Single Nucleotide Polymorphisms of Tissue Inhibitor of Metalloproteinase Genes in Familial Moyamoya Disease

NEUROSURGERY VOLUME 62 | NUMBER 6 | JUNE 2008 | E1384

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Single Nucleotide Polymorphisms of Tissue Inhibitors ofMetalloproteinase 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 ofmetalloproteinase-2 (TIMP2) and -4 (TIMP4) genes in patientsdiagnosed as having familial moyamoya disease (MMD), todetermine whether sequence variations of these genes wererelated to familial MMD. The study was based on familialMMD gene mapping linkage analysis. TIMP2 and TIMP4 genesspan known MMD loci. Moreover, down-regulation of TIMPgenes may cause matrix metalloproteinase (MMP) overactivity.In their work, the authors found that a polymorphism in thepromoter region of the TIMP2 gene was significantly associatedwith familial MMD (2). In particular, a G/C heterozygousgenotype in the TIMP2 gene at position 2418 was present innine of 11 familial MMD patients, resulting in a modification ofthe “motif” that recognizes the transcription factor Sp1. Thefrequency of the G/C genotype at position 2418 in familialMMD cases differed significantly from its frequency in normalcontrols and in nonfamilial MMD cases.

To explain this finding, Kang et al. hypothesized that thederegulation of TIMPs can disrupt the balance between MMPsand TIMPs, resulting in erroneous smooth muscle cell (SMC)dynamics, leading to the MMD phenotype. Such a theory isintriguing, 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 currentlythere 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 twinsaffected by MMD (1). The incidence rate of MMD in monozy-gotic twins is 80%, markedly higher than in siblings (3). Todate, 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 monozygotictwins. In genomic deoxyribonucleic acid (DNA) samples takenfrom our monozygotic twins, we amplified 1) the promoterregion, 2) the exon regions, and 3) the intron-exon junctions ofTIMP2 and TIMP4 genes.

In our patients, the sequence analysis of exon 3 of the TIMP2gene indicated the presence of the well-characterized polymor-phism G/A at position +853. However, to our surprise, we didnot find the G/C heterozygous genotype at position 2418 in thepromoter region of the TIMP2 gene, as described by Kang et al.(2). MMD in Caucasians can present with a more benign formof the disease, as compared with the disease in Asians (4). Thismilder form, as well as other specific features, may be theexpression of different gene mutations.

In conclusion, despite the presence of a single nucleotidepolymorphism, our study did not provide any further evidenceto support the model proposed by Kang et al.

Vincenzo AndreoneSimona ScalaCeleste TucciDaniele Di NapoliItalo LinfanteAndrea TessitoreAntonio FaiellaNaples, 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 nucleotidepolymorphisms of tissue inhibitor of metalloproteinase genes in familialmoyamoya disease. Neurosurgery 58:1074–1080, 2006.

3. Yamauchi T, Houkin K, Tada M, Abe H: Familial occurrence of moyamoyadisease. Clin Neurol Neurosurg 2 [Suppl]:S162–S167, 1997.

4. Yilmaz EY, Pritz MB, Bruno A, Lopez-Yunez A, Biller J: Moyamoya: IndianaUniversity 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 TIMP2gene showed the presence of the polymorphism G/A at posi-tion +853 in exon 3 and the absence of the G/C heterozygousgenotype at position 2418 in the promoter region. In ourstudy, the G/A genotype at position +853 was present in sixof 11 patients with familial MMD (5). However, no signifi-cant difference was found between the frequency of the G/Aheterozygous genotype at position +853 in familial MMDpatients versus normal control participants or versus nonfa-milial MMD participants. This polymorphism would producechange in the third nucleotide of the 101st codon of TIMP2from TCG to TCA, resulting in serine in both instances, andthus it is a silent variant.

In a study by Kanai (4), nine of 10 pairs were concordant forMMD among monozygotic twins; a genetic study of this pop-ulation would produce fruitful results for understanding thepathophysiology of the disease. Thus, it would be valuable tofind genetic causes or predisposing factors among the reported12 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 relatedto familial MMD have been reported (2, 3, 6, 7), and we believethat various relevant genes in these loci could be investigatedin this special subgroup of patients.

Hyun-Seung KangSeung-Ki KimKyu-Chang WangSeoul, 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 familialmoyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet64:533–537, 1999.

3. Inoue TK, Ikezaki K, Sasazuki T, Matsushima T, Fukui M: Linkage analysis ofmoyamoya 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 nucleotidepolymorphisms of tissue inhibitor of metalloproteinase genes in familialmoyamoya 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 moyamoyadisease (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 NEUROSURGERY has greatimplications, as most future references will be based on thispresentation. Articles discussing historical perspectives shouldbe 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 citedand credits are appropriately given to original contributors. Itis 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 andbiomechanically strongest.

We previously presented a technique of fixation that involvesscrew insertion into the base of the spinous process of the axisor into the spinolaminar junction (2). One to two screws wereinserted to secure fixation of a plate. The superior end of theplate was fixed to the occipital bone with either screws orwires. 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 polyaxialscrews were used instead of monoaxial screws, and rods wereused instead of plates.

Atul GoelMumbai, 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. ActaNeurochir (Wien) 129:47–53, 1994.

4. Goel A, Desai K, Muzumdar D: Atlantoaxial fixation using plate and screwmethod: 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 thearticle.

Dr. Goel’s contributions to the development of atlantoaxialfixation are significant and were referenced appropriately in thesection 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 involvespolyaxial screws in C1 connected via a rod to the C2 screws, theHarms technique was a more relevant reference than themonoaxial screw and plate method described by Dr. Goel.

