalpan, Mexico
1. Casmiro M, Maitan S, De Pasquale F, Cova V, Scarpa E, Vignatelli L; NSE
study group: Cerebrospinal fluid and serum neuron-specific enolase concen-
trations in a normal population. Eur J Neurol 12:369–374, 2005.
2. Kacira T, Kemerdere R, Atukeren P, Hanimoglu H, Sanus GZ, Kucur M,
Tanriverdi T, Gumustas K, Kaynar MY: Detection of caspase-3, neuron spe-
cific enolase, and high-sensitivity C-reactive protein levels in both cere-
brospinal fluid and serum of patients after aneurysmal subarachnoid hemor-
rhage. Neurosurgery 60:674–680, 2007.
3. Ramont L, Thoannes H, Volondat A, Chastang F, Millet MC, Maquart FX:
Effects of hemolysis and storage condition on neuron-specific enolase (NSE)
in cerebrospinal fluid and serum: Implications in clinical practice. Clin Chem
Lab Med 43:1215–1217, 2005.
DOI: 10.1227/01.NEU.0000315884.10566.F9
In Reply:
Dr. Soto-Hernandez commented on two points related to our
recently published article (4). His first comment was on serum
levels of NSE. It is well known that numerous substances are
released into the CSF and blood as part of the brain damage
after SAH, but the ideal damage marker would have to satisfy
certain requirements: to be localized intracellularly, to be pres-
ent at a high concentration in brain tissue, and, finally, to be rel-
atively easy to detect. NSE (gg-enolase) is an intracellular pro-
tein predominantly found in neuron cytoplasm and in
neuroendocrine cells in insignificant concentration (7). This is
one of the most important reasons for us to include NSE as a
possible marker of neuronal damage in our study. NSE was
originally thought to be specific to neuronal cells but was sub-
sequently found in some nonneuronal, nonneuroendocrine
cells also (7, 11). However, its relative abundance in both neu-
ronal and neuroendocrine cells makes it a marker of these two
cell types. Clinical studies have shown that elevated serum lev-
els of NSE have been associated with unfavorable outcome in
traumatic brain injury and large volumes of cerebral infarction
(2, 10, 12). Furthermore, elevated levels are associated with
some neurodegenerative diseases (3, 5). Altogether, findings
from some central nervous system diseases causing neuronal
damage suggest that NSE may be a specific marker of neu-
ronal damage.
There have been limited numbers of studies regarding NSE
levels in aneurysmal SAH patients, and all of them evaluated
serum levels (6, 9). The serum levels of NSE were found to be
correlated with the amount of blood in the subarachnoid space
(high Fisher grade), and the serum levels were found to be
higher in patients with vasospasm, which generally occurs
between Days 4 and 14, being maximum on Day 7 after the
ictus (6, 9). The findings indicate that the persistence of NSE in
either serum or CSF days after the hemorrhage probably
reflects continuous release from the damaged neurons. A signif-
icant correlation between NSE levels in CSF and serum has
also been demonstrated in patients with coma (8). On the other
hand, NSE has also been found in peripheral neuroendocrine
cells and in blood platelets, so serum NSE may not be only of
central origin, as Dr. Soto-Hernandez comments in his letter.
This point may be true, but, in our study, none of the patients
had small-cell lung cancer or neuroendocrine neoplasms,
which can cause elevation of serum NSE levels. Therefore, the
elevation of serum NSE levels in our patients seems to be
attributable to a central nervous system origin.
Another finding that supports the hypothesis that the dam-
aged neuron may be the source of NSE in our study was that
the elevated CSF levels of NSE correlated with the elevated
serum levels of NSE within the first 3 days of SAH, in which no
vasospasm is expected to occur. It has been shown that serum
levels increase about the time when delayed ischemic neurolog-
ical deficits develop, and they remain elevated for several days
afterward in SAH patients (6). This suggests that NSE is contin-
uously released into the CSF from ischemic neurons and that
the cellular injury resulting from cerebral vasospasm may
progress for at least several days after the onset of vasospasm.
