Neurosurgical forum Letters to the editor

Subarachnoid hemorrhage To The Editor: We read with great interest the re­ cent article by Kuo et al.1 (Kuo CP, Wen LL, Chen CM, et al: Attenuation of neurological injury with early baica­ lein treatment following subarachnoid hemorrhage in rats. Laboratory investigation. J Neurosurg 119:1028–1037, Oc­­ tober 2013). Ruptured aneurysm–related subarachnoid hemor­ rhage (SAH) is an emergent neurosurgical condition re­ quiring clipping or embolization of the aneurysm. More­ over, SAH-induced vasospasm often leads to cerebral infarction and morbidity, or death. Kuo et al. conducted a laboratory investigation to evaluate the effect of baicalein reduction of neurological injury in the early stage after SAH. They found that baicalein significantly decreased mortality and neuronal injury. Moreover, treatment with baicalein was associated with a decrease in reactive oxy­ gen species (ROS) and better neurological scores. Their study provided an important potential appli­ cation of baicalein in the improvement of SAH-induced neuronal injury and cerebral vasospasm, and aroused the curiosity of readers to ask whether the effect of baicalein is through direct passage through the blood-brain barrier to regulate the cerebral inflammation and ROS, or indi­ rectly regulates the peripheral blood inflammation to im­ prove the outcome of SAH-induced vasospasm. Tsung-Ying Yu Chao-Hung Chen Man-Wei Hua Chiao-Chin Lee Dueng-Yuan Hueng, M.D., Ph.D. Tri-Service General Hospital National Defense Medical Center Taipei, Taiwan, R.O.C.

Disclosure The authors report no conflict of interest. Reference   1.  Kuo CP, Wen LL, Chen CM, Huh B, Cherng CH, Wong CS, et al: Attenuation of neurological injury with early baicalein treatment following subarachnoid hemorrhage in rats. Labora­ tory investigation. J Neurosurg 119:1028–1037, 2013

Response: We thank Yu et al. for their interest in our article about the neuroprotective effect of baicalein through direct regulation of cerebral inflammation or in­ direct regulation of peripheral inflammation after SAH. Both inflammatory and oxidative stress responses defi­ nitely represent the critical pathways in the pathogenesis of cerebral vasospasm pursuant to SAH.1,2 Huang et al.3 previously demonstrated that baicalein has both antiin­ J Neurosurg / Volume 120 / January 2014

flammatory and antioxidative activities in rats. In our cur­ rent study, we investigated only the antioxidative stress effect of baicalein by examining superoxide dismutase, catalase, and malondialdehyde levels in the brain tissues (hippocampi and cortices). We found that cerebral vaso­ spasm and brain injury were decreased and neurological outcomes were improved. According to the study of Tsai et al.,4 baicalein is able to penetrate the blood-brain barrier. Therefore, we believe that baicalein can both directly and indirectly regulate inflammation and the oxidative stress effect after SAH. However, our results only provided evidence of the an­ tioxidative stress effect of baicalein, which might occur through both direct and indirect regulation. Chang-Po Kuo, M.D. Ching-Tang Wu, M.D. Tri-Service General Hospital National Defense Medical Center Taipei, Taiwan, R.O.C.

References   1.  Dumont AS, Dumont RJ, Chow MM, Lin CL, Calisaneller T, Ley KF, et al: Cerebral vasospasm after subarachnoid hemor­ rhage: putative role of inflammation. Neurosurgery 53:123– 135, 2003   2.  Kuo CP, Lu CH, Wen LL, Cherng CH, Wong CS, Borel CO, et al: Neuroprotective effect of curcumin in an experimental rat model of subarachnoid hemorrhage. Anesthesiology 115: 1229–1238, 2011  3. Huang WH, Lee AR, Yang CH: Antioxidative and anti-in­ flammatory activities of polyhydroxyflavonoids of Scutellaria baicalensis GEORGI. Biosci Biotechnol Biochem 70:2371– 2380, 2006   4.  Tsai TH, Liu SC, Tsai PL, Ho LK, Shum AY, Chen CF: The effects of the cyclosporin A, a P-glycoprotein inhibitor, on the pharmacokinetics of baicalein in the rat: a microdialysis study. Br J Pharmacol 137:1314–1320, 2002 Please include this information when citing this paper: published online October 4, 2013; DOI: 10.3171/2013.6.JNS131156. ©AANS, 2014

Radiographic resolution To The Editor: We found the report by Takagi et al.4 in the Journal of Neurosurgery of considerable interest (Takagi I, Shakur SF, Lukas RV, et al: Spontaneous radio­ graphic resolution and subsequent redemonstration of an untreated glioblastoma. Case report. J Neurosurg 115:24– 29, July 2011). In this paper the authors offered two expla­ nations for why this patient’s untreated glioblastoma no longer enhanced on MRI. We believe that there is a third explanation that was not fully explored but warrants our attention whenever using MRI for tumor follow-up. While 285

Neurosurgical forum the authors did not describe the details of imaging in their report, we have reasons to suspect that the second study, in which the tumor did not appear to enhance, was per­ formed on a 3-T scanner using a gradient echo T1-weight­ ed technique. There are a number of factors that contribute to the magnitude of tumor enhancement on MRI. These include time elapsed from injection, the contrast agent selected and its dose, the specific scan technique, and field strength. It has long been an accepted fact that gradient echo T1weighted techniques offer less sensitivity to gadolinium contrast compared to spin echo T1 imaging techniques.1 Nevertheless, it is not uncommon to see gradient echo T1weighted techniques used on 3-T scanners for both preand postcontrast imaging. This technique is commonly used at 3 T both to circumvent the inherently lower T1 tissue contrast encountered at high field strength and to limit power deposition, since this may be an issue at high field strengths. The known limitations of the gradient echo technique for postcontrast imaging seems to be tacitly ac­ cepted for 3 T, however, perhaps with the hope that 3-T scanners may be inherently more sensitive to gadolinium. The latter is widely accepted but without substantial ex­ perimental proof at concentrations comparable to those encountered in brain tumors. We think it is important to consider the possibility that the apparent lack of enhancement described in this report could be an artifact of technique. While just conjecture on our part, since the scan details were not included, that ex­ planation seems much more likely and better fits the prin­ ciple of Occam’s razor than the concept of spontaneous regression of a glioblastoma. While much to be desired, that theory runs counter to decades of imaging experience with this tumor. The famous physician-writer Dr. Arthur Conan Doyle had his character Sherlock Holmes use this reasoning in such circumstances, “Once you eliminate the impossible, whatever remains, no matter how improbable, must be the truth.” In this particular case the possibility of an MR artifact certainly seems in the realm of the pos­ sible. We also have experimental evidence that indicates that diminished contrast sensitivity should be expected on 3D gradient echo imaging at 3 T,2 and this limitation of 3-T MR has also been described in at least one previous report.3 Our interest in this pitfall was stimulated by our own experience with a case of metastatic disease to the brain that demonstrated resolution of enhancement in a fashion remarkably similar to that noted in this Journal of Neurosurgery report (Fig. 1). Whether or not field strength and scan technique alone explain the findings in this particular case, we believe it is important for radiologists and neurosurgeons alike to con­ sider carefully the effect of technique and field strength on postcontrast MRI. Standardizing and optimizing the factors that contribute to apparent contrast—field strength, agent, dose, time from injection, and scan technique—will minimize the effects of technique on the postcontrast tu­ mor enhancement qualities. Francis Cloran, M.D. Jimmy S. Lee, M.D., Ph.D. Alexander Mamourian, M.D. Hospital of the University of Pennsylvania Philadelphia, PA