We take issue with the comment by Dr. Goel that we assertedthat 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 tobe equivalent to other methods of C2 fixation (5, 7), we specif-ically cautioned the reader that this was a new techniquerequiring further study before widespread implementation. Wedid, however, suggest that C2 laminar screws are potentiallysafer 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 spinousprocess of C2 in constructs of occipital-C2 fixation has,indeed, been reported by Dr. Goel (1). However, althoughboth Dr. Goel’s technique and ours involve screw placementinto 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 thatthe Wright technique is a novel method of fixation not basedon the technique of Dr. Goel.

E1384 | VOLUME 62 | NUMBER 6 | JUNE 2008 www.neurosurgery-online.com

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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. Wewould strongly agree that review articles in any journal shouldwidely cite relevant literature and be historically accurate. Wecommend Dr. Goel for strongly advocating this practice butwere surprised by his recent review article on atlantoaxial fix-ation (4), in which he cited only one technique other than hisown and failed to mention the Wright technique.

Neill M. WrightTodd J. StewartSt. 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. ActaNeurochir (Wien) 129:47–53, 1994.

3. Goel A, Desai KI, Muzumdar DP: Atlantoaxial fixation using plate and screwmethod: A report of 160 treated patients. Neurosurgery 51:1351–1357, 2002.

4. Goel A, Sharma P, Dange N, Kulkarni AG: Techniques in the treatment ofcraniovertebral 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 rodfixation. Spine 26:2467–2471, 2001.

7. Lapsiwala SB, Anderson PA, Oza A, Resnick DK: Biomechanical comparisonof four C1 to C2 rigid fixative techniques: Anterior transarticular, posteriortransarticular, 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 Spine3:409–414, 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 andBailes (2) and Baird and Levy (1). I would like to offer someinsight and comments with regard to the attempt to establishgreater 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 aforce sufficient to render him or her unconscious.” This cannotbe said about amateur boxing, in which fatalities are extraordi-narily rare. Amateur boxing has a completely different scoringsystem that emphasizes finesse and awards no points for theforce of a blow. In fact, a punch that knocks down an opponentis worth no more than a jab. Technically speaking, there is no

such thing as a knockout (KO) or technical knockout (TKO) inamateur boxing; rather, the designation “referee stops contest”(RSC) is used. The scoring system reinforces the philosophy ofamateur boxing that the goal is to outbox and outpoint theopponent, not to render the opponent unconscious (this is alsothe reason why body punching is so much more prevalent inamateur boxing). Toward that end, numerous other tactics areused to make neural injury much less likely in amateur boxing,not the least of which are heavier gloves, use of headgear, andshorter duration of bouts.

Boxing, in fact, is a full-blown subculture with its own set ofpeculiarities, and there have been changes in the sport overthe past several decades that have not all been positive. Onesuch change that affected boxing in Philadelphia, and the mid-Atlantic region in general, was the advent of gambling inAtlantic City, NJ, in the mid-1970s. The frequent shows at thecasinos required more professional fighters to fill the cards; soinstead of a young amateur accumulating two or three hundredamateur fights before testing the professional ranks, youngfighters instead turned professional when they had much lessexperience and ring savvy. The commercialization of the sporthas created countless young “undefeated” and untested boxersto generate interest. These untested younger fighters oftenbuild impressive records fighting boxers who are less than “upto the mark” and who, in some cases, make a career of beingtraveling opponents. (Variations in state laws regarding boxingmake it advantageous for those seeking loopholes to choosemore lax states as venues.) There is no reason not to establisha nationwide organization to regulate the sport. There is noexcuse, in the digital age, that prevents tracking fighters so thatthey 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 changesin equipment have been slow in coming and lag substantiallybehind other sports. Little has changed in the manufacturing ofboxing gloves and headgear since the use of porous foaminstead of horsehair. The successful reengineering of footballhelmets has been a topic in this very publication. It can beargued that the porous foam headgear worn by amateurs doeslittle for safety and provides a larger target. The current head-gear is almost identical to what I wore as an amateur 30 yearsago. I am certain that better materials can be utilized to increasethe efficacy of headgear.

It is very honorable to explore ways to avoid fatalities inboxing, but the vast majority of neural injuries in boxing are theresult 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 includeEugene “Cyclone” Hart, who fell from the ring to a concretefloor in a bout versus Denny Moyer in 1971, sustaining a closedhead injury, and Meldrick Taylor in his bout against Julio CesarChavez in 1990; neither Hart nor Taylor ever returned to hisprior level of performance). Rather, fighters begin a gradualslide from their peak (however humble it may be) and continue


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to fight, absorbing and compounding their injuries, which oftenlead to full-blown dementia pugilistica, sometimes severalyears after they have retired.

There are several things that can be done to improve safetyimmediately in professional boxing: Implement a weigh-in sys-tem, similar to that endorsed by the National WrestlingCoaches Association, that calculates a participant’s ideal bodyweight; the individual then competes at the specified weightclass for the season. Implore manufacturers to design betterequipment and consider the use of heavier gloves. Create anationwide regulatory agency with the power to enforce theirdecisions. Lastly, give consideration to a scoring system morein line with that of amateur boxing.

I understand that there is much concern that changes willdiminish the popularity of the sport. Boxing, along withwrestling and soccer, enjoys a place among the most ancient ofsports. Participation has reached an all-time high in popularity,but that is, in large part, the result of trendy non-mainstreamparticipation, as many individuals box to achieve fitness butare not necessarily viewers of the sport. However, there is anelement of bloodlust in some people, and this is largely beingsatiated by pay-per-view events, such as mixed martial arts.Boxing is unlikely to be outlawed and has managed to survivethrough very tough times. Now is a good time to focus onchanging some of the fundamental objectives of professionalboxing to reflect the “sweet science” so it does not degenerateinto the side show of mixed martial arts bouts. Real ProWrestling is a new franchise designed to popularize the greatsport of freestyle wrestling by advocates of amateur wrestlingand give it an identity distinct from that of what was formerlythe World Wrestling Federation. What better time is there toenact similar changes in boxing?