Persistent elevation of the intracranial pressure and associated
cerebral edema might perhaps cause the continuing release of
NSE from neurons in SAH. Although the clinical studies that
we mentioned, including studies of traumatic brain injury, cere-
bral ischemia, and neurodegenerative diseases, as well as our
study, supported the idea that the serum or CSF levels might
reflect the severing of the central nervous system lesions, we
insist that serum levels of NSE must be cautiously interpreted;
taking into consideration the clinical features of the patients;
thus, a larger population of SAH patients is required.
Nevertheless, we do not claim but propose that NSE may be a
marker of neuron damage after SAH.
The second comment was that the control group included in
our study (4) consisted of patients with normal-pressure
hydrocephalus. We stated in the article (4) that the control
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group should include healthy volunteers for at least the serum
samples because hydrocephalus is also a central nervous sys-
tem disease in which the levels of NSE may be increased (1).
We agree with Dr. Soto-Hernandez that control patients with
normal-pressure hydrocephalus do not reflect a normal popu-
lation, since strongly elevated NSE levels were found in the
CSF of patients with severe hydrocephalus (Grade III) (1).
Therefore, we suggest that control groups in future studies
should include subjects undergoing diagnostic venipuncture
or lumbar puncture.
Taner Tanriverdi
Istanbul, Turkey
1. Beems T, Simons KS, van Geel WJA, de Reus HPM, Vos PE, Verbeek MM:
Serum and CSF-concentrations of brain specific proteins in hydrocephalus.
Acta Neurochir (Wien) 145:37–43, 2003.
2. Berger RP, Pierce MC, Wisniewski SR, Adelson PD, Clark RSB, Ruppel RA,
Kochanek PM: Neuron-specific enolase and S100B in cerebrospinal fluid after
severe traumatic brain injury in infants and children. Pediatrics 109:1–6, 2002.
3. Cunningham RT, Morrow JI, Johnston CF, Buchanan KD: Serum neuron-
specific enolase concentrations in patients with neurological disorders. Clin
Chim Acta 230:117–124, 1994.
4. Kacira T, Kemerdere R, Atukeren P, Hanimoglu H, Sanus GZ, Kucur M,
Tanriverdi T, Gumustas K, Kaynar MY: Detection of caspase-3, neuron spe-
cific enolase, and high-sensitivity C-reactive protein levels in both cere-
brospinal fluid and serum of patients after aneurysmal subarachnoid hemor-
rhage. Neurosurgery 60:674–680, 2007.
5. Kohira I, Tsuji T, Ishizu H, Takao Y, Wake A, Abe K, Kuroda S: Elevation of
neuron-specific enolase in serum and cerebrospinal fluid of early stage
Creutzfeldt-Jakob disease. Acta Neurol Scand 102:385–387, 2000.
6. Mabe H, Suzuki S, Mase M, Umemura A, Nagai H: Serum neuron-specific
enolase levels after subarachnoid hemorrhage. Surg Neurol 36:170–174, 1991.
7. Marangos PJ: Neuron specific enolase, a clinically useful marker for neurons
and neuroendocrine cells. Annu Rev Neurosci 10:269–295, 1987.
8. Martens P, Raabe A, Johnsson P: Serum S-100 and neuron-specific enolase for
prediction of regaining consciousness after global cerebral ischemia. Stroke
29:2363–2366, 1998.
9. Oertel M, Schumacher U, McArthur DL, Kastner S, Boker DK: S-100B and
NSE: Markers of initial impact of subarachnoid hemorrhage and their relation
to vasospasm and outcome. J Clin Neurosci 13:834–840, 2006.
10. Pleinesi UE, Morganti-Kossmann MC, Rancan M, Joller H, Trentz O,
Kossmann T: S-100fl reflects the extent of injury and outcome, whereas neu-
ronal specific enolase is a better indicator of neuroinflammation in patients
with severe traumatic brain injury. J Neurotrauma 18:491–498, 2001.
11. Schmechel DE, Marangos PJ, Martin BM, Winfield S, Burkhart DS, Roses AD,
Ginns EI: Localization of neuron-specific enolase (NSE) mRNA in human
brain. Neurosci Lett 76:233–238, 1987.
12. Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, Pertuiset B, De Villiers
JC: A universal subarachnoid hemorrhage scale: Report of a committee of the
World Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry
51:1457, 1988.
DOI: 10.1227/01.NEU.0000315855.17297.62
Treatment Options for Third Ventricular Colloid Cysts:
Comparison of Open Microsurgical versus
Endoscopic Resection
To the Editor:
I read with great interest the article by Horn et al. (1) compar-
ing microsurgical and endovascular outcomes for colloid cysts
of the third ventricle. After analyzing 55 patients, they con-
cluded that neuroendoscopic resection is comparatively safe
and as effective as microsurgical resection. They also recom-
mend neuroendoscopy as a first line of treatment for these
lesions. Their study, quite admirably, attempts to address a com-
mon contemporary debate that aims to identify the best way of
managing this relatively uncommon condition. However, the
title and the conclusion of the article, I feel, do not accurately
reflect their own observations. The title mentions a comparison
of “microsurgical” and “endoscopic” approaches to the colloid
cyst, when, in fact, they only compared the transcallosal micro-
surgical approach with the endoscopic one. There were no cases
treated with the transcortical transventricular microsurgical
approach in their series. It is perhaps an injustice to generalize
the outcome of a selected transcallosal approach to the entire
gamut of microsurgical approaches, as the techniques, invasive-
ness, and potential complications differ considerably in different
microsurgical approaches.
The authors point out that more than 40% of patients in the
endoscopic group were left with residual cysts. The authors
cite several other series that highlight a similar problem with
the endoscopic approach. The proponents of endoscopy may
rightly argue that a significant proportion of the patients left
with residual cysts may never become symptomatic again and
therefore are potentially “cured” (2); the skeptics, on the con-
trary, are justifiably concerned about incompletely treating an
otherwise benign condition. In any case, there seems to be a
trade-off of completeness of surgical resection with the inva-
siveness of the approach selected (3).
My own preference for treating various pathologies in this
region, including colloid cysts, has been for a transcortical-
transventricular approach. With the precision offered by recent
image-guidance systems facilitating miniature craniotomies, I
believe that, with this approach, it is possible to be minimally
invasive and radical simultaneously, thereby combining the
advantages offered by both approaches discussed by the
authors of this article. The scalp incision, the corticotomy, and
the postoperative stay in a meticulously executed transcortical-
transventricular approach are almost identical to those associ-
ated with an endoscopic approach (Fig. C2).
In the surgery for colloid cysts, there are two specific factors
related to operative intervention that can result in postopera-
tive complications. These are inadvertent mechanical or ther-
mal damage to the vital neurovascular structures during surgi-
cal manipulation and, secondly, spillage of cyst contents
and/or blood into the ventricular cavities. In my experience,
the transcortical-transventricular route not only allows the sur-
geon ideal exposure and adequate room for safe bimanual
maneuvering of instruments within the ventricle, but also helps
to ensure that there is no spillage of blood or cyst contents out-
side the operative field by carefully isolating the operative area
from the dependent parts of the ventricular system, where cyst
contents and blood are likely to accumulate without the sur-
geon being aware of it.
Unfortunately, both the endoscopic and trancallosal
approaches have their own inherent limitations that cannot be
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completely overcome irrespective of the skill and experience of
the operator. After having read the article carefully, I now feel
more confident in recommending the “gold standard” transcor-
tical-transventricular microsurgical method for excision of col-
loid cysts, even at the cost of being labeled as “traditional” or
“conservative.” Contrary to the authors’ conclusion, I feel that
their observations suggest that microsurgery (the transcallosal
approach in the authors’ series), in fact, does not have a higher
complication rate than the endoscopic approach but is more
likely to effect a complete resection of the lesion and therefore
should be recommended. The ideal surgical approach for any
colloid cyst is as much a function of the cyst location, its size,
and the presence of ventricular engorgement as it is of the indi-
vidual surgeon’s own experience, preference, and skills; it may
therefore be imprudent to recommend one universal approach
for all colloid cysts. Nevertheless, this informative and timely
article also highlights another interesting observation that, in
an attempt to embrace surgical minimalism, perhaps we all
tend to downplay the fact that there is often a price to pay for
the minimal invasiveness and also that, in the management of
many of these conditions, colloid cysts included, less is not
always more.