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Fig. 1.  A: Axial T1-weighted image obtained at an outside site using spin echo technique (TR 600 msec, TE 17 msec) with chemical fat suppression. It well demonstrates a faintly apparently enhancing periventricular lesion (arrow).  B: The patient was referred to our hospital for diagnosis and treatment of this lesion and a second scan was obtained using a 3-T MR scanner and an MP-RAGE (magnetization-prepared rapid gradient echo) technique (TR 1760 msec, TE 3.1 msec). On that scan the lesion no longer shows enhancement as seen here on the corresponding axial slice. No steroids or other medications had been administered to explain this change in appearance, and regression of a non-neoplastic process was a consideration.  C: Two months later a third scan was obtained, this time on a 1.5-T MR unit with a spin echo technique (TR 600 msec, TE 20 msec). On this axial section obtained at the same level as the images in A and B, the lesion once again enhances and has also enlarged compared with the first scan. At this point the lesion was biopsied and proved to be a brain metastasis from a lung primary. Disclosure The authors report no conflict of interest. References   1.  Chappell PM, Pelc NJ, Foo TK, Glover GH, Haros SP, Enz­ mann DR: Comparison of lesion enhancement on spin echo and gradient-echo images. Am J Neuroradiol 15:37–44, 1994   2.  Cloran FJ, Mamourian AC: Relative insensitivity of T1 gradi­­ ent echo MR imaging at 3T to low concentrations of contrast: in vitro validation. Presented at the annual meeting of the Amer­ ican Society of Neuroradiology, New York, 2012 (Abstract) (http://www.abstractsonline.com/Plan/ViewAbstract.aspx? sKey=5ee9ef38-5be6-4fc5-90da-86c3e7aa8c5d&cKey= 38 0 e b c1d -9 f 15 - 4 e e e -9 c f 6 - e 0 a 0 b 89 32 62 c & m Key= %7bB43DF973-66E7-42DF-9876-FF1C2C806C5E%7d) [Ac­ cessed September 12, 2013]   3.  Kato Y, Higano S, Tamura H, Mugikura S, Umetsu A, Murata T, et al: Usefulness of contrast-enhanced T1-weighted sam­ pling perfection with application-optimized contrasts by using

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Neurosurgical forum different flip angle evolutions in detection of small brain me­ tastasis at 3T MR imaging: comparison with magnetizationprepared rapid acquisition of gradient echo imaging. AJNR Am J Neuroradiol 30:923–929, 2009   4.  Takagi I, Shakur SF, Lukas RV, Eller TW: Spontaneous radio­ graphic resolution and subsequent redemonstration of an un­ treated glioblastoma. Case report. J Neurosurg 115:24–29, 2011

Response: No response was received from the au­ thors of the original article. Please include this information when citing this paper: published online October 11, 2013; DOI: 10.3171/2012.7.JNS121070. ©AANS, 2014

Aggressive behavior To The Editor: This letter is in reference to the recent article by Torres et al.8 (Torres CV, Sola RG, Pastor J, et al: Long-term results of posteromedial hypothalamic deep brain stimulation for patients with resistant aggres­ siveness. Clinical article. J Neurosurg 119:277–287, Au­ gust 2013). Those authors reported their experience with deep brain stimulation (DBS) of the posteromedial hy­ pothalamus in 6 patients with aggressive behavior. The results of this procedure have been excellent. The authors need to be commended for reporting these experiences with psychosurgery, which has been on the wane. Re­ garding this research, I would like to highlight the work conducted by Professors B. Ramamurthi, V. Balasubra­ maniam, and T.S. Kanaka at the Madras Institute of Neu­ rology in Chennai, India.1–6 Six hundred three stereotactic surgical procedures were performed for patients with ag­ gressive behavior over the course of 25 years. Of these 603 procedures, 480 were amygdalotomies and 123 were hypothalamotomies. Fifty were primary hypothalamoto­ mies and 73 were secondary hypothalamotomies (after failed amygdalotomy). The target for hypothalamotomy proposed by Balasubramaniam and Ramamurthi was slightly in front of and below Sano’s target.6,7 This, by far, is one of the largest experiences with stereotactic amyg­ dalotomy and hypothalamotomy for aggressive behavior. Vengalathur Ganesan Ramesh, M.Ch. Chettinad Superspeciality Hospital Chennai, Tamilnadu, India Disclosure The author reports no conflict of interest. References   1.  Balasubramaniam V, Kanaka TS: Amygdalotomy and hypo­ thalamotomy—a comparative study. Confin Neurol 37:195– 201, 1975   2.  Balasubramaniam V, Kanaka TS, Ramanujam PB, Ramamurthi B: Stereotaxic-hypothalamotomy. Confin Neurol 35:138–143, 1973   3.  Balasubramaniam V, Ramamurthi B: Stereotaxic amygdalot­ omy. Proc Aust Assoc Neurol 5:277–278, 1968   4.  Balasubramaniam V, Ramamurthi B: Stereotaxic amygdalot­ omy in behavior disorders. Confin Neurol 32:367–373, 1970

