NEUROSURGERY TABLE OF CONTENTS BY TOPIC MARCH 2007 VOLUME 60 NUMBER 3 Pages 417–587 Articles are grouped by categories, complete author listings can be found on preceding Table of Contents ANATOMY NEUROPSYCHOLOGY 563 Lancisi’s Nerves and the Seat of the Soul: Antonio Di leva 434 Coiling versus Clipping for the Treatment of Aneurysmal Subarachnoid Hemor- CEREBROVASCULAR rhage: A Longitudinal Investigation into Cognitive Outcome: Duncan Frazer 434 Coiling versus Clipping for the Treatment of Aneurysmal Subarachnoid Hemor- NEUROPROTECTION rhage: A Longitudinal Investigation into Cognitive Outcome: Duncan Frazer 546 Treatment of Traumatic Brain Injury with a Combination Therapy of Marrow 443 Embolization Before Radiosurgery Reduces the Obliteration Rate of Stromal Cells and Atorvastatin in Rats: Asim Mahmood Arteriovenous Malformations: Yuri M. Andrade-Souza NEURORESTORATION 453 Radiosurgery to Reduce the Risk of First Hemorrhage from Brain 417 Rebuilding Lost Hearing using Cell Transplantation: Tetsuji Sekiya Arteriovenous Malformations: Keisuke Maruyama 546 Treatment of Traumatic Brain Injury with a Combination Therapy of Marrow 483 Extradural Transcavernous Approach to Cavernous Sinus Hemangiomas: Stromal Cells and Atorvastatin in Rats: Asim Mahmood Ashish Suri 497 Evaluation and Treatment of Patients with Suspected Normal Pressure Hydro- PAIN cephalus on Long-term Warfarin Anticoagulation Therapy: C. Rory Goodwin 580 CyberKnife Targeting the Pterygopalatine Ganglion for the Treatment of Chronic Cluster Headaches: Shivanand P. Lad 511 Color Intensity Projection of Digitally Subtracted Angiography for the Visualization of Brain Arteriovenous Malformations: Keith S. Cover RADIOSURGERY 531 p53 May Play an Orchestrating Role in Apoptotic Cell Death after 443 Embolization Before Radiosurgery Reduces the Obliteration Rate of Experimental Subarachnoid Hemorrhage: Julian Cahill Arteriovenous Malformations: Yuri M. Andrade-Souza 569 An Astroblastoma Mimicking a Cavernous Malformation: Case Report: 453 Radiosurgery to Reduce the Risk of First Hemorrhage from Brain Luis M. Tumialán Arteriovenous Malformations: Keisuke Maruyama 572 Giant, Partially Thrombosed Aneurysm Develops after Remote Angiographically 460 Stereotactic Radiosurgery for Vestibular Schwannomas in Patients with Negative Subarachnoid Hemorrhage: Case Report: Udaya K. Kakarla Neurofibromatosis Type 2: An Analysis of Tumor Control, Complications, 577 Adjunctive Rheolytic Thrombectomy for Central Venous Sinus Thrombosis: and Hearing Preservation Rates: David Mathieu Technical Case Report: Jacobo Kirsch 471 Gamma Knife Radiosurgery in the Management of Malignant Melanoma 579 Hyperbaric Oxygen in the Treatment of a Radiosurgical Complication: Brain Metastases: David Mathieu Technical Case Report: Michael Lynn 579 Hyperbaric Oxygen in the Treatment of a Radiosurgical Complication: COMPLICATIONS Technical Case Report: Michael Lynn 497 Evaluation and Treatment of Patients with Suspected Normal Pressure Hydro- 580 CyberKnife Targeting the Pterygopalatine Ganglion for the Treatment of cephalus on Long-term Warfarin Anticoagulation Therapy: C. Rory Goodwin Chronic Cluster Headaches: Shivanand P. Lad 579 Hyperbaric Oxygen in the Treatment of a Radiosurgical Complication: SPINE Technical Case Report: Michael Lynn 503 Minimally Invasive Lumbar Spinal Decompression in the Elderly: Outcomes of CRAINAL BASE 50 Patients Aged 75 Years and Older: David S. Rosen 483 Extradural Transcavernous Approach to Cavernous Sinus Hemangiomas: 516 Litigation of Missed Cervical Spine Injuries in Patients Presenting with Blunt Ashish Suri Traumatic Injury: Gregory P. Lekovic ENDOVASCULAR 575 Acute Presentation of Spinal Epidural Cavernous Angiomas: Case Report: 434 Coiling versus Clipping for the Treatment of Aneurysmal Subarachnoid Hemor- Giuseppe Caruso rhage: A Longitudinal Investigation into Cognitive Outcome: Duncan Frazer SPORT 443 Embolization Before Radiosurgery Reduces the Obliteration Rate of 490 In Vivo Study of Head Impacts in Football: A Comparison of National Collegiate Arteriovenous Malformations: Yuri M. Andrade-Souza Athletic Association Division I versus High School Impacts: Brock Schnebel 577 Adjunctive Rheolytic Thrombectomy for Central Venous Sinus Thrombosis: STEREOTAXY Technical Case Report: Jacobo Kirsch 443 Embolization Before Radiosurgery Reduces the Obliteration Rate of HYDROCEPHALUS Arteriovenous Malformations: Yuri M. Andrade-Souza 497 Evaluation and Treatment of Patients with Suspected Normal Pressure Hydro- 453 Radiosurgery to Reduce the Risk of First Hemorrhage from Brain cephalus on Long-term Warfarin Anticoagulation Therapy: C. Rory Goodwin Arteriovenous Malformations: Keisuke Maruyama IMAGING 460 Stereotactic Radiosurgery for Vestibular Schwannomas in Patients with 511 Color Intensity Projection of Digitally Subtracted Angiography for the Neurofibromatosis Type 2: An Analysis of Tumor Control, Complications, Visualization of Brain Arteriovenous Malformations: Keith S. Cover and Hearing Preservation Rates: David Mathieu 524 Quantum Dots are Phagocytized by Macrophages