Kishor A. Choudhari
Belfast, United Kingdom
1. Horn EM, Feiz-Erfan I, Bristol RE, Lekovic GP, Goslar PW, Smith KA, Nakaji
P, Spetzler RF: Treatment options for third ventricular colloid cysts:
Comparison of open microsurgical versus endoscopic resection. Neurosurgery
60:613–620, 2007.
2. Longatti P, Godano U, Gangemi M, Delitala A, Morace E, Genitori L, Alafaci
C, Benvenuti L, Brunori A, Cereda C, Cipri S, Fiorindi A, Giordano F, Mascari
C, Oppido PA, Perin A, Tripodi M: Cooperative study by the Italian neuroen-
doscopy group on the treatment of 61 colloid cysts. Childs Nerv Syst
22:1263–1267, 2006.
3. Zohdi A, El Kheshin S: Endoscopic approach to colloid cysts. Minim Invasive
Neurosurg 49:263–268, 2006.
DOI: 10.1227/01.NEU.0000315856.94425.6F
In Reply:
Although the conclusions in our article (1) stated that the
endoscopic approach is a safe first-line treatment, we believe
that an open microsurgical approach is equally viable. In fact,
we still perform approximately half of our procedures through
an open transcallosal approach. We are well aware that our
study was limited to comparison of only one type of microsur-
gical approach with the endoscopic approach. We feel that this
approach is most appropriate since it completely avoids tra-
versing normal cortical tissue. If Dr. Choudhari believes that
the transcortical-transventricular approach is the “gold stan-
dard” approach for treating colloid cysts, then we welcome the
inclusion of the supporting data in a comparative fashion in the
neurosurgical literature.
Eric M. Horn
Robert F. Spetzler
Phoenix, Arizona
1. Horn EM, Feiz-Erfan I, Bristol RE, Lekovic GP, Goslar PW, Smith KA, Nakaji
P, Spetzler RF: Treatment options for third ventricular colloid cysts:
Comparison of open microsurgical versus endoscopic resection. Neurosurgery
60:613–620, 2007.
DOI: 10.1227/01.NEU.0000315857.02050.B9
Toward the Emergence of Nanoneurosurgery: Part III—
Nanomedicine: Targeted Nanotherapy, Nanosurgery and
Progress toward the Realization of Nanoneurosurgery
To the Editor:
The article by Leary et al. (5) made for interesting reading,
especially as it focused on aspects of nanotechnology as
applied to the treatment of diseases of the human nervous sys-
tem. That there was a particular need for such an article, which
would attract neuroscientists, particularly neurosurgeons,
toward engaging in research in this discipline, is made obvious
by the fact that, of the 114 references at the end of this article,
only six are from neurosciences journals (1, 2, 4, 6–8). This
seems to be more on account of lack of awareness rather than
a dearth in the potential application of this field to neuro-
surgery, as can be gauged from Tables 2 and 3in the article. In
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FIGURE C2. Photographs showing the transcortical-transventricular
minimally invasive approach. A, precoronal right frontal skin incision. B,
trans-sulcal approach for an image-guided corticotomy less than an inch
in length. Cand D, microscopic photographs pre-excision (C) and postex-
cision (D) of the colloid cyst (black arrow). The cyst bed (D) is gently
packed with cotton balls for hemostasis after cyst resection.

fact, one can enumerate a few additional examples in which the
already available nanotechnology derivatives can be put to use
in neurosurgery in the near future.
Nonlesional epilepsy surgery provides one such example.