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  5.  Balasubramaniam V, Ramamurthi B, Jagannathan K, Kaly­ anaraman S: Stereotaxic amygdalotomy. Neurol India 15:119– 122, 1967   6.  Ramamurthi B, Balasubramaniam V: Stereotaxic hypothala­ motomy in aggressive behavior, in Samii M (ed): Surgery in and Around the Brain Stem and the Third Ventricle. Ber­ lin: Springer-Verlag, 1986, pp 547–549   7.  Sano K, Yoshioka M, Ogashiwa M, Ishijima B, Ohye C: Pos­ tero-medial hypothalamotomy in the treatment of aggressive behaviors. Confin Neurol 27:164–167, 1966   8.  Torres CV, Sola RG, Pastor J, Pedrosa M, Navas M, GarcíaNavarrete E, et al: Long-term results of posteromedial hy­ pothalamic deep brain stimulation for patients with resistant aggressiveness. Clinical article. J Neurosurg 119:277–287, 2013

Response: We greatly appreciate the comments of­ fered by Dr. Ramesh. Psychosurgery has a long history of controversy, mostly due to its indiscriminate use, the lack of clear criteria for the selection of patients, and the pau­ city of objective outcome measures. However, it has also had notable successes regarding severe problems such as refractory aggressiveness, providing quality of life to patients who otherwise were destined to social exclusion and would have required restraining by physical means. The large series reported by professors B. Ramamurthi, V. Balasubramaniam, and T. S. Kanaka yielded successful outcomes in as many as 76% of patients, with a mortality rate of 4%, all during a period in which MRI and other technical advances had not yet been developed.1–6 The ra­ tionale for selecting the lesion site was solid, and as was the case for many of the current DBS procedures (which have been based on previous lesioning experiences), was the basis for the selection of our target for the treatment of refractory aggressiveness with DBS. Compared to lesioning, DBS is a reversible and safer form of treatment. However, it is fundamental that DBS treatments are performed in highly specialized centers equipped with adequate technology, and that patients are selected by multidisciplinary teams following strict cri­ teria. Also, objective methods of assessment must be uti­ lized and all procedures must adhere to the highest ethical criteria. It is likely that DBS indications will grow and a larger number of patients will benefit from this procedure over the next years. We believe that lesioning procedures, however, may continue to have a role in certain cases in which DBS is contraindicated or cannot be implemented, always safeguarding the same ethical standards and ap­ proach to the work. Cristina V. Torres, M.D., Ph.D. Rafael G. Sola, M.D., Ph.D. Jesús Pastor, M.D., Ph.D. Manuel Pedrosa, M.D., Ph.D. Marta Navas, M.D. Eduardo García-Navarrete, M.D., Ph.D. Elena Ezquiaga, M.D., Ph.D. Eduardo García-Camba, M.D., Ph.D. University Hospital La Princesa Madrid, Spain References   1.  Balasubramaniam V, Kanaka TS: Amygdalotomy and hypo­

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Neurosurgical forum thalamotomy—a comparative study. Confin Neurol 37:195– 201, 1975   2.  Balasubramaniam V, Kanaka TS, Ramamurthi B: Surgical treatment of hyperkinetic and behavior disorders. Int Surg 54: 18–23, 1970   3.  Balasubramaniam V, Kanaka TS, Ramandujam PB, Rama­ murthi B: Stereotaxic-hypothalamotomy. Confin Neurol 35: 138–143, 1973   4.  Balasubramaniam V, Kanaka TS, Ramanujam PV, Rama­ murthi B: Sedative neurosurgery. A contribution to the behav­ ioural sciences. J Indian Med Assoc 53:377–381, 1969   5.  Balasubramaniam V, Ramamurthi B: Stereotaxic amygdalot­ omy. Proc Aust Assoc Neurol 5:277–278, 1968   6.  Balasubramaniam V, Ramamurthi B: Stereotaxic amygdalot­ omy in behavior disorders. Confin Neurol 32:367–373, 1970 Please include this information when citing this paper: published online October 11, 2013; DOI: 10.3171/2013.6.JNS131269. ©AANS, 2014

Thyroid and meningioma To The Editor: I read with great interest this article by Sughrue et al.1 (Sughrue ME, Kane AJ, Shangari G, et al: Prevalence of previous extracranial malignancies in a series of 1228 patients presenting with meningioma. Clinical article. J Neurosurg 113:1115–1121, Novem­ ber 2010). The authors reported an epidemiological link between papillary thyroid carcinoma and meningioma. They encourage further studies to detect the common pathogenetic cause between the two diseases. Regarding other benign diseases associated with me­ ningiomas, I reviewed the records for meningiomas that have been surgically treated since 1978 at Di Venere Hos­ pital in Bari and the Neurosurgical Clinic of University of Rome Tor Vergata. I’ve also noticed in women the nearly constant coexistence of meningiomas with various types of thyroid disease. In our series the thyroid disease most frequently associated with meningiomas is benign mul­ tinodular goiter. Very often the patients were receiving thyroid replacement therapy after thyroidectomy. I also noticed that women with meningiomas and thyroid disease were frequently affected by other benign diseases, such as uterine fibroadenoma and fibrocystic mastopathy. In my opinion this survey, which is based on our ex­ perience of more than 30 years, deserves a further thor­ ough genetic and epidemiological study. Filiberto Contratti, M.D. University of Rome Rome, Italy

Disclosure The author reports no conflict of interest. Reference  1.  Sughrue ME, Kane AJ, Shangari G, Parsa AT, Berger MS, McDermott MW: Prevalence of previous extracranial malig­ nancies in a series of 1228 patients presenting with meningi­ oma. Clinical article. J Neurosurg 113:1115–1121, 2010

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Response: No response was received from the au­ thors of the original article. Please include this information when citing this paper: published online November 1, 2013; DOI: 10.3171/2011.2.JNS101991. ©AANS, 2014