and Colocalize with 471 Gamma Knife Radiosurgery in the Management of Malignant Melanoma Experimental Gliomas: Heather Jackson Brain Metastases: David Mathieu INFECTION 579 Hyperbaric Oxygen in the Treatment of a Radiosurgical Complication: 571 Cerebellar Cryptococcoma in a Patient with Undiagnosed Sarcoidosis: Technical Case Report: Michael Lynn Case Report: Charles W. Kanaly 580 CyberKnife Targeting the Pterygopalatine Ganglion for the Treatment of LEGACY Chronic Cluster Headaches: Shivanand P. Lad 555 Evolution of the Human Brain: Changing Brain Size and the Fossil Record: SURGICAL APPROACH Min S. Park 483 Extradural Transcavernous Approach to Cavernous Sinus Hemangiomas: 563 Lancisi’s Nerves and the Seat of the Soul: Antonio Di leva Ashish Suri MEDICOLEGAL SURGICAL TECHNIQUE 516 Litigation of Missed Cervical Spine Injuries in Patients Presenting with Blunt 580 CyberKnife Targeting the Pterygopalatine Ganglion for the Treatment of Traumatic Injury: Gregory P. Lekovic Chronic Cluster Headaches: Shivanand P. Lad MICROVASCULAR TRAUMA 434 Coiling versus Clipping for the Treatment of Aneurysmal Subarachnoid Hemor- 490 In Vivo Study of Head Impacts in Football: A Comparison of National Collegiate rhage: A Longitudinal Investigation into Cognitive Outcome: Duncan Frazer Athletic Association Division I versus High School Impacts: Brock Schnebel MINIMALLY INVASIVE 516 Litigation of Missed Cervical Spine Injuries in Patients Presenting with Blunt 503 Minimally Invasive Lumbar Spinal Decompression in the Elderly: Outcomes of Traumatic Injury: Gregory P. Lekovic 50 Patients Aged 75 Years and Older: David S. Rosen 546 Treatment of Traumatic Brain Injury with a Combination Therapy of Marrow MOLECULAR BIOLOGY Stromal Cells and Atorvastatin in Rats: Asim Mahmood 579 Hyperbaric Oxygen in the Treatment of a Radiosurgical Complication: TUMOR Technical Case Report: Michael Lynn 460 Stereotactic Radiosurgery for Vestibular Schwannomas in Patients with MOLECULAR & CELLULAR BIOLOGY Neurofibromatosis Type 2: An Analysis of Tumor Control, Complications, 417 Rebuilding Lost Hearing using Cell Transplantation: Tetsuji Sekiya and Hearing Preservation Rates: David Mathieu 524 Quantum Dots are Phagocytized by Macrophages and Colocalize with 471 Gamma Knife Radiosurgery in the Management of Malignant Melanoma Experimental Gliomas: Heather Jackson Brain Metastases: David Mathieu 531 p53 May Play an Orchestrating Role in Apoptotic Cell Death after 483 Extradural Transcavernous Approach to Cavernous Sinus Hemangiomas: Experimental Subarachnoid Hemorrhage: Julian Cahill Ashish Suri 546 Treatment of Traumatic Brain Injury with a Combination Therapy of Marrow 524 Quantum Dots are Phagocytized by Macrophages and Colocalize with Stromal Cells and Atorvastatin in Rats: Asim Mahmood Experimental Gliomas: Heather Jackson MOLECULAR & CELLULAR NEUROSURGERY 569 An Astroblastoma Mimicking a Cavernous Malformation: Case Report: 417 Rebuilding Lost Hearing using Cell Transplantation: Tetsuji Sekiya Luis M. Tumialán 546 Treatment of Traumatic Brain Injury with a Combination Therapy of Marrow 574 Intracavernous Trigeminal Ganglion Amyloidoma: Case Report: Stromal Cells and Atorvastatin in Rats: Asim Mahmood Markus J. Bookland NANONEUROSURGERY VASCULAR 524 Quantum Dots are Phagocytized by Macrophages and Colocalize with 575 Acute Presentation of Spinal Epidural Cavernous Angiomas: Case Report: Experimental Gliomas: Heather Jackson Giuseppe Caruso

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REBUILDING LOST HEARING USING CELL TRANSPLANTATION

Tetsuji Sekiya, M.D. OBJECTIVE: The peripheral auditory nervous system (cochlea and auditory nerve) has Departments of Otolaryngology a complex anatomy, and it has traditionally been thought that once the sensorineural and Head and Neck Surgery, structures are damaged, restoration of hearing is impossible. In the past decade, how- Kyoto University Graduate School of Medicine, ever, the potential to restore lost hearing has been intensively investigated using molec- Kyoto, Japan ular and cell biological techniques, and we can now part with such a pessimistic view. In this review, we examine an important field in hearing restoration research: cell trans- Ken Kojima, M.D. plantation. Departments of Otolaryngology, Head and Neck Surgery, METHODS: Most efforts in this field have been directed to the replacement of hair cells and Establishment of International by transplantation to the cochlea. Here, we focus on transplantation to the auditory Center of Excellence for Integration nerve, from the side of the cerebellopontine angle rather than the cochlea. of Transplantation Therapy and Regenerative Medicine, RESULTS: Delivery of cells to the cochlea is potentially damaging, and nerve cells trans- Kyoto University Graduate planted distally to the Schwann-glial transitional zone (cochlear side) may become School of Medicine, inhibited when they reach the transitional zone. The auditory nerve is probably the Kyoto, Japan most suitable route for cell transplantation. Masahiro Matsumoto, M.D. CONCLUSION: The auditory nerve occupies