As is so well illustrated in Figure 21 of the article, intracapillary
platinum nanoelectrodes in proximity to the spinal cord have
been shown to provide larger and more differentiated signal
amplitudes than surface electrodes. This derivative can find
immediate application in locating an epileptogenic focus at the
neuronal level. Using one of the nanoscale drug delivery vehi-
cles, apoptosis-inducing agents may be transfected to destroy
these neuronal cells. Alternatively, nanotechnology derivatives,
such as a polymer nanowire bouquet, can be used to inactivate
such neurons through neurostimulation. Neurovascular com-
pression syndromes provide another example in which the
intracapillary platinum nanowires placed in proximity to the
root entry zone of the involved cranial nerve can pinpoint the
location of the offending vessel. Yet another application could
be in intraoperative neuromonitoring during operations in and
around brainstem, in which recordings from appropriately
placed platinum nanowires in the brainstem capillaries may
substitute for and improve upon the conventional brainstem
evoked response recording techniques. Of course, development
of tiny robotic submarines navigating through the bloodstream,
as mentioned in the article, or in the subarachnoid space (3)
may take several years.
I would request the authors to clarify one point made in the
article. They mentioned that the delivery of drugs such as anti-
neoplastic and anti-human immunodeficiency virus agents to
the central nervous system is limited because of their inability
to cross the blood-brain barrier (BBB) and that nanoparticles, by
virtue of their small size, help in overcoming this obstacle.
However, the exact mechanism by which the small size of
nanoparticles enables other large-sized molecules in crossing
the BBB is not mentioned.
Surinder N. Kundra
New Delhi, India
1. Chung SH, Clark DA, Gabel CV, Mazur E, Samuel AD: The role of the AFD
neuron in C. elegans thermotaxis analyzed using femtosecond laser ablation.
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4. Leary SP, Liu CY, Apuzzo ML: Toward the emergence of nanoneurosurgery:
Part II—Nanomedicine: Diagnostics and imaging at the nanoscale level.
Neurosurgery 58:805–823, 2006.
5. Leary SP, Liu CY, Apuzzo ML: Toward the emergence of nanoneurosurgery:
Part III—Nanomedicine: Targeted nanotherapy, nanosurgery and progress
toward the realization of nanoneurosurgery. Neurosurgery 58:1009–1026,
2006.
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surgery: Part I—Progress in nanoscience, nanotechnology, and the compre-
hension of events in the mesoscale realm. Neurosurgery 57:600–634, 2005.
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tems and neurosurgery: A new era in a new millennium. Neurosurgery
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DOI: 10.1227/01.NEU.0000315858.40168.C1
In Reply:
We appreciate Dr. Kundra’s insightful question regarding
“the exact mechanism by which the small size of nanoparticles
enables other large-sized molecules in crossing the BBB,” which
was submitted in response to recent articles from our institu-
tion regarding nanotechnology applications to neurosurgery
(12–14). A number of recent articles have demonstrated the
unique advantages offered by innovations in nanotechnology
to achieve enhanced BBB penetration. The following is a brief
summary of the results from some of these articles; it is organ-
ized into subtopics on the basis of the goal of BBB penetration.
We hope it offers a satisfactory answer to this question.
Imaging Contrast Agents. Innovations incorporating nanotech-
nology, and in particular nanoparticles, have been investigated
for improving the understanding and penetration of the BBB.
For example, much work has been recently reported regarding
the use of iron oxide nanoparticles as imaging and therapeutic
agents (7, 18–20). In vivo animal studies have investigated the
use of iron oxide nanoparticles as magnetic resonance imaging
(MRI) contrast agents (21). Rats with 9L gliosarcoma or C6
glioma tumors were injected with dextran-coated iron oxide
nanoparticles. After 24 hours, accumulation in the tumor was
10-fold greater than in adjacent brain tissue (18). Human stud-
ies have demonstrated sharp tumor enhancement in gliomas
and metastatic tumors after iron oxide nanoparticle administra-
tion (4, 30). Enhancement with coated iron oxide nanoparticles
peaks at 24 to 48 hours, and tumor borders remain sharp for
days. This differs from gadolinium enhancement, in which the
tumor border blurs within hours of administration. The mech-
anism of nanoparticle-mediated tumor enhancement is pre-
sumably secondary to the leaky BBB with subsequent uptake
into reactive cells, such as astrocytes and macrophages (17, 20).