Trigeminal neuralgia To The Editor: We read with great interest the article by Kouzounias et al.4 (Kouzounias K, Lind G, Schechtmann G, et al: Comparison of percutaneous balloon compression and glycerol rhizotomy for the treatment of trigeminal neuralgia. Clinical article. J Neurosurg 113:486–492, Sep­ tember 2010). We would like to discuss some aspects and know the authors’ opinions about some observations. Percutaneous balloon compression and retrogasse­ rian glycerolization are only 2 of numerous therapeutic procedures that can be performed for trigeminal neural­ gia; other treatments include microvascular decompres­ sion in the posterior cranial fossa, 5 stereotactic radiosur­ gery,3 radiofrequency thermocoagulation,2 and peripheral alcohol injections.6 Regarding the results reported by the authors with the 2 procedures, with particular attention to the rate of pain recurrence, it should be noted that these therapeutic tools can be considered temporary therapeutic choices for a large percentage of patients. Because of the high rate of recurrence in our previous experience,1 we have not performed glycerolization for the treatment of trigeminal neuralgia for many years, prefer­ ring other methods which we select according to the indi­ vidual characteristics of our patients (age and general con­ dition) and their specific case of trigeminal neuralgia (the branch of the nerve involved, the severity of symptoms). We would like to know why the authors didn’t consid­ er, in the Discussion (under “The Therapeutic Spectrum for TN”), the peripheral alcohol injection, which is very effective in our experience, especially in older patients with trigeminal neuralgia involving the V2 (instillation of 2 ml of absolute alcohol through the infraorbital fora­ men). This simple procedure has allowed us to provide patients with a pain-free period ranging from 2 to 6 years. Regarding balloon compression, we would like to know why the authors perform the procedure under gen­ eral anesthesia with endotracheal intubation. We perform the same procedure under sedation with propofol, as the authors described for glycerolization. In contrast to the authors, we don’t consider hemifacial hypesthesia a complication of balloon compression (which is a harmful procedure) but its aim in order to achieve a satisfactory result regarding pain control. Accordingly, we think that the problem with general anesthesia is that it is not pos­ sible to test the produced hemifacial hypesthesia during the procedure and decide to stop the procedure itself, or to continue inflating the balloon or change its position if hemifacial hypoesthesia has not been produced. In our experience, the patients in whom we did not achieve a marked hemifacial hypesthesia experienced J Neurosurg / Volume 120 / January 2014

Neurosurgical forum early pain recurrence; in other words, in order to achieve a durable good result with this procedure, a marked hypesthesia has to be provoked to the entire hemifacial area because it is not possible to select only the involved branch of the trigeminal nerve. For this reason, we pro­ pose this therapeutic solution only when other procedures have failed. We would like to know if in the reported ex­ perience the authors observed absence of pain recurrence in patients in whom no hemifacial hypesthesia was pro­ duced after the procedure; we would also like to know, if possible, if pain recurrence occurred at the same time with recovery of facial sensitivity.

Mario Francesco Fraioli, M.D. Damiano Lisciani, M.D. University of Rome “Tor Vergata” Rome, Italy Chiara Fraioli, M.D. CIRAD Villa Benedetta Rome, Italy

Disclosure The authors report no conflict of interest. References   1.  Fraioli B, Esposito V, Guidetti B, Cruccu G, Manfredi M: Treatment of trigeminal neuralgia by thermocoagulation, glycerolization, and percutaneous compression of the gasse­ rian ganglion and/or retrogasserian rootlets: long-term results and therapeutic protocol. Neurosurgery 24:239–245, 1989   2.  Fraioli MF, Cristino B, Moschettoni L, Cacciotti G, Fraioli C: Validity of percutaneous controlled radiofrequency thermo­ coagulation in the treatment of isolated third division trigemi­ nal neuralgia. Surg Neurol 71:180–183, 2009   3.  Kondziolka D, Zorro O, Lobato-Polo J, Kano H, Flannery TJ, Flickinger JC, Lunsford LD: Gamma Knife stereotactic radio­ surgery for idiopathic trigeminal neuralgia. Clinical article. J Neurosurg 112:758–765, 2010   4.  Kouzounias K, Lind G, Schechtmann G, Winter J, Linderoth B: Comparison of percutaneous balloon compression and glycerol rhizotomy for the treatment of trigeminal neuralgia. Clinical article. J Neurosurg 113:486–492, 2010   5.  McLaughlin MR, Jannetta PJ, Clyde BL, Subach BR, Comey CH, Resnick DK: Microvascular decompression of cranial nerves: lessons learned after 4400 operations. J Neurosurg 90:1–8, 1999   6.  McLeod NM, Patton DW: Peripheral alcohol injections in the management of trigeminal neuralgia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104:12–17, 2007

Response: No response was received from the au­ thors of the original article. Please include this information when citing this paper: published online November 1, 2013; DOI: 10.3171/2012.12.JNS101876. ©AANS, 2014

Perforators To The Editor: A very practical article on the use of cranial perforators was published in the Journal of Neurosurgery by Vogel et al.4 (Vogel TW, Dlouhy BJ, Howard MA III: Don’t take the plunge: avoiding adverse J Neurosurg / Volume 120 / January 2014

events with cranial perforators. Clinical article. J Neurosurg 115:570–575, September 2011). The authors have provided information regarding a very basic event, that is, “the plunge” with the perforator. Many neurosurgeons have experienced this event. The article refers to Robert S. Hudson as the inventor of the Hudson brace;2 however, the authors fail to men­ tion William Henry Hudson, an itinerant surgeon of the American South who performed craniotomies in the late 1800s and early 1900s.1 Dr. William H. Hudson designed drill bits for use on a brace and wrote “… as long as there is resistance in the bottom of the opening they will cut; when this resistance ceases, they will not move further.”3 In his 1920 surgical textbook, Dr. W. W. Keen reported testing William H. Hudson’s new burs at an AMA meet­ ing (as reported by Dr. Fincher1). This test of the bur in­ volved a blindfolded surgeon who was to drill into the temporal bone of a cadaver, trying to drill into the brain. The drill stopped cutting and the dura mater was unin­ jured. Other than this historical oversight, the authors have provided us with an informative article, and I shall use their recommendations to enhance my own practice. Jimmy D. Miller, M.D., J.D. Greenwood Leflore Hospital Greenwood, MS

Disclosure The author reports no conflict of interest. References   1.  Fincher EF: William Henry Hudson: itinerant neurosurgeon; 1862-1917. J Neurosurg 16:123–134, 1959   2.  Hudson RS: On the use of the trephine in depressed fractures of the skull. Br Med J 2:75–76, 1877   3.  Hudson WH: A new method of performing operations on the skull. Surg Gyn Obstet 10:180–183, 1910   4.  Vogel TW, Dlouhy BJ, Howard MA III: Don’t take the plunge: avoiding adverse events with cranial perforators. Clinical ar­ ticle. J Neurosurg 115:570–575, 2011