an important position not only in neuro- Departments of Otolaryngology surgery but also in various diseases in other disciplines, and several lines of recent evi- and Head and Neck Surgery, dence indicate that it is a key target for hearing restoration. It is familiar to most neu- Kyoto University Graduate School of Medicine, rosurgeons, and the recent advances in the molecular and cell biology of inner-ear Kyoto, Japan development are of direct importance to neurorestorative medicine. In this article, we review the anatomy, development, and molecular biology of the auditory nerve and Matthew C. Holley, Ph.D. cochlea, with emphasis on the advances in cell transplantation. Department of Biomedical Sciences, KEY WORDS: Auditory nerve, Auditory neurons, Cell transplantation, Embryonic stem cells, Hair cells, The University of Sheffield, Sheffield, England Hearing restoration, Neural stem cells, Spiral ganglion cells

Neurosurgery 60:417–433, 2007 DOI: 10.1227/01.NEU.0000249189.46033.42 www.neurosurgery-online.com Juichi Ito, M.D. Departments of Otolaryngology and Head and Neck Surgery, Kyoto University Graduate “Progress in science depends on new techniques, implant technology, molecular biology, and School of Medicine, new discoveries, and new ideas, probably in that stem cell biology have established the poten- Kyoto, Japan order.” tial to restore lost hearing, and we can now Reprint requests: —Sydney Brenner part with such a pessimistic view. Regenera- Tetsuji Sekiya, M.D., tive strategies broadly include gene therapy, Departments of Otolaryngology he auditory nervous system is far more drug treatment, and cell transplantation, all of and Head and Neck Surgery, complex than other sensory nervous sys- which are being explored in the auditory sys- Kyoto University Graduate tems (117). The sensorineural structures tem (62, 63). All avenues should be pursued School of Medicine, T Sakyou-ku, Kyoto, 606–8507 Japan. within the mammalian cochlea, including the because it is likely that future success will Email: [email protected] sensory hair cells and the auditory nerve, have depend on a combination of treatments, such evolved into a highly sophisticated mechano- as gene transfection combined with delivery Received, October 4, 2005. electrical mechanism for processing sound (49, of growth factors. In this review, we focus Accepted, July 29, 2006. 50, 68). Unfortunately, these structures have a specifically on the progress and potential for predilection for mechanical and ototoxic dam- cell transplantation to replace auditory neu- age (154, 163, 165), and it has traditionally rons and sensory hair cells. been thought that once they are damaged, Cell transplantation is simple in principle, restoration of hearing is impossible. In the but, in reality, it is an extremely complex past decade, however, advances in cochlear process that requires a highly structured

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approach for accurate interpretation of experimental data peripheral nerve toward the spinal cord or brainstem abruptly (98, 205). stop when they meet the astrocytes in the central nervous sys- First, it is important to establish that cell replacement will tem (CNS) (14, 19, 44). Thus, the cells transplanted to the solve the clinical problem. For example, mutations in gap- cochlear side into the portion of the auditory nerve distal to the junction proteins lead to hair-cell loss and account for half of Schwann-glial transitional zone (TZ) may become inhibited the genetic forms of deafness (183), but hair cells do not express when they reach the TZ. We emphasize that this biological phe- these molecules, and replacing them will not reduce the asso- nomenon makes the auditory nerve the most suitable route ciated hearing loss. Knowledge of the biology of the system is and host for cell transplantation. a key factor in understanding the potential of the therapy. Second, the origin and conditioning of the donor cells used Anatomy of the Cochlea and Auditory Neurons for transplantation is critical and introduces a substantial source of variation between experiments. There are many dif- Overview ferent types of stem cells, including those from embryonic and The auditory nerve includes a bundle of bipolar auditory tissue-specific sources (94). Such cells can be conditioned, for neurons (spiral ganglion neurons) whose cell bodies are situ- example, by culture media containing growth factors known to ated in Rosenthal’s canal in the temporal bone (Fig. 1). The influence cell differentiation during development or by trans- axons (central processes) of the auditory neurons are observed fection with transcription factors necessary for cell differentia- in the CPA and are called the auditory nerve or, clinically, the tion. This approach demands detailed knowledge of normal cochlear nerve. They project to second-order neurons in the developmental processes and the key regulatory molecules that cochlear nuclei, which are located within the brainstem. The guide differentiation of each cell type. dendrites (peripheral processes) project to