Richard C. MendelJupiter, 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 thatamateur boxing is much safer than its professional counter-part. The two have evolved along differing philosophies to thepoint that they are almost incomparable with regard to the riskof acute and chronic injuries. Amateur boxing’s emphasis hasalways been on the safety of the athlete, while the professionalversion of the sport has been more concerned with promotionand economics.

Unfortunately, this lack of focus on safety has been, and willcontinue to be, paid for by the athlete who dies or, much more

commonly, is disabled. Although this study addressed acuteneurological injuries in boxing, they are uncommon. It can besafely 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 traumain all contact sports (2, 6, 7).

I also agree that athletes are at particular risk duringupswings in the popularity of the sport. Similar to the situationdescribed in the mid-Atlantic region, the recent demand forexperienced female athletes now exceeds the supply, and manyunderprepared female boxers move quickly through the ama-teur and professional ranks—often without developing thedefensive skills needed to avoid serious injury when facing amore experienced opponent (1).

With regard to equipment changes, one must remember thatthe original purpose of headgear and gloves was to preventcuts and hand injuries during training. Few adaptations havebeen made over the past century. The evolution of safety equip-ment in the sport has been and is currently hampered by theunanswered question of which is more dangerous: a fast knock-out or the continuous accumulation of subconcussive blows for36 minutes. Many, including myself, feel that the new andincreasingly popular sport of mixed martial arts, which uses noheadgear and much smaller gloves, is actually neurologicallysafer than professional boxing, because stoppages and knock-outs occur much sooner. Until this question is answered, it isuncertain whether a change in headgear and gloves to absorbmore force would be a detriment to the athlete. Along a similarline, imagine you are the sideline physician during a football orhockey game, and a participant receives a blow to the headresulting in temporary unconsciousness or near unconscious-ness. Would giving the athlete 8 seconds to recover and returnto 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 shorttime-out to clear his or her head before resuming being struckis 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 headgearand mouthpieces of athletes. In a perfect world, the deviceswould be worn during both sparring and matches, and athreshold of punishment to the central nervous system couldbe established that, if exceeded, would result in forfeiture ofthe match or the end of a career. I agree that weigh-in proto-cols can significantly affect the vulnerability of the athlete’scentral nervous system and that the immediate implementa-tion of such a system would benefit boxing. Often, athletesdehydrate themselves to “make weight” and then rapidlyrehydrate. Studies are currently being conducted in boxers toanalyze the effects of this practice on central nervous systemosmolality and electrolyte balances that could predispose anathlete to cerebral edema (4).


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As has been eloquently discussed, there are many problemswith boxing that could be easily corrected. A federal commis-sion that has the oversight and authority to enforce nationaland uniform changes is long overdue. Some states, such asNew Jersey, New York, and Nevada, have model programs,while others, including mine, do not even routinely test forhepatitis B/C and human immunodeficiency virus in a sportthat often involves the exchange of blood. Because the sharingof information between states is so important to the safety ofthe athletes, such a regulatory agency should create a nationaldatabank for all medical information. Currently, we have onlyFightfax and the Federal Suspension List, whose accuracy reliesheavily on the individual reporting the information (3).

Vincent J. MieleMorgantown, 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 aNational Football League player. Neurosurgery 58:E1003; author reply E1003;discussion E1003, 2006.

3. Goodman M: Ringside Physician and former Chairman of the MedicalAdvisory 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 inretired 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 onthe 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 bythe authors, perpetuating the general confusion regarding thedescription 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 venouscorrosion cast studies, we have never found any connectionbetween 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 thedura 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 adural venous sinus, as seems to be the case in Figures 4 and 5 inthe publication by Tubbs et al.

Our study also revealed a dural venous channel embeddedin the dura mater underlying the lesser sphenoid wing, whichopened laterally into the anterior branch of the middlemeningeal veins in the region of the pterion, and medially intothe anterior and superior aspects of the cavernous sinus (CS)(5). Three venous tributaries of this dural venous sinus wereobserved: a diploic vein of the orbital roof, a diploic vein of thegreater sphenoid wing, and, on one occasion, an ophthalmo-meningeal vein of Hyrtl, confirming its function in draining theneurocranium. This dural venous sinus responds to thedescription of Breschet’s SphS, as cited by Cruveilhier: “thissinus receives several branches from the skull bones, the duramater, and the diploic vein of the temporal (bone)” (2), withoutmention of any cortical drainage. This view corresponds toBreschet’s illustrations, which are reproduced in the article byTubbs et al., although, unfortunately, it cannot be confirmed inBreschet’s original monograph on the cranial and spinal venoussystem (1), as the text accompanying the illustrations was pub-lished incompletely (5).

The term “venous sinus of the lesser sphenoid wing” seemsto better describe this channel, which lacks any topographicrelation with the parietal bone (Fig. C1) (5, 8). This term should,however, not be used to describe the course of the SMCV underthe 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 venouschannel that originates under the lesser sphenoid wing a shortdistance lateral to the anterior clinoid process, which thencourses within the lateral wall of the CS before emptying intothe emissary vein of the middle cranial fossa. This vessel corre-sponds to a typical laterocavernous sinus. The laterocavernoussinus was recently described, and it represents the second mostfrequent drainage pathway of the SMCV in the middle cranialfossa (3, 6). It courses within the dural layers of the lateral wallof the CS and drains into the emissary veins of the middle cra-nial fossa, the superior petrosal sinus, or the posterior aspect ofthe CS. Tubbs et al. mention this type of drainage pathway ofthe SMCV, along with the alternative termination of the SMCVinto the paracavernous sinus and the CS, but they seem to havefailed 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 tentorialsinus (of Padget) toward the laterosellar region in late uterineor early postnatal life (3, 6), we can only agree with the sugges-tion by Tubbs et al. that the variable drainage patterns of theSMCV relate to the fate of the primitive tentorial sinus in theadult. The primitive tentorial sinus is the drainage pathway ofthe primitive SMCV and deep middle cerebral vein and of thefuture constituents of the basal vein of Rosenthal (4). We dis-agree, however, with the affirmation by Tubbs et al. (7) that theportion of the tentorial sinus anterior to the cavernous sinus isthe sphenoparietal sinus. According to Padget (4), the SphS


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derives from the embryonic prootic sinus (the precursor of theCS, 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 theprimitive tentorial sinus, which lies in the inner (deep) durallayer. In fact, Padget clearly states that the remnant of the ten-torial sinus in postnatal stages has been erroneously calledSphS (4).