Response: No response was received from the au­ thors of the original article. Please include this information when citing this paper: published online November 1, 2013; DOI: 10.3171/2011.10.JNS111631. ©AANS, 2014

Propofol for severe traumatic brain injury To The Editor: In a multicenter randomized con­ trolled trial (RCT), Kelly and colleagues2 allocated 42 adults with predominantly severe traumatic brain injury (TBI) to infusions of morphine or propofol (Kelly DF, Goodale DB, Williams J, et al: Propofol in the treatment of moderate and severe head injury: a randomized, pro­ spective double-blinded pilot trial. J Neurosurg 90:1042– 1052, June 1999). The authors sought to determine drug safety and the influence of these agents on mortality, favorable neurological outcome (defined as a Glasgow Outcome Scale score of 4 to 5), and intracranial pressure 289

Neurosurgical forum (ICP). Despite its publication more than 12 years ago, this trial continues to be widely cited and to inform interna­ tional guidelines.1 Its findings contributed to a Level II recommendation for the use of propofol for control of ICP in TBI by the 2007 Brain Trauma Foundation Guidelines.1 In their post hoc analysis displayed in Table 7, Kel­ ly et al.2 reported that high-dose (≥ 100 mg/kg for ≥ 24 hours and beginning within 48 hours of injury) versus low-dose propofol resulted in a significantly higher rate of favorable neurological outcomes at 6 months (70% vs 38.5%, p < 0.05). This finding is also described in the evidence tables and text of the 2007 Brain Trauma Foun­ dation Guidelines.1 However, while conducting a recent systematic review of RCTs on the effect(s) of sedation in patients with severe TBI,3 we compared categorical data by using the 2-sided Fisher exact test and relative risks with 95% confidence intervals. We noted that in the highdose propofol group, 7 (70%) of 10 patients had a favor­ able neurological outcome versus 5 (38.5%) of 13 in the low-dose group (a nonsignificant result; p = 0.20), which translates into an RR of 1.82 and a 95% CI that includes 1 (0.81–4.05).3 The observed difference in this apparently nonsignificant outcome may have been confounded by the variability in clinical characteristics within this analyzed patient subgroup, such as age, time from injury, Glasgow Coma Scale score, and rate of hematoma evacuation. We recognize that the significance of this result may have been determined using a method different from ours. However, given the ongoing influence of this welldesigned trial, we respectfully request clarification of the statistical methodology used to obtain the reported significant result. In general, we recommend the use of relative risks and 95% confidence intervals because we believe this method provides the greatest clarity when reporting differences in clinical outcomes. Moreover, as “high dose propofol can produce significant morbidity,”1 and alternate sedative agents have differential effects on ICP and clinical outcomes,3 there is an urgent need for further multicenter RCTs comparing propofol and differ­ ent sedatives at varying dosages in critically ill patients with severe TBI. Derek J. Roberts, M.D. Peter D. Faris, Ph.D. David A. Zygun, M.D., M.Sc., F.R.C.P.C. University of Calgary Calgary, AB, Canada Disclosure The authors report no conflicts of interest. References   1.  Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al: Guidelines for the management of severe traumatic brain injury. XI. Anesthetics, analgesics, and sedatives. J Neurotrauma 24 Suppl 1:S71–S76, 2007   2.  Kelly DF, Goodale DB, Williams J, Herr DL, Chappell ET, Rosner MJ, et al: Propofol in the treatment of moderate and severe head injury: a randomized, prospective double-blinded pilot trial. J Neurosurg 90:1042–1052, 1999   3.  Roberts DJ, Hall RI, Kramer AH, Robertson HL, Gallagher CN, Zygun DA: Sedation for critically ill adults with severe

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traumatic brain injury: a systematic review of randomized controlled trials. Crit Care Med 39:2743–2751, 2011

Response: No response was received from the au­ thors of the original article. Please include this information when citing this paper: published online November 1, 2013; DOI: 10.3171/2011.12.JNS111110. ©AANS, 2014

Blood-brain barrier To The Editor: We are interested in the experimental investigation by Nduom et al.1 (Nduom EK, Yang C, Mer­ rill MJ, et al: Characterization of the blood-brain barrier of metastatic and primary malignant neoplasms. Laboratory investigation. J Neurosurg 119:427–433, August 2013). The blood-brain barrier (BBB) plays important roles in the physiological barrier to pathogen attack. Breakdown of the BBB has been proposed when astrocytomas grow or malignant metastases lead to severe brain edema and neurological compromise. Nduom et al.1 investigated the integrity of the BBB using immunofluorescence to dem­ onstrate the continuity of glial fibrillary acidic protein (GFAP; astrocyte marker), CD31 (endothelial marker), and aquaporin 4 (AQ4) among specimens of astrocytoma, gli­ oma, and metastatic cervical cancer. They concluded that contrast-enhanced lesions in patients with metastatic or primary malignancies match to regions of collapse of the astrocyte–endothelial cell association of the BBB, includ­ ing defect of normal perivascular astrocytic construction on AQ4 and GFAP immunohistochemistry. Nonenhancing lesions on MRI are related to maintenance of the common astrocyte–endothelial cell connection of the undamaged BBB. There is one minor concern that they did not address, that is, whether cases enrolled in their study received os­ motic diuretic (such as mannitol) treatment or not. Man­ nitol altering the BBB has been reported in metastases patients who received osmotic diuretic treatment for brain edema.2 Therefore, treatment with osmotic diuretics may become a confounding factor for breakdown of the BBB and must be claimed in their study. Dueng-Yuan Hueng, M.D., Ph.D. Huey-Kang Sytwu, M.D., Ph.D. Tri-Service General Hospital National Defense Medical Center Taipei, Taiwan

Disclosure The authors report no conflict of interest. References   1.  Nduom EK, Yang C, Merrill MJ, Zhuang Z, Lonser RR: Char­ acterization of the blood-brain barrier of metastatic and pri­ mary malignant neoplasms. Laboratory investigation. J Neu­ rosurg 119:427–433, 2013   2.  Palma L, Bruni G, Fiaschi AI, Mariottini A: Passage of manni­ tol into the brain around gliomas: a potential cause of rebound phenomenon. A study on 21 patients. J Neurosurg Sci 50:63– 66, 2006