the hair cells in the Third, techniques for cell delivery must take account of the cochlea (Fig. 1). anatomy and molecular environment to ensure that donor Approximately 92% of auditory neurons are classed as cells are able to reach the target sites with minimal damage to Type 1 and approximately 8% are classed as Type 2 (150) host tissues. (Fig. 2). Ten to 20 Type 1 neurons converge on each inner Fourth, the state of the host tissue determines the environ- hair cell. In contrast, each Type 2 auditory neuron contacts ment into which donor cells are delivered. Some degeneration about 30 to 60 outer hair cells (Fig. 2) (150). Hearing sensation or damage may be necessary to induce a positive response is derived from the output of a remarkably small number of from donor cells (52, 169), but advanced degenerative states hair cells: fewer than 16,000 in each human inner ear. These may mean that there are few endogenous factors left to stimu- hair cells are mechanoelectrical transducers. Vibration of the late appropriate responses from donor cells (169). basilar membrane deflects the apical stereociliary hair bun- These four major issues encompass a substantial number of dles and generates receptor potentials that modulate spiking variables that might affect the outcome of a transplantation activity in the afferent auditory nerve fibers (68). Although experiment, and it is imperative to regulate as many as possible inner hair cells are the primary sensory receptors, outer hair if we are to develop systematic progress towards a therapeutic cells can convert their receptor potentials into cell-length application. One of the most important elements for progress is changes that can enhance the tuning properties of the basilar a group of well-characterized model systems with which to test membrane and consequently of the inner hair-cell responses the functional outcome of an experiment. We are fortunate in (158). Efferent innervation by fibers from the olivary nucleus having several excellent mammalian models for the loss of hair caudally and the dorsal nucleus of the trapezoid body ros- cells (25, 27, 42) and auditory neurons (162, 165). trally also provide regulation of the sensitivity of the inner Most work in the inner ear to date has focused on the and outer hair cells (181). Inner and outer hair cells are replacement of hair cells by transplantation of various types of organized with extraordinary precision along the cochlea and donor cells directly into the cochlea. We highlight the potential are separated from one another by the processes of nonex- for auditory neuronal-cell transplantation through the audi- citable supporting cells (Fig. 3). These supporting cells have tory nerve from the side of the cerebellopontine angle (CPA). highly specialized structural properties that ensure efficient There are several reasons for this emphasis. Auditory neurons mechanical coupling between the hair cells and the basilar are implicated not only in neurosurgical diseases but also in membrane. various diseases in other disciplines (4, 53, 56, 130, 133, 159, The driving force for mechanoelectrical transduction in hair 164–168, 170–178, 189, 217). Thus, recent advances in auditory cells comes from a specialized gradient of potassium ions gen- research are of direct importance to neurosurgeons performing erated between three fluid-filled chambers, called scalae, con- surgery in the CPA, where the auditory nerve resides (74, 129, taining either endolymph or perilymph (Fig. 1). The hair cells 157). Furthermore, auditory neuronal cells suitable for trans- occupy a critical position at the boundary between the scala plantation can be cultured in vitro (123, 141), and there are media, which contains endolymphatic fluid rich in potassium suitable animal models on which to test ability for regenerating ions, and the scala tympani, which contains perilymphatic fluid the auditory nerve (162, 165). Finally, rebuilding the damaged that is rich in sodium ions and similar to cerebrospinal fluid auditory nervous system as a whole is most likely to be accom- (199). The differential ionic composition of these fluids helps to plished from the side of the CPA. Growing axons from the generate the endocochlear potential, which drives potassium

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FIGURE 1. Basic anatomy of the auditory nerve, cochlea, and surrounding implants (CI) and auditory brainstem implants (ABIs). CA, cochlear aque- structures. The auditory nerve is a bundle of bipolar auditory neurons. The duct; ELS, endolymphatic sac; HC, hair cells; IAC, internal auditory canal; axons connect with the cochlear nucleus cells, and the dendrites connect VA, vestibular aqueduct. Inset, three-dimensional representation of tempo- with the hair cells. Previously reported approaches to transplant cells into ral bone. The area indicated by the dotted rectangle is detailed in Figure the membranous labyrinth (A–D) where the membranes enclosing fluid- 3 (adapted from, Sekiya T, Kojima K, Matsumoto M, Kim TS, Tamura T, filled spaces (endo- or perilymphatic