It remains unclear to us why Tubbs et al. failed to demonstratethe 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 moreobvious SMCV. Indeed, close inspection of their Figure 7 reveals

a possible intradural vascular structure filled with blue latexcoursing along the ridge of the lesser sphenoid wing toward theCS. This unlabeled structure in Figure 7 could well correspond toa venous sinus of the lesser sphenoid wing (4).

Diego San Millán RuízBaltimore, Maryland

Jean H.D. FaselGeneva, Switzerland

Philippe GailloudBaltimore, Maryland

1. Breschet G: Anatomic, Physiological, and Pathological Research on the VenousSystem and Especially on the Venous Channels in Bone [in French]. Paris, Villeretet 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, RüfenachtDA: Angiographic anatomy of the laterocavernous sinus. AJNR Am JRoentgenol 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 sphenoparietalsinus of Breschet, does it exist? An anatomic study. AJNR Am J Neuroradiol25:112–120, 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 sphenoparietalsinus. Neurosurgery 60 [Suppl 1]:ONS9–ONS12, 2007.

8. Wolf BS, Huang YP, Newman CM: The superficial sylvian venous drainagesystem. 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 ofthe veins of the middle cranial fossa with our anatomic study.Our study was based on observations of injected cadavericspecimens, 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 inour specimens. Indeed, other reports, such as the classic andelegant descriptions of the dural venous sinuses by Browderand Kaplan (1), have stated this. Moreover, the findings of Dr.Albert Rhoton, one of the most lauded neurosurgeons of ourday, 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 thesuperficial sylvian vein for the SphS. We would counter that heis confused in his interpretation of our figures, as none of thesedemonstrated 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 twodistinct parallel channels under the lesser sphenoidwing: the superficial middle cerebral vein (SMCV)(arrows) and the venous sinus of the lesser sphenoidwing (arrowheads). The venous sinus of the lessersphenoid wing drains medially into the anterior por-tion of the cavernous sinus (CS) over the terminationof the superior ophthalmic vein (SOV). A diploic veinof the roof of the orbit (double arrowhead) joins themiddle portion of the sinus. In this case, the SMCVdrains 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 withWolf et al. (7) that the term “sinus of the lesser sphenoid wing”may more accurately portray the “sphenoparietal” sinus. Suchterminology 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, theportion of the tentorial sinus anterior to the CS has beendescribed as giving rise to the SphS, as described by Diamond(2). Padget (4) actually stated that the SphS is derived from theembryonic prootic sinus—specifically, from the anteroparietalmeningeal sinus—and that remnants of the tentorial sinus areincorporated into this structure. When this extends to the regionof the CS, it is properly called the SphS (4).

R. Shane TubbsBirmingham, 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 sinusesof 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 sphenoparietalsinus. Neurosurgery 60 [Suppl 1]:ONS9–ONS12, 2007.

7. Wolf BS, Huang YP, Newman CM: The superficial sylvian venous drainagesystem. Am J Roentgenol Radium Ther Nucl Med 89:389–410, 1963.

DOI: 10.1227/01.NEU.0000315881.18190.7E

Percutaneous Transforaminal Lumbar Interbody Fusionfor 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 someof the terminology used regarding the “mini-open” transforam-inal lumbar interbody fusion (TLIF) is misleading. The authorsdescribe a Wiltse muscle-splitting approach and call it “o-TLIF,” “open TLIF,” and “mini-open TLIF.” They use theseterms interchangeably in their article.

Gerald Rodts and I previously published a description of a“mini-open TLIF” to describe a Wiltse approach performed viaan expandable tube. It is our impression that a Wiltse approachdone through an expandable tube allows for a relativelysmaller incision and less tissue trauma in patients with deeplumbar musculature. The “mini-open TLIF” is not the same asa standard Wiltse TLIF, in my opinion. The authors are to becommended for their work comparing percutaneous TLIF tothe standard Wiltse TLIF.

Praveen V. MummaneniSan Francisco, California

1. Scheufler K-M, Dohmen H, Vougioukas VI: Percutaneous transforaminallumbar 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 alternativenovel surgical technique are compared. We appreciate andfully endorse this statement. Indeed, we used the more tradi-tional “standard” Wiltse approach with a limited midline skinincision (5 cm/single level), bilateral paramedian fascial inci-sions, and blunt intermuscular dissection toward the facetand pedicle entry points. The novel (truly, “mini-open”) para-median muscle-splitting approach via expandable tubularretractors described in the recent article by Mummaneni andRodts (1) is distinctly different from the traditional Wiltseapproach, is technically similar to our percutaneous technique(using smaller tubes), and yields clinical results comparable tothose reported in our article (2). We apologize for this lack ofsemantic precision.