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Neurosurgical forum Response: We appreciate the interest that Drs. Hueng and Sytwu expressed in our recent report. To gain insight into features of the astrocytic component of the BBB in metastatic and primary brain tumors, we analyzed post­ contrast MRI and compared that with the corresponding immunohistochemical and histological features of the astrocytic component of the neoplastic vasculature. We found that there was breakdown of the normal astrocyte– endothelial cell relationship of the BBB in areas of contrast extravasation on postcontrast MRI. Alternatively, in neo­ plastic regions without enhancement on postcontrast MRI, the normal physiological astrocyte-endothelial BBB rela­ tionship was maintained. In their letter, Drs. Hueng and Sytwu indicate man­ nitol can be used to open the BBB and, if used, could affect the study results. To support their assertion, they cite a study by Palma and colleagues.3 Nevertheless, that study did not indicate that intravenous mannitol opened the BBB but rather demonstrated that “mannitol may leak through the altered BBB near gliomas” into adjacent white matter, which is consistent with the BBB disruption associated with contrast-enhancing gliomas examined in our study. Moreover, the same study found that there was minimal to no leakage of mannitol into the immediately surrounding white matter associated with meningiomas or metastases. The authors concluded that “in brain tis­ sue surrounding extrinsic tumors like meningiomas and metastases, the BBB is largely normal or undisrupted, and edema builds up from leaking neoplastic vessels by bulk flow,” which is consistent with our study findings and previous analyses of neoplastic vascular permeability and edema.2 There are therapeutic situations in which mannitol can be used to purposely disrupt the BBB. Specifically, BBB disruption can occur when high doses of intraarte­ rial (intracarotid or intravertebral artery) mannitol (200– 300 ml) are given as a bolus over 30 seconds, which is performed in association with intraarterial chemothera­ peutic delivery for treatment of intracranial neoplastic processes.1,4 Consequently, while in specific circumstanc­ es mannitol delivered rapidly and intraarterially can open the BBB, we are confident that the findings of our study are consistent with previous data/findings and that intra­ venous infusions of perioperative mannitol would not im­ pact the results. Edjah K. Nduom, M.D.1,2 Zhengping Zhuang, M.D., Ph.D.2 Russell R. Lonser, M.D.2,3 1 Emory University Atlanta, GA 2 National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, MD 3 The Ohio State University Wexner Medical Center Columbus, OH References   1.  Kroll RA, Neuwelt EA: Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neu­ rosurgery 42:1083–1100, 1998   2.  Lonser RR, Vortmeyer AO, Butman JA, Glasker S, Finn MA, Ammerman JM, et al: Edema is a precursor to central nervous

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system peritumoral cyst formation. Ann Neurol 58:392–399, 2005   3.  Palma L, Bruni G, Fiaschi AI, Mariottini A: Passage of manni­ tol into the brain around gliomas: a potential cause of rebound phenomenon. A study on 21 patients. J Neurosurg Sci 50:63– 66, 2006  4. Wang M, Etu J, Joshi S: Enhanced disruption of the blood brain barrier by intracarotid mannitol injection during tran­ sient cerebral hypoperfusion in rabbits. J Neurosurg Anes­ thesiol 19:249–256, 2007 Please include this information when citing this paper: published online November 1, 2013; DOI: 10.3171/2013.6.JNS131197. ©AANS, 2014

Transcranial electrical stimulation and monitoring To The Editor: We read the article written by Ito et al.3 (Ito E, Ichikawa M, Itakura T, et al: Motor evoked potential monitoring of the vagus nerve with transcranial electrical stimulation during skull base surgeries. Clini­ cal article. J Neurosurg 118:195–201, January 2013). We agree with the idea of monitoring corticobulbar responses from laryngeal muscles after transcranial electric stimu­ lation (TES) during skull base surgery, but unfortunately we have major objections to the applied methodology in their article. Recording of laryngeal muscle responses using an en­ dotracheal tube with recording electrode embedded with­ in is an appropriate method when stimulating (mapping) the vagus nerve at the neck (superior or inferior laryngeal nerve). This method is mostly used during thyroidectomy. In these settings one can map a single nerve (laryngeal su­ perior or inferior nerve) and no other muscles are involved in recorded responses than laryngeal muscles. If the method of recording laryngeal activity (corti­ cobulbar response) is applied with an endotracheal tube after TES of the lateral part of the primary motor cortex, many muscles of the neck get activated in addition to the laryngeal muscles. Large surface electrodes of the endo­ tracheal tube can easily detect this activity. This can bring a false negative response (and laryngeal nerves could get damaged), but activity of surrounding muscle picked up by large surface electrodes of the endotracheal tube might mimic laryngeal responses.1 As an example, we show in Fig. 1 how TES activates tongue muscle innervated by the hypoglossal nerve and contaminates the corticobulbar responses recorded from mentalis muscle innervated by the facial nerve. This might occur if the recording is performed using large recording surfaces of electroencephalography (EEG) needle elec­ trodes, but not by very small recording surfaces of hook wire electrodes. The patient in Fig. 1 woke up with facial palsy, but still had response recorded with EEG needle electrodes. In this patient, far-field response from tongue muscle contributed to the amplitude of facial corticobul­ bar motor evoked potentials (MEPs) recorded in mentalis muscle. Dong et al.2 previously published a study showing that the methodology for eliciting corticobulbar responses 291

Neurosurgical forum in patients under general anesthesia includes delivering a short train of stimuli and comparing the response with the result after delivering a single TES (Fig. 1). This method allows one to distinguish between corticobulbar and pe­ ripheral responses. The peripheral responses elicited by a single stimulus are due to the activation of the peripheral part of the cranial nerves by the spreading of current de­ livered through the scalp. If the current spreads to the peripheral part of cranial nerves, the response should be present after a single TES as well as after a train of TES. When the corticobulbar tract is exclusively activated by a train of stimuli, a single stimulus applied transcranially will not elicit a response. Unfortunately, Ito and his colleagues did not follow this recommendation; therefore they cannot be sure about the origin of their recorded responses.