spaces) are mechanically breached. Ito J: Cell transplantation to the auditory nerve and cochlear duct. Exp Thick black arrows indicate the site for electrical stimulations for cochlear Neurol 198:12–24, 2006 [169]). ions through mechanotransduction channels in the hair bun- enveloped in endoneurium (44). The interface is penetrated dles (199). If the endocochlear potential is compromised, either only by axons (44), and it acts as an intractable barrier for by natural degenerative processes or by mechanical damage to regenerating processes from the peripheral side toward the the membranes sealing the scalae, then transduction cannot central side. However, cells or projections coming from the cen- occur, and hearing fails. Replacement of hair cells or neurons tral side can pass the TZ (3, 44, 124), which is a crucial factor in would not solve this kind of hearing loss. planning cell transplantation.

The TZ of the Auditory Nerve Auditory Neurons in Clinical Medicine The myelination and external milieu of the peripheral and central projections of the cranial nerves are different, and, in the Auditory Neurons in Neurosurgery auditory nerve, the central projection is long (193). The inter- The auditory neurons hold a unique position clinically (56, face between the peripheral nervous system and the CNS por- 164–168, 170–179, 211). They are often exposed in the CPA dur- tions is called the TZ or the Obersteiner-Redlich zone (127, ing surgery for cranial-based lesions, such as vestibular 171). It can be clearly identified under the light microscope schwannomas, and for microvascular decompression proce- (Fig. 4). Centrally from the TZ, myelin sheaths are formed by dures for hemifacial spasm and trigeminal neuralgia (74, 81, oligodendrocytes, and the supporting tissue is astrocytic. 129, 157). In these situations, the axons may receive direct trau- Peripherally, the sheaths are formed by Schwann cells that are matic stress and any residual hearing of the patients may be

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FIGURE 3. Hair cells and supporting cells. The hair cells are buffered from FIGURE 2. Innervation pattern of two types of auditory neurons to inner and one another by the processes of nonexcitable supporting cells, and, conse- outer hair cells. There are two types in auditory neurons, Type 1 and 2. quently, an alternating cell pattern between hair cells and supporting cells is Approximately 92% of auditory neurons are Type 1 and approximately 8% of taken. Vibration of the basilar membrane causes deflections of the stereociliary auditory neurons are Type 2. Ten to 20 Type 1 neurons converge on each bundles on the hair cells apices and then transmitter release from the hair cell inner hair cell. In contrast, each Type 2 auditory neuron contacts about 30 to bases, leading to generation of action potentials in the auditory nerve fibers. 60 outer hair cells. The outer hair cells actively produce amplification or attenuation of the response of the inner hair cells. The supporting cells could play important roles endangered (165). Especially in treating bilateral vestibular in hair cell regeneration. schwannomas in neurofibromatosis II (NF2), such traumatic stress can cause total hearing loss (165), which, in the middle of life, imposes a formidable burden on these patients. In vestibular schwannomas, given the site of origin near the auditory nerve in the CPA, primary degeneration of the audi- tory nerve is intuitively logical as a cause of hearing loss; this has been histopathologically verified (12, 32, 35, 75, 191). Dysfunction at the level of the organ of Corti also contributes to hearing loss (136, 191). This is probably caused by vascular compromise attributable to compression of the internal audi- PM tory artery (106), together with alteration in inner-ear fluid, accumulation of toxic materials, changes in intralabyrinthine pressure, and loss of efferent tuning (9, 35, 126, 136, 191). Interestingly, in patients with vestibular schwannoma, there is a tendency for the hair cells to remain undamaged despite CM profound degeneration of the auditory neurons (106, 132, 191). This means that in vestibular schwannoma patients, especially those with smaller vestibular schwannomas, in whom the hair A cells are assumed to be well preserved, reconstruction of the auditory nerve may provide the chance to recover from hearing loss. Therefore, it is worth investigating whether or not audi- tory nerve regeneration can establish synaptic contacts with remaining hair cells distally (110) and with the cochlear nucleus cells proximally in patients with vestibular schwannoma. FIGURE 4. TZ of the auditory nerve (rat, hematoxylin and eosin stain). The CNS portion of the auditory nerve (A) extends peripherally, taking a domelike Auditory Neurons in Other Disciplines shape (arrowheads). Then, the interface between the peripheral myelin (PM) Most types of congenital and acquired hearing loss arise portion and central myelin (CM) portion of the auditory neurons can be clearly identified and called the TZ or the Obersteiner-Redlich zone (arrow- from damage to, or loss of, cochlear hair cells and/or their heads). Note that the Rosenthal’s canals are densely packed with the auditory associated auditory neurons (30, 111). However, selective ganglion cells (arrows). The TZ becomes an intractable barrier for regenerat- degeneration of auditory neurons with relative retention of hair ing neurites from the peripheral side toward the central side. Scale bar, 200 cells is observed in various clinical disorders, such as heredi- µm (adapted from, Sekiya T, Kojima K, Matsumoto M, Kim TS, Tamura T, tary sensorimotor neuropathy, formerly known as Charcot- Ito J: Cell transplantation to the auditory nerve and cochlear duct. Exp Neurol Marie-Tooth disease (10, 133, 138), Friedreich’s ataxia (159, 185), 198:12–24, 2006 [169]).

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Mohr-Tranebjaerg syndrome (112), Refsum’s disease (130), the most cases, it is associated with loss of hair cells (116). mitochondrial disorders (222), and others (122, 198). Some of Ototoxic drugs and acoustic overstimulation may also injure these disorders are caused by myelin protein gene mutations the hair cells primarily (48). Outer hair cells seem to be more (17, 20, 31). Recently, such clinical and pathological conditions sensitive than inner hair cells, and they tend to be lost first were described as auditory neuropathy, characterized by (48). The high-frequency end of the cochlea is also more sen- abnormal auditory nerve function. The diagnosis is verified as sitive than the low-frequency end. For example, after amino- absent or profoundly distorted auditory brainstem responses in glycoside treatment, outer hair cells at the base of the the presence of normal outer hair cell activity, which is detected cochlea are lost, and, with continued drug treatment, the by preserved otoacoustic emissions and/or cochlear micro- damage progresses toward the apex (43). Inner hair cells are phonics (188, 189). more resistant than outer hair cells, and their demise is gen- A dissociated behavior between the auditory neurons and erally seen only after outer hair cells in their immediate the hair cells is contrasted with the intimate relationships vicinity have been lost (43). In neurosurgical practice, cis- between the auditory neurons and the cochlear nucleus cells, platin is an indispensable antitumorant for the treatment of where the input from the auditory neurons is indispensable some types of pineal region tumors (18, 37), but this agent for the development of the cochlear nucleus cells (150). Hair may cause hair-cell damage (111, 192). Under conditions in cells can differentiate autonomously and can acquire their nor- which the primary lesion site is the hair cell, replenishment mal specialized physiological properties in the absence of audi- of lost hair cells by regeneration or cell transplantation tory neurons (57, 152, 184). In Atoh1-null mutants, which lack should lead to recovery of hearing. hair cells, the branches of the VIIIth cranial nerve reached the Collectively, it may be worthwhile to combine cell- hair-cell epithelial regions, indicating that some aspects of transplantation therapy for auditory neurons with that for hair pathfinding by auditory neurons is not mediated by hair cells cells to widen the possibility of cell-transplantation therapy for (13). In mice that lack sensory neurons as a result of a null rebuilding lost hearing. Despite the complexity of inherited mutation in the gene for Ngn1 (neurogenin 1, Neurog1), the hair hearing loss and the fact that more than half of the genetic cells seem to be normal, which is consistent with the idea that forms of deafness are not directly linked to hair cells or neurons normal innervation is not required for hair cell differentiation, (183), most forms of hearing loss worldwide are related to at least not until birth (46, 180). In NeuroD-null mutants, the noise, ototoxic drugs, and age. Replacement of hair cells and auditory neuroblasts fail to delaminate properly, but the hair neurons could potentially benefit many millions of people. cells also survive (79, 100). Molecular Embryology of the Cochlea Auditory Neurons in Cochlear Implant and Auditory Neurons and Auditory Brainstem Implant Normal differentiation of specific cell types is governed by The successful performance of cochlear implants depends particular combinations of intrinsic and extrinsic regulatory on the presence of a sufficient number of viable auditory neu- factors, such as transcription factors and growth factors, rons (Fig. 1) (4, 82, 217). Auditory brainstem implants (ABI) respectively. If we are to nurture the differentiation of donor have been performed in the condition where bilateral auditory cells towards hair cells and auditory neuronal phenotypes, it is nerves are seriously damaged, as experienced in the patients important to understand the molecular events that occur dur- with neurofibromatosis II (24, 53, 139). In ABI, although the ing normal development. It may then be possible to condition cochlear nucleus is directly and electrically stimulated in the