Interaction of polyethylene glycol surface moieties on the
nanoparticles with the brain endothelial cells may also have
contributed to tumor uptake (3). A recent report illustrates mul-
tiple advantages of using nanoparticles in brain tumors. The
authors constructed a multifunctional polymeric nanoparticle
that contained a tumor vasculature-targeting peptide, photody-
namic therapy sensitizer, and MRI contrast agent (24). The sur-
face-localized F3 peptide on the nanoparticle allowed binding
to the tumor cell surface. The nanoparticle was then internal-
ized, conferring photosensitivity to the cells, owing to the pres-
ence of Photofrin (Axcan Pharma, Birmingham, AL) in the
nanoparticle. Iron oxide within the nanoparticle yielded
enhancement on MRI.
Dual imaging with MRI and fluorescence microscopy has
been demonstrated with a single multifunctional nanoparticle
(Figures 7 and 8of the article) (8, 30). In one study, dual imag-
ing was achieved by coating an iron oxide nanoparticle with
the near-infrared fluorescent molecule Cy5.5. Preoperative
imaging of green fluorescence protein-transfected 9L gliosar-
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coma tumors implanted in rat brains demonstrated the func-
tionality of the nanoparticles as MRI contrast agents. Surgical
exposure showed good comparison of near-infrared fluores-
cent imaging to the green fluorescence protein fluorescence of
the tumors (8). In another study, clorotoxin, a glioma-targeting
peptide, was attached to nanoparticles capable of similar dual
imaging (30). Tumor-specific binding and cellular uptake of
the multimodal nanoparticle by 9L gliosarcoma cells was
demonstrated with MRI and light microscopy.
Chemotherapy. The primary roadblock for nanoparticle-
mediated delivery of pharmacological agents to central nerv-
ous system (CNS) tumors is the BBB, which has also limited the
access of many traditional chemotherapeutic agents to the
CNS. Nanoparticles may be targeted to the CNS but must also
avoid uptake by the reticuloendothelial system and have suffi-
cient circulation time in plasma to reach the CNS. Two factors
that limit reticuloendothelial system uptake of nanoparticles
are hydrophilic coating and small size (10–100 nm). Nano-
particles that have demonstrated successful CNS penetration
typically meet these criteria. Further specificity of nanoparticles
for a specific location or disease can be achieved through
attachment of a targeting ligand (25).
Targeting a therapeutic agent using this technique could also
limit systemic drug exposure. Drug loading into nanoparticles
can be achieved by absorption, encapsulation, and covalent
linkage (23). Properties of the nanoparticle such as size, surface
morphology, surface charge, hydrophobicity and type of target-
ing ligand may be optimized depending on the neurological
disease. To date, polybutylcyanoacrylate (PBCA) nanoparticles
represent the most promising nanoparticle candidates for
glioma chemotherapy. Studies in animals used PBCA nanopar-
ticles coated with a surfactant such as polysorbate 80. This sur-
factant promotes delivery of the nanoparticle to the brain via
receptor-mediated endocytosis by brain endothelial cells.
Specifically, polysorbate 80 absorbs apolipoprotein E in plasma,
which is then internalized by the low-density lipoprotein
uptake system (10). Covalent attachment of apolipoproteins
such as E3, A-I, or B-100 to nanoparticles also facilitates brain
endothelial cell uptake and central nervous system drug deliv-
ery, possibly secondary to similar low- or high-density lipopro-
tein receptor-mediated endocytosis (9). Nanoparticles without
covalently attached apolipoprotein show a correlation between
surfactant-mediated apolipoprotein A-I surface adsorption and
drug delivery across the BBB (22).