Isabel Fernández-Conejero, M.D. University Hospital of Bellvitge Barcelona, Spain Vedran Deletis, M.D., Ph.D. Institute for Neurology and Neurosurgery St Luke’s-Roosevelt Hospital New York, New York Disclosure

The authors report no conflict of interest. References  1. Bigelow DC, Patterson T, Weber R, Stecker MM, Judy K:

Comparison of endotracheal tube and hookwire electrodes for monitoring the vagus nerve. J Clin Monit 17:217–220, 2002  2. Dong CC, MacDonald DB, Akagamia R, Westerberg B, Alkhani A, Kanaan I, et al: Intraoperative facial motor evoked potential monitoring with transcranial electrical stimulation during skull base surgery. Clin Neurophysiol 116:588–596, 2005   3.  Ito E, Ichikawa M, Itakura T, Ando H, Matsumoto Y, Oda K, et al: Motor evoked potential monitoring of the vagus nerve with transcranial electrical stimulation during skull base surgery. Clinical article. J Neurosurg 118:195–201, 2013

Response: We would like to thank Dr. FernandezConejero and Dr. Deletis for their interest in and com­ ments regarding our article. As Dr. Fernandez-Conejero has mentioned in the letter, the methodology used for monitoring cranial nerves is important and should be re­ producible. During TES, the stimulation is not restricted to the primary motor cortex because a relatively high-in­ tensity stimulus is necessary to overcome skin and skull impedance, and this leads to current spread. In TES, many muscle groups are simultaneously ac­ tivated because the motor cortex is widely stimulated. Therefore, if the target muscle is not appropriately select­ ed at the recording site, a far-field response may produce a false-negative result. We agree that recording using a hook wire instead of an EEG needle is theoretically a more preferable way of eliminating the far-field response at a recording site on the target muscle. According to the paper by Bigelow et al.,2 recordings obtained from the endotracheal tube by using bipolar hook wire electrodes

Fig. 1.  Corticobulbar motor evoked potentials recorded from mentalis muscle after TES of the motor cortex in a patient with a vestibular schwannoma.  A: Axial MR image showing a right vestibular schwannoma.  B: Facial corticobulbar MEPs recorded with hook wire electrodes from mentalis muscle. The facial nerve was accidentally damaged during surgery and facial corticobulbar MEPs disappeared (closing).  C: Facial corticobulbar MEPs recorded with an EEG needle from mentalis muscle. After damaging the facial nerve there is still a recordable response (asterisk), which is a far-field response that belongs to surrounding muscles such as the tongue (closing).

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Neurosurgical forum are useful in surgery, because these recordings have max­ imum sensitivity. Therefore, recordings obtained using endotracheal tube electrodes may contain the far-field re­ sponse evoked by the laryngeal response. Although we do not believe that neck muscles surrounding the vocal cord are activated in our method, we would need to conduct further studies to verify this. The onset latency by current spread to the peripheral part of cranial nerves is shorter than the onset latency by TES by approximately 4–5 msec. The onset latency ob­ served in our study (12.4 ± 1.8 msec) was longer than the onset latency observed with direct nerve stimulation, and was similar to the onset latency observed with direct cor­ tical stimulation (13.97 ± 1.11 msec).3 On the basis of these data, we have performed intraoperative monitoring. De­ pending on the duration of onset latency, we can confirm the presence or absence of current spread. In patients with short-onset latency, we have always performed single TES and have ensured the absence of current spread. In addition, high-frequency multiple TES may di­ rectly stimulate the extracranial segment of cranial nerves because of current spread, without conduction through the corticobulbar tract (CBT).1 Reduced electrical in­ tensity can reduce the problems associated with current spread.4 In the present study, the motor cortex was stimu­ lated at 20% above the threshold level, and this may have helped reduce current spread. Therefore, our method for CBT monitoring was effective and did not lead to current spread. Eiji Ito, M.D., Ph.D. Chubu Rosai Hospital Nagoya, Japan Takeshi Itakura, B.S. Kiyoshi Saito, M.D., Ph.D. Fukushima Medical University Fukushima, Japan

References   1.  Akagami R, Dong CC, Westerberg BD: Localized transcra­ nial electrical motor evoked potentials for monitoring cranial nerves in cranial base surgery. Neurosurgery 57 (1 Suppl): 78–85, 2005  2. Bigelow DC, Patterson T, Weber R, Stecker MM, Judy K: Comparison of endotracheal tube and hookwire electrodes for monitoring the vagus nerve. J Clin Monit 17:217–220, 2002   3.  Deletis V, Fernández-Conejero I, Ulkatan S, Rogić M, Carbó EL, Hiltzik D: Methodology for intra-operative recording of the corticobulbar motor evoked potentials from cricothyroid muscles. Clin Neurophysiol 122:1883–1889, 2011   4.  Goto T, Muraoka H, Kodama K, Hara Y, Yako T, Hongo K: Intraoperative monitoring of motor evoked potential for the facial nerve using a cranial peg-screw electrode and a “thresh­ old-level” stimulation method. Skull Base 20:429–434, 2010 Please include this information when citing this paper: published online November 8, 2013; DOI: 10.3171/2013.6.JNS131278. ©AANS, 2014

Effects of erythropoietin To The Editor: We read with great interest the article J Neurosurg / Volume 120 / January 2014