donor cells with relevant soluble factors or to drive them to brainstem with the auditory nerve bypassed (Fig. 1), it is favor- differentiate by transfection with the appropriate regulatory able to preserve as many of the central processes of the audi- gene. Developmental studies are an essential prerequisite for tory nerve for as long as possible. This is because central this approach. process injury not only causes auditory nerve degeneration, but also transsynaptic (neuronal) degeneration of the cochlear Formation of the Otic Placode and Otocyst nucleus cells and cells in the higher auditory nuclei (33, 118, Most cells of the inner ear, including the hair cells and sen- 204). The efficacy of ABI undoubtedly depends not only on the sory neurons, are derived from the otic placode, which is the number of surviving cochlear nucleus cells, but also on the first visible sign of inner-ear development (Fig. 5A) (54). The preservation of the higher auditory relay nuclei. The auditory placode is an ectodermal thickening that is formed adjacent to neurons thus have a dramatic influence on the development Rhombomeres 5 and 6 of the hindbrain (125). It is induced by and maintenance of the cochlear nuclear complex (142, 155). the combined influence of Fgf3 from the hindbrain and Fgf10 The information presented in this section provides compelling from the adjacent mesenchyme (5, 11). The mammalian otic evidence that many patients should benefit from our ability to placode invaginates (Fig. 5B) and pinches off from the surface regenerate or replace auditory neurons. ectoderm to form an epithelial sac, which is referred to as the otocyst or otic vesicle (Fig. 5C). The space between the hind- Hair Cells in Clinical Medicine brain and the surface ectoderm is populated by periotic mes- The decline in hearing with age, known as presbycusis, is enchymal cells and by some neural crest cells from which the most common form of sensorineural hearing loss. In Schwann cells develop (Fig. 5B).

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ABThickening of otic placode invagination

x delaminating cells hindbrain POM notochord Neural crest cells

otocyst (otic vesicle) C Delamination of Ganglion progenitor cells FIGURE 6. A possible plan of cell fate specification in the developing inner ear of mammals. Some genes involved in the acquisition of cell fate are indicated. Some transcription factors or marker proteins are indicated in the boxes. delaminated cells As development continues, morphological changes occur Sensory within the otocyst to reshape this simple sac into an elaborate D (hair cells) Formation region fluid-filled labyrinth that includes both auditory and vestibular of the membranous sensory structures (Fig. 5D). The semicircular canals form in the labyrinth and dorsal region of the otocyst, the endolymphatic sac projects auditory neurons dorsally from the midregion, and the cochlear duct begins to with peripheral and central coil from the ventral region. Within the labyrinth, six regions of connection cochlear epithelium become specified as sensory patches that will form cochlear duct the five vestibular epithelia and the single auditory epithelium, nucleus each of which is composed of hair cells and supporting cells. cells axons dendrites auditory neurons Concomitant with these changes within the labyrinth, periotic mesenchymal cells condense around the developing ear to FIGURE 5. Embryology of the auditory neurons and related structures. The form the bony labyrinth (125, 145). hair cells and auditory neurons are derived from the placode. A part of the pla- code thickens (arrows, A), invaginates (arrows, B), and pinches off from the Differentiation of Auditory Neurons surface ectoderm to form the otocyst (otic vesicle) (C). Individual neuroblasts Our knowledge about the genes expressed during the forma- delaminate as the otocyst forms and coalesce to form the developing auditory tion of the auditory nervous system is still reasonably limited, and vestibular ganglion cells (C). Delaminating ganglions from various areas despite of the amazing accumulation of molecular data during of the otocyst project back neurons to their areas of origin (D, curved arrow). the past several decades. In this section, several important reg- The immature neurons enter the brainstem as the axons of the auditory nerve ulatory genes are described in addition to those mentioned in (arrows, D). POM, periotic mesenchyme. the previous section (Fig. 6). As the otocyst forms from embry- onic Day E9, individual neuroblasts expressing Ngn1 delami- The cochlea develops from a single, ventral projection of the nate from the anteroventral epithelium, migrate through the otocyst that forms around embryonic Day E10.5. Ventral basement membrane and surrounding mesenchyme, and then epithelial-cell phenotypes are induced through a combination coalesce to form the auditory and vestibular ganglia (Fig. 5, C of the expression of the transcription factor Six1 and a signal- and D) (137, 144). Delaminating neuroblasts from various areas ing molecule Shh, which is secreted