Previous investigations have studied the brain distribution
and therapeutic efficacy of polysorbate 80 PBCA nanoparticles
loaded with doxorubicin (6, 29). When the nanoparticles were
injected intravenously into healthy rats, a 60-fold higher dox-
orubicin concentration was achieved in the brain compared
with systemic doxorubicin administration. Coated nanoparti-
cles yield significantly higher brain concentrations of the drug
than administration of uncoated PBCA nanoparticles loaded
with doxorubicin. These nanoparticles were also evaluated in a
rat glioblastoma model (101/8). Rats treated with polysorbate
80-coated PBCA nanoparticles loaded with doxorubicin
demonstrated a significant increase in survival compared with
control groups. No additional toxicity was observed that could
be attributed to the linking of doxorubicin to nanoparticles (5).
Nanoparticles can be designed with properties that facilitate
migration into the brain, and they present new opportunities
for pharmacological agents previously discarded because of
their inability to cross the BBB (11, 26–28). For example,
nanoparticles coated with polysorbate 80 adsorb apolipopro-
teins B and E and then undergo receptor-mediated endocytosis
by brain capillary endothelial cells. Recent work has demon-
strated delivery of pharmacological agents across the BBB
using this mechanism (1, 2). Other diagnostic or therapeutic
interventions that use nanoparticles as brain delivery vehicles
include gene therapy (31, 32) and imaging contrast agents (dis-
cussed above).
Surface properties of nanoparticles may also affect the func-
tion of the BBB. Recent work showed that the surface charge of
the nanoparticle affected BBB integrity and permeability (15).
Neutral and low-concentration anionic nanoparticles had no
effect on the BBB, whereas high-concentration anionic nanopar-
ticles and cationic nanoparticles disrupted the BBB. Further-
more, brain uptake was greater for low-concentration anionic
nanoparticles than neutral or cationic nanoparticles.
BBB Investigations. Modeling of the BBB may assist scientists
devise novel methods for delivering diagnostic and therapeu-
tic agents to intracranial lesions. Current modeling techniques
may not allow sufficient astrocyte-endothelial cell contact. One
recently reported model used nanofabrication techniques to
create a silicon nitride membrane that was an order of magni-
tude thinner and significantly more porous than commercially
available membranes, although a tighter endothelial-astrocyte
junction was not observed (16). Central nervous system dis-
ease may lead to breakdown of the BBB, which can then be
exploited during diagnostic or therapeutic intervention. Virus-
sized iron oxide-based nanoparticles have been studied in
humans as contrast agents for evaluation of inflammatory
CNS lesions such as multiple sclerosis, lymphoma, acute dis-
seminated encephalomyelitis (ADEM), and vascular lesions
(Table 2 in the article) (17). Enhancement due to iron oxide
nanoparticles showed differences compared with gadolinium
enhancement. Less enhancement compared with gadolinium
was generally observed for demyelinating inflammatory
lesions such as multiple sclerosis and ADEM, although one
case of ADEM showed significantly more enhancement with
iron oxide nanoparticles. Patients with stroke showed signifi-
cantly greater iron oxide nanoparticle enhancement compared
with gadolinium, but this may have related to the timing of
the studies. Another notable finding was a cavernous malfor-
mation patient in whom iron oxide nanoparticles revealed
prominent enhancement compared with no significant
enhancement with gadolinium.
Furthermore, modeling of the BBB may assist scientists in
devising novel methods for delivering diagnostic and thera-
peutic agents to intracranial lesions. Current modeling tech-
niques may not allow sufficient astrocyte-endothelial cell con-
tact. One recently reported model used nanofabrication
techniques to create a silicon nitride membrane that was an
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order of magnitude thinner and significantly more porous than
commercially available membranes, although a tighter
endothelial-astrocyte junction was not observed.
Conclusion. Concepts from nanotechnology will advance our
understanding of physiological and pathological states of the
central nervous system. Improved investigation and circum-
vention of the BBB will likely present new opportunities for
systemic treatments for neurological diseases. The examples
discussed above represent some of the initial work in this area,
and further investigations are necessary to bring benchtop pos-
sibilities to clinical reality. The authors welcome any further
questions or discussion in this area and appreciate the oppor-
tunity to respond.
James B. Elder
Charles Y. Liu
Michael L.J. Apuzzo
Los Angeles, California
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