Kai-Michael ScheuflerZürich, 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 transforaminallumbar 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, andHigh-sensitivity C-reactive Protein Levels in BothCerebrospinal Fluid and Serum of Patients afterAneurysmal Subarachnoid Hemorrhage

To the Editor:I read with interest the article by Kacira et al. (2) regarding

neuron-specific enolase (NSE) after aneurysmal subarachnoidhemorrhage (SAH). Two points deserve comment. CSF andserum 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 CSFlevels of NSE showed a trend to increase toward Days 5 and 7,suggesting that neuronal damage increased, and they alsostressed the finding of higher NSE levels in CSF relative toserum toward Day 7. Enolase, an essential glycolytic enzyme,is a dimeric enzyme composed of α, β, and γ subunits. NSEcomprises two isoforms, γγ- and αγ, which are synthesized byneurons and neuroendocrine tissues. An αγ isoform is abun-dant in erythrocytes (3).


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One analytical study demonstrated a significant correlationbetween the NSE concentration and hemolysis in the sample,either CSF or serum, owing to the amount of NSE releasedfrom 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 processin the subarachnoid space after SAH, with larger amounts ofNSE released from erythrocytes on Day 7, and not necessarilycaused by neuronal damage. Since no hemolysis was present inserum, the NSE serum levels remained in a lower range.

In future studies, an index of hemolysis or determinations offree hemoglobin in CSF would probably be useful to clarifythe interpretation of NSE levels in hemorrhagic CSF samplesand the role of NSE in the pathogenesis and prognosis ofaneurysmal SAH. The use of CSF samples from patients withnormal-pressure hydrocephalus as a control group does notreflect a normal population, as was recognized by the authors.Patients undergoing spinal anesthesia for surgical proceduresoutside central nervous system served as a control group in aprevious study of NSE in CSF (1).

Jose L. Soto-HernandezTlalpan, Mexico

1. Casmiro M, Maitan S, De Pasquale F, Cova V, Scarpa E, Vignatelli L; NSEstudy 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 ChemLab 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 serumlevels of NSE. It is well known that numerous substances arereleased into the CSF and blood as part of the brain damageafter SAH, but the ideal damage marker would have to satisfycertain 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 inneuroendocrine cells in insignificant concentration (7). This isone of the most important reasons for us to include NSE as apossible marker of neuronal damage in our study. NSE wasoriginally 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 twocell types. Clinical studies have shown that elevated serum lev-els of NSE have been associated with unfavorable outcome intraumatic brain injury and large volumes of cerebral infarction(2, 10, 12). Furthermore, elevated levels are associated withsome neurodegenerative diseases (3, 5). Altogether, findingsfrom some central nervous system diseases causing neuronaldamage suggest that NSE may be a specific marker of neu-ronal damage.

There have been limited numbers of studies regarding NSElevels in aneurysmal SAH patients, and all of them evaluatedserum levels (6, 9). The serum levels of NSE were found to becorrelated with the amount of blood in the subarachnoid space(high Fisher grade), and the serum levels were found to behigher in patients with vasospasm, which generally occursbetween Days 4 and 14, being maximum on Day 7 after theictus (6, 9). The findings indicate that the persistence of NSE ineither serum or CSF days after the hemorrhage probablyreflects continuous release from the damaged neurons. A signif-icant correlation between NSE levels in CSF and serum hasalso been demonstrated in patients with coma (8). On the otherhand, NSE has also been found in peripheral neuroendocrinecells and in blood platelets, so serum NSE may not be only ofcentral origin, as Dr. Soto-Hernandez comments in his letter.This point may be true, but, in our study, none of the patientshad small-cell lung cancer or neuroendocrine neoplasms,which can cause elevation of serum NSE levels. Therefore, theelevation of serum NSE levels in our patients seems to beattributable 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 thatthe elevated CSF levels of NSE correlated with the elevatedserum levels of NSE within the first 3 days of SAH, in which novasospasm is expected to occur. It has been shown that serumlevels increase about the time when delayed ischemic neurolog-ical deficits develop, and they remain elevated for several daysafterward in SAH patients (6). This suggests that NSE is contin-uously released into the CSF from ischemic neurons and thatthe cellular injury resulting from cerebral vasospasm mayprogress for at least several days after the onset of vasospasm.Persistent elevation of the intracranial pressure and associatedcerebral edema might perhaps cause the continuing release ofNSE from neurons in SAH. Although the clinical studies thatwe mentioned, including studies of traumatic brain injury, cere-bral ischemia, and neurodegenerative diseases, as well as ourstudy, supported the idea that the serum or CSF levels mightreflect the severing of the central nervous system lesions, weinsist 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 amarker of neuron damage after SAH.

The second comment was that the control group included inour study (4) consisted of patients with normal-pressurehydrocephalus. We stated in the article (4) that the control


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group should include healthy volunteers for at least the serumsamples 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 withnormal-pressure hydrocephalus do not reflect a normal popu-lation, since strongly elevated NSE levels were found in theCSF of patients with severe hydrocephalus (Grade III) (1).Therefore, we suggest that control groups in future studiesshould include subjects undergoing diagnostic venipunctureor lumbar puncture.

Taner TanriverdiIstanbul, 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 aftersevere 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. ClinChim 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 ofneuron-specific enolase in serum and cerebrospinal fluid of early stageCreutzfeldt-Jakob disease. Acta Neurol Scand 102:385–387, 2000.

6. Mabe H, Suzuki S, Mase M, Umemura A, Nagai H: Serum neuron-specificenolase levels after subarachnoid hemorrhage. Surg Neurol 36:170–174, 1991.

7. Marangos PJ: Neuron specific enolase, a clinically useful marker for neuronsand neuroendocrine cells. Annu Rev Neurosci 10:269–295, 1987.

8. Martens P, Raabe A, Johnsson P: Serum S-100 and neuron-specific enolase forprediction of regaining consciousness after global cerebral ischemia. Stroke29:2363–2366, 1998.

9. Oertel M, Schumacher U, McArthur DL, Kastner S, Boker DK: S-100B andNSE: Markers of initial impact of subarachnoid hemorrhage and their relationto 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 patientswith 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 humanbrain. Neurosci Lett 76:233–238, 1987.

12. Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, Pertuiset B, De VilliersJC: A universal subarachnoid hemorrhage scale: Report of a committee of theWorld Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry51:1457, 1988.

DOI: 10.1227/01.NEU.0000315855.17297.62

Treatment Options for Third Ventricular Colloid Cysts:Comparison of Open Microsurgical versusEndoscopic 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 safeand as effective as microsurgical resection. They also recom-mend neuroendoscopy as a first line of treatment for theselesions. Their study, quite admirably, attempts to address a com-mon contemporary debate that aims to identify the best way ofmanaging this relatively uncommon condition. However, thetitle and the conclusion of the article, I feel, do not accuratelyreflect their own observations. The title mentions a comparisonof “microsurgical” and “endoscopic” approaches to the colloidcyst, when, in fact, they only compared the transcallosal micro-surgical approach with the endoscopic one. There were no casestreated with the transcortical transventricular microsurgicalapproach in their series. It is perhaps an injustice to generalizethe outcome of a selected transcallosal approach to the entiregamut of microsurgical approaches, as the techniques, invasive-ness, and potential complications differ considerably in differentmicrosurgical approaches.

The authors point out that more than 40% of patients in theendoscopic group were left with residual cysts. The authorscite several other series that highlight a similar problem withthe endoscopic approach. The proponents of endoscopy mayrightly argue that a significant proportion of the patients leftwith residual cysts may never become symptomatic again andtherefore are potentially “cured” (2); the skeptics, on the con-trary, are justifiably concerned about incompletely treating anotherwise benign condition. In any case, there seems to be atrade-off of completeness of surgical resection with the inva-siveness of the approach selected (3).

My own preference for treating various pathologies in thisregion, including colloid cysts, has been for a transcortical-transventricular approach. With the precision offered by recentimage-guidance systems facilitating miniature craniotomies, Ibelieve that, with this approach, it is possible to be minimallyinvasive and radical simultaneously, thereby combining theadvantages offered by both approaches discussed by theauthors of this article. The scalp incision, the corticotomy, andthe 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 factorsrelated 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 contentsand/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 bimanualmaneuvering of instruments within the ventricle, but also helpsto ensure that there is no spillage of blood or cyst contents out-side the operative field by carefully isolating the operative areafrom the dependent parts of the ventricular system, where cystcontents and blood are likely to accumulate without the sur-geon being aware of it.

Unfortunately, both the endoscopic and trancallosalapproaches have their own inherent limitations that cannot be


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completely overcome irrespective of the skill and experience ofthe operator. After having read the article carefully, I now feelmore 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 thattheir observations suggest that microsurgery (the transcallosalapproach in the authors’ series), in fact, does not have a highercomplication rate than the endoscopic approach but is morelikely to effect a complete resection of the lesion and thereforeshould be recommended. The ideal surgical approach for anycolloid 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 maytherefore be imprudent to recommend one universal approachfor all colloid cysts. Nevertheless, this informative and timelyarticle also highlights another interesting observation that, inan attempt to embrace surgical minimalism, perhaps we alltend to downplay the fact that there is often a price to pay forthe minimal invasiveness and also that, in the management ofmany of these conditions, colloid cysts included, less is notalways more.

Kishor A. ChoudhariBelfast, United Kingdom

1. Horn EM, Feiz-Erfan I, Bristol RE, Lekovic GP, Goslar PW, Smith KA, NakajiP, Spetzler RF: Treatment options for third ventricular colloid cysts:Comparison of open microsurgical versus endoscopic resection. Neurosurgery60:613–620, 2007.

2. Longatti P, Godano U, Gangemi M, Delitala A, Morace E, Genitori L, AlafaciC, Benvenuti L, Brunori A, Cereda C, Cipri S, Fiorindi A, Giordano F, MascariC, Oppido PA, Perin A, Tripodi M: Cooperative study by the Italian neuroen-doscopy group on the treatment of 61 colloid cysts. Childs Nerv Syst22:1263–1267, 2006.

3. Zohdi A, El Kheshin S: Endoscopic approach to colloid cysts. Minim InvasiveNeurosurg 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 believethat an open microsurgical approach is equally viable. In fact,we still perform approximately half of our procedures throughan open transcallosal approach. We are well aware that ourstudy was limited to comparison of only one type of microsur-gical approach with the endoscopic approach. We feel that thisapproach is most appropriate since it completely avoids tra-versing normal cortical tissue. If Dr. Choudhari believes thatthe transcortical-transventricular approach is the “gold stan-dard” approach for treating colloid cysts, then we welcome theinclusion of the supporting data in a comparative fashion in theneurosurgical literature.

Eric M. HornRobert F. SpetzlerPhoenix, Arizona

1. Horn EM, Feiz-Erfan I, Bristol RE, Lekovic GP, Goslar PW, Smith KA, NakajiP, Spetzler RF: Treatment options for third ventricular colloid cysts:Comparison of open microsurgical versus endoscopic resection. Neurosurgery60:613–620, 2007.

DOI: 10.1227/01.NEU.0000315857.02050.B9

Toward the Emergence of Nanoneurosurgery: Part III—Nanomedicine: Targeted Nanotherapy, Nanosurgery andProgress 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 asapplied to the treatment of diseases of the human nervous sys-tem. That there was a particular need for such an article, whichwould attract neuroscientists, particularly neurosurgeons,toward engaging in research in this discipline, is made obviousby the fact that, of the 114 references at the end of this article,only six are from neurosciences journals (1, 2, 4, 6–8). Thisseems to be more on account of lack of awareness rather thana dearth in the potential application of this field to neuro-surgery, as can be gauged from Tables 2 and 3 in the article. In


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FIGURE C2. Photographs showing the transcortical-transventricularminimally invasive approach. A, precoronal right frontal skin incision. B,trans-sulcal approach for an image-guided corticotomy less than an inchin length. C and D, microscopic photographs pre-excision (C) and postex-cision (D) of the colloid cyst (black arrow). The cyst bed (D) is gentlypacked with cotton balls for hemostasis after cyst resection.

fact, one can enumerate a few additional examples in which thealready available nanotechnology derivatives can be put to usein neurosurgery in the near future.