by Tseng et al.18 (Tseng MY, Hutchinson PJ, Richards HK, et al: Acute systemic erythropoietin therapy to reduce de­ layed ischemic deficits following aneurysmal subarach­ noid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. Clinical article. J Neurosurg 111:171–180, July 2009). In the study of Tseng et al., erythropoietin (EPO) was considered to be beneficial in the early phase of treatment for patients with aneurysmal subarachnoid hemorrhage (aSAH), which was indicated by the p value 0.039 comparing the favorable Glasgow Outcome Scale (GOS) score with the unfavorable GOS score, using the Pearson chi-square test.14 But by using a more accurate method (the Fisher’s exact text5), one can calculate that the p value is 0.066 above 0.05. So the im­ provement in GOS score in the EPO group was not sig­ nificant compared with that in the placebo group. Subarachnoid hemorrhage is one of the neurosurgi­ cal emergencies with high rates of deaths and complica­ tions, and aSAH accounts for 80% of SAH.17 Until now, cerebral vasospasm, which can lead to delayed cerebral ischemia or even cerebral infarction, has been consid­ ered the primary cause of morbidity and death following SAH.6,10 Although today’s technology, such as aneurysm clipping and endovascular treatment, can effectively con­ trol bleeding and prevent rebleeding, delayed cerebral vasospasm—usually occurring approximately 4–9 days after aSAH—still has a serious impact on the prognosis of patients.8,15,21 Recently, whether or not EPO has neuroprotective ef­ fects has become a hot topic of research.11 In experimental research, EPO has been shown to play a protective role in ischemic vascular injury by activating the EPO receptor, Akt1, and mitochondrial modulation,3,4 or by avoiding the neuronal death mediated by nitric oxide and cathepsin.13 Moreover, a meta-analysis and a systemic review have confirmed the efficacy of EPO in an animal model of is­ chemia.7,12 However, the effect of EPO on patients with delayed cerebral vasospasm or cerebral infarction follow­ ing aSAH has not been clear. There are 3 possible main reasons that EPO treatment was not superior to placebo, which are also supported by the study of Tseng et al.18 One reason could be the dose of the EPO. The reported maximum dose of EPO providing the neuroprotective effect in animal experiments was 450 IU/kg during each 48-hour period,3 but in clinical trials the dose of EPO was not confirmed in a small range but in a wide range.16 So we conjecture that the dose of EPO would affect the prognosis of clinical patients, which has been reported in animal experiments.19 Another possible reason is that, to remit the delayed cerebral vasospasm and cerebral infarction, the time window of EPO intervention should be limited. As mentioned previously, delayed ce­ rebral vasospasm usually occurs approximately 4–9 days after aSAH,8,15,21 but the early studies reported that the time until EPO took effect was more than 3 days,3,20 so the earlier or later treatment might be ineffective. The fi­ nal possible reason is that the neuroprotective effect of EPO could be hindered by calcium channel blockers.9 Ni­ modipine, a common calcium antagonist, must be used in patients with aSAH to alleviate cerebral vasospasm, based on the treatment guidelines of SAH, because it is 293

Neurosurgical forum the only confirmed effective drug;1,2 as a result, the role of EPO in neuroprotection may be interfered with.

Ying-li Gu, Ph.D.1,2 Zhong-xin Zhao, Ph.D.2 1 The Fourth Affiliated Hospital of Harbin Medical University Harbin, China 2 West China Hospital Chengdu, Sichuan Province, China Disclosure The authors report no conflict of interest. References

  1.  Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, et al: Guidelines for the management of aneu­ rysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Coun­ cil, American Heart Association. Stroke 40:994–1025, 2009   2.  Biondi A, Ricciardi GK, Puybasset L, Abdennour L, Longo M, Chiras J, et al: Intra-arterial nimodipine for the treat­ ment of symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage: preliminary results. AJNR Am J Neuroradiol 25:1067–1076, 2004   3.  Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, et al: Erythropoietin crosses the blood-brain bar­ rier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97:10526–10531, 2000   4.  Chong ZZ, Kang JQ, Maiese K: Erythropoietin is a novel vas­ cular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation 106:2973–2979, 2002   5.  Fisher R: On the interpretation of chi-square from contingen­ cy tables, and the calculation of P. J Roy Stat Soc 85:87–94, 1922   6.  Heros RC, Zervas NT, Varsos V: Cerebral vasospasm after sub­ arachnoid hemorrhage: an update. Ann Neurol 14:599–608, 1983  7. Jerndal M, Forsberg K, Sena ES, Macleod MR, O’Collins VE, Linden T, et al: A systematic review and meta-analysis of erythropoietin in experimental stroke. J Cereb Blood Flow Metab 30:961–968, 2010  8. Kassell NF, Torner JC, Haley EC Jr, Jane JA, Adams HP, Kongable GL: The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: overall management re­ sults. J Neurosurg 73:18–36, 1990   9.  Koshimura K, Murakami Y, Sohmiya M, Tanaka J, Kato Y: Ef­ fects of erythropoietin on neuronal activity. J Neurochem 72: 2565–2572, 1999

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10.  Kosty T: Cerebral vasospasm after subarachnoid hemorrhage: an update. Crit Care Nurs Q 28:122–134, 2005 11.  Kumral A, Tuzun F, Oner MG, Genç S, Duman N, Ozkan H: Erythropoietin in neonatal brain protection: the past, the pres­ ent and the future. Brain Dev 33:632–643, 2010 12.  Minnerup J, Heidrich J, Rogalewski A, Schäbitz WR, Wellmann J: The efficacy of erythropoietin and its analogues in animal stroke models: a meta-analysis. Stroke 40:3113–3120, 2009 13.  Ozden H, Durmaz R, Kanbak G, Uzuner K, Aral E, Kartkaya K, et al: Erythropoietin prevents nitric oxide and cathepsinmediated neuronal death in focal brain ischemia. Brain Res 1370:185–193, 2011 14.  Pearson K: On the criterion that a given system of deviations from the probable in the case of a correlated system of vari­ ables is such that it can be reasonably supposed to have arisen from random sampling. Phil Mag 50:157–175, 1900 15.  Pluta RM, Hansen-Schwartz J, Dreier J, Vajkoczy P, Mac­ donald RL, Nishizawa S, et al: Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought. Neurol Res 31:151–158, 2009 16.  Springborg JB, Moller C, Gideon P, Jørgensen OS, Juhler M, Olsen NV: Erythropoietin in patients with aneurysmal sub­ arachnoid haemorrhage: a double blind randomised clinical trial. Acta Neurochir (Wien) 149:1089–1101, 2007 17.  Suarez JI, Tarr RW, Selman WR: Aneurysmal subarachnoid hemorrhage. N Engl J Med 354:387–396, 2006 18.  Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pick­ ard JD, Erber WN, et al: Acute systemic erythropoietin ther­ apy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, doubleblind, placebo-controlled trial. Clinical article. J Neurosurg 111:171–180, 2009 19.  Ulusal I, Tari R, Ozturk G, Aycicek E, Aktar F, Kotil K, et al: Dose-dependent ultrastructural and morphometric alterations after erythropoietin treatment in rat femoral artery vasospasm model. Acta Neurochir (Wien) 152:2161–2166, 2010 20.  Wang L, Zhang Z, Wang Y, Zhang R, Chopp M: Treatment of stroke with erythropoietin enhances neurogenesis and an­ giogenesis and improves neurological function in rats. Stroke 35:1732–1737, 2004 21.  Weir B, Grace M, Hansen J, Rothberg C: Time course of vaso­ spasm in man. J Neurosurg 48:173–178, 1978

Response: No response was received from the au­ thors of the original article. Please include this information when citing this paper: published online November 1, 2013; DOI: 10.3171/2012.2.JNS12122. ©AANS, 2014

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