Nonlesional epilepsy surgery provides one such example.As is so well illustrated in Figure 21 of the article, intracapillaryplatinum nanoelectrodes in proximity to the spinal cord havebeen shown to provide larger and more differentiated signalamplitudes than surface electrodes. This derivative can findimmediate application in locating an epileptogenic focus at theneuronal level. Using one of the nanoscale drug delivery vehi-cles, apoptosis-inducing agents may be transfected to destroythese neuronal cells. Alternatively, nanotechnology derivatives,such as a polymer nanowire bouquet, can be used to inactivatesuch neurons through neurostimulation. Neurovascular com-pression syndromes provide another example in which theintracapillary platinum nanowires placed in proximity to theroot entry zone of the involved cranial nerve can pinpoint thelocation of the offending vessel. Yet another application couldbe in intraoperative neuromonitoring during operations in andaround brainstem, in which recordings from appropriatelyplaced platinum nanowires in the brainstem capillaries maysubstitute for and improve upon the conventional brainstemevoked response recording techniques. Of course, developmentof 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 thearticle. They mentioned that the delivery of drugs such as anti-neoplastic and anti-human immunodeficiency virus agents tothe central nervous system is limited because of their inabilityto cross the blood-brain barrier (BBB) and that nanoparticles, byvirtue of their small size, help in overcoming this obstacle.However, the exact mechanism by which the small size ofnanoparticles enables other large-sized molecules in crossingthe BBB is not mentioned.

Surinder N. KundraNew Delhi, India

1. Chung SH, Clark DA, Gabel CV, Mazur E, Samuel AD: The role of the AFDneuron in C. elegans thermotaxis analyzed using femtosecond laser ablation.BMC Neurosci 7:30, 2006.

2. Kennedy PR, Bakay RA: Restoration of neural output from a paralyzedpatient by a direct brain connection. Neuroreport 9:1707–1711, 1998.

3. Kundra SN: Microelectromechanical systems and neurosurgery: A new era ina new millennium. Neurosurgery 50:9, 2001 (letter).

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 progresstoward the realization of nanoneurosurgery. Neurosurgery 58:1009–1026,2006.

6. Leary SP, Liu CY, Yu C, Apuzzo ML: Toward the emergence of nanoneuro-surgery: Part I—Progress in nanoscience, nanotechnology, and the compre-hension of events in the mesoscale realm. Neurosurgery 57:600–634, 2005.

7. Roy SP, Ferrara LA, Fleischman AJ, Benzel EC: Microelectromechanical sys-tems and neurosurgery: A new era in a new millennium. Neurosurgery49:779–798, 2001.

8. Sretavan DW, Chang W, Hawkes E, Keller C, Kliot M: Microscale surgery onsingle axons. Neurosurgery 57:635–646, 2005.

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 nanoparticlesenables other large-sized molecules in crossing the BBB,” whichwas submitted in response to recent articles from our institu-tion regarding nanotechnology applications to neurosurgery(12–14). A number of recent articles have demonstrated theunique advantages offered by innovations in nanotechnologyto achieve enhanced BBB penetration. The following is a briefsummary 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 investigatedfor improving the understanding and penetration of the BBB.For example, much work has been recently reported regardingthe use of iron oxide nanoparticles as imaging and therapeuticagents (7, 18–20). In vivo animal studies have investigated theuse of iron oxide nanoparticles as magnetic resonance imaging(MRI) contrast agents (21). Rats with 9L gliosarcoma or C6glioma tumors were injected with dextran-coated iron oxidenanoparticles. After 24 hours, accumulation in the tumor was10-fold greater than in adjacent brain tissue (18). Human stud-ies have demonstrated sharp tumor enhancement in gliomasand metastatic tumors after iron oxide nanoparticle administra-tion (4, 30). Enhancement with coated iron oxide nanoparticlespeaks at 24 to 48 hours, and tumor borders remain sharp fordays. This differs from gadolinium enhancement, in which thetumor border blurs within hours of administration. The mech-anism of nanoparticle-mediated tumor enhancement is pre-sumably secondary to the leaky BBB with subsequent uptakeinto reactive cells, such as astrocytes and macrophages (17, 20).

Interaction of polyethylene glycol surface moieties on thenanoparticles with the brain endothelial cells may also havecontributed to tumor uptake (3). A recent report illustrates mul-tiple advantages of using nanoparticles in brain tumors. Theauthors constructed a multifunctional polymeric nanoparticlethat 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 bindingto 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 thenanoparticle. Iron oxide within the nanoparticle yieldedenhancement on MRI.

Dual imaging with MRI and fluorescence microscopy hasbeen demonstrated with a single multifunctional nanoparticle(Figures 7 and 8 of the article) (8, 30). In one study, dual imag-ing was achieved by coating an iron oxide nanoparticle withthe near-infrared fluorescent molecule Cy5.5. Preoperativeimaging 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. Surgicalexposure showed good comparison of near-infrared fluores-cent imaging to the green fluorescence protein fluorescence ofthe tumors (8). In another study, clorotoxin, a glioma-targetingpeptide, was attached to nanoparticles capable of similar dualimaging (30). Tumor-specific binding and cellular uptake ofthe multimodal nanoparticle by 9L gliosarcoma cells wasdemonstrated 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 theaccess of many traditional chemotherapeutic agents to theCNS. Nanoparticles may be targeted to the CNS but must alsoavoid uptake by the reticuloendothelial system and have suffi-cient circulation time in plasma to reach the CNS. Two factorsthat limit reticuloendothelial system uptake of nanoparticlesare hydrophilic coating and small size (10–100 nm). Nano-particles that have demonstrated successful CNS penetrationtypically meet these criteria. Further specificity of nanoparticlesfor a specific location or disease can be achieved throughattachment of a targeting ligand (25).

Targeting a therapeutic agent using this technique could alsolimit systemic drug exposure. Drug loading into nanoparticlescan be achieved by absorption, encapsulation, and covalentlinkage (23). Properties of the nanoparticle such as size, surfacemorphology, surface charge, hydrophobicity and type of target-ing ligand may be optimized depending on the neurologicaldisease. To date, polybutylcyanoacrylate (PBCA) nanoparticlesrepresent the most promising nanoparticle candidates forglioma 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 viareceptor-mediated endocytosis by brain endothelial cells.Specifically, polysorbate 80 absorbs apolipoprotein E in plasma,which is then internalized by the low-density lipoproteinuptake system (10). Covalent attachment of apolipoproteinssuch as E3, A-I, or B-100 to nanoparticles also facilitates brainendothelial cell uptake and central nervous system drug deliv-ery, possibly secondary to similar low- or high-density lipopro-tein receptor-mediated endocytosis (9). Nanoparticles withoutcovalently attached apolipoprotein show a correlation betweensurfactant-mediated apolipoprotein A-I surface adsorption anddrug delivery across the BBB (22).

Previous investigations have studied the brain distributionand therapeutic efficacy of polysorbate 80 PBCA nanoparticlesloaded with doxorubicin (6, 29). When the nanoparticles wereinjected intravenously into healthy rats, a 60-fold higher dox-orubicin concentration was achieved in the brain comparedwith systemic doxorubicin administration. Coated nanoparti-cles yield significantly higher brain concentrations of the drugthan administration of uncoated PBCA nanoparticles loadedwith doxorubicin. These nanoparticles were also evaluated in arat glioblastoma model (101/8). Rats treated with polysorbate80-coated PBCA nanoparticles loaded with doxorubicindemonstrated a significant increase in survival compared with

control groups. No additional toxicity was observed that couldbe attributed to the linking of doxorubicin to nanoparticles (5).Nanoparticles can be designed with properties that facilitatemigration into the brain, and they present new opportunitiesfor pharmacological agents previously discarded because oftheir 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 endocytosisby brain capillary endothelial cells. Recent work has demon-strated delivery of pharmacological agents across the BBBusing this mechanism (1, 2). Other diagnostic or therapeuticinterventions that use nanoparticles as brain delivery vehiclesinclude 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 ofthe nanoparticle affected BBB integrity and permeability (15).Neutral and low-concentration anionic nanoparticles had noeffect on the BBB, whereas high-concentration anionic nanopar-ticles and cationic nanoparticles disrupted the BBB. Further-more, brain uptake was greater for low-concentration anionicnanoparticles than neutral or cationic nanoparticles.

BBB Investigations. Modeling of the BBB may assist scientistsdevise novel methods for delivering diagnostic and therapeu-tic agents to intracranial lesions. Current modeling techniquesmay not allow sufficient astrocyte-endothelial cell contact. Onerecently reported model used nanofabrication techniques tocreate a silicon nitride membrane that was an order of magni-tude thinner and significantly more porous than commerciallyavailable membranes, although a tighter endothelial-astrocytejunction was not observed (16). Central nervous system dis-ease may lead to breakdown of the BBB, which can then beexploited during diagnostic or therapeutic intervention. Virus-sized iron oxide-based nanoparticles have been studied inhumans as contrast agents for evaluation of inflammatoryCNS lesions such as multiple sclerosis, lymphoma, acute dis-seminated encephalomyelitis (ADEM), and vascular lesions(Table 2 in the article) (17). Enhancement due to iron oxidenanoparticles showed differences compared with gadoliniumenhancement. Less enhancement compared with gadoliniumwas generally observed for demyelinating inflammatorylesions such as multiple sclerosis and ADEM, although onecase of ADEM showed significantly more enhancement withiron oxide nanoparticles. Patients with stroke showed signifi-cantly greater iron oxide nanoparticle enhancement comparedwith gadolinium, but this may have related to the timing ofthe studies. Another notable finding was a cavernous malfor-mation patient in whom iron oxide nanoparticles revealedprominent enhancement compared with no significantenhancement with gadolinium.

Furthermore, modeling of the BBB may assist scientists indevising 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 nanofabricationtechniques to create a silicon nitride membrane that was an


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order of magnitude thinner and significantly more porous thancommercially available membranes, although a tighterendothelial-astrocyte junction was not observed.

Conclusion. Concepts from nanotechnology will advance ourunderstanding of physiological and pathological states of thecentral nervous system. Improved investigation and circum-vention of the BBB will likely present new opportunities forsystemic treatments for neurological diseases. The examplesdiscussed 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 furtherquestions or discussion in this area and appreciate the oppor-tunity to respond.

James B. ElderCharles Y. LiuMichael L.J. ApuzzoLos Angeles, California

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2. Alyautdin RN, Tezikov EB, Ramge P, Kharkevich DA, Begley DJ, Kreuter J:Significant entry of tubocurarine into the brain of rats by adsorption topolysorbate 80-coated polybutylcyanoacrylate nanoparticles: An in situ brainperfusion study. J Microencapsul 15:67–74, 1998.

3. Brigger I, Morizet J, Aubert G, Chacun H, Terrier-Lacombe MJ, Couvreur P,Vassal G: Poly(ethylene glycol)-coated hexadecylcyanoacrylate nanospheresdisplay a combined effect for brain tumor targeting. J Pharmacol Exp Ther303:928–936, 2002.

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DOI: 10.1227/01.NEU.0000315859.40168.88


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