from the notochord and of the otocyst project dendrites back to the sensory epithelia floorplate (11). In the absence of Shh, neither the cochlear duct and axonal processes to the cochlear nuclei (Fig. 5D) (1, 63). nor the auditory neuron develops, and the expression of sev- eral critical transcription factors, including Ngn1, NeuroD, Pax2, Ngn1, NeuroD, GATA binding protein 3, Tbx1 Otx1, Otx2, and Tbx1, is significantly reduced (99, 144). Shh is In null mutants for Ngn1, both auditory and vestibular neu- required for the specification of the majority of auditory and rons are absent, showing that this gene is essential for the dif- vestibular ganglion precursors through the regulation of Ngn1 ferentiation of all inner-ear sensory neurons (105). Ngn1-null expression (144). Activation or transfection of this gene in mutants also show a variety of defects in the sensory epithelia, donor cells may be important or even essential for successful indicating that it might normally have a role in the differentia- replacement of auditory neurons by cell transplantation. tion of sensory hair cells and supporting cells as well as the sen-

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sory neurons (104). Overexpression of Tbx1 in the otocyst factors, such as glial cell-derived neurotrophic factor, ciliary decreases the number of Ngn1-positive neuronal precursors neurotrophic factor, and fibroblast growth factor (FGF)-1 and and reduces the size of the auditory and vestibular ganglion. -2 participate in the postnatal survival after deafferentation (84, Conversely, in Tbx1 mutants, the number of Ngn1-positive pre- 93, 186, 197, 214). cursors and the size of the ganglion increase (137). In addition to such trophic factors, electrical activity in audi- Ngn1 is rapidly followed by the expression of NeuroD in the tory neurons plays a vital role to maintain and modulate the otocyst and in delaminating neuroblasts (79, 100). In null auditory neurons (7, 59, 92, 102, 149, 206). Membrane depolar- mutants for NeuroD, migration of both auditory and vestibular ization of auditory neurons activate voltage sensitive Ca2+ neuroblasts is compromised, although there is a significantly channels (58), causing the rise in intracellular Ca2+. This event greater depletion of auditory neurons (79, 100). NeuroD is activates multiple prosurvival signaling pathways, such as expressed in all neuroblasts (79, 100), but it seems to be down- Ca2+/calmodulin dependent kinases II and IV and protein regulated much earlier in auditory neuroblasts after delamina- kinase A (55). tion than in vestibular neuroblasts. The zinc-finger transcrip- tion factor GATA binding protein 3 (GATA3) transiently and Differentiation of Hair Cells selectively regulates NeuroD in auditory neuroblasts and may Hair cells and supporting cells are selected from a population confer specific properties on them (90). GATA3 is restricted to of common epithelial progenitors. Cell lineage studies do not the medial zone of neuroblast delamination (89, 146) and is support speculation that the auditory neurons are derived from only expressed in the auditory ganglion (89, 146). Therefore, the a common field of progenitors, although some areas of after migration, auditory and vestibular ganglion neurons can overlap have been reported (40, 45, 86). be distinguished by their reciprocal expression of GATA3 and NeuroD (Fig. 6). Differences between the ganglia may need to Atoh1, Hes1, Hes5, and Zic1 be exploited during transplantation to ensure appropriate tar- Atoh1, a murine homolog of the bHLH-transcription factor geting of cells within the inner ear. atonal (Drosophila), previously known as Math1, is absolutely required for hair-cell specification in mice (13, 207). Atoh1 Neurotrophins and their Receptors in Auditory Neurons knockout mice lack sensory hair cells (13). Transfection of Atoh1 Hair cells provide much of the trophic support required for into postnatal rat cochlear cultures results in ectopic hair cells maintenance and survival of auditory neurons. They express outside of the normal sensory region (219). Hes genes are closely brain-derived neurotrophic factor (BDNF) and neurotrophic allied with Atoh1 and signaling via the notch family of membrane factor 3 (NT-3), and the auditory neurons synthesize the high- receptors. They tend to be negative regulators of hair cell affinity tyrosine kinase receptors (trk) B and C (134, 135, 160, differentiation (220). Knockout of Hes1 leads to an increased 202). In neonatal mice with targeted deletions of both BDNF number of inner hair cells, whereas knockout of Hes5 leads to and NT-3, all neurons in all inner-ear ganglia are lost (39, 47, increased numbers of outer hair cells (220, 221). Zic genes are 97). Similarly, neonatal mice that lack both the trkB and trkC neural inhibitors in the developing chick spinal cord and the receptors lose the majority of their cochlea-vestibular ganglion inner ear that are regulated by the Bmp–signaling pathway (8, neurons (113, 161). 121, 201). The binding of Zic1 to the Math1-enhancer region is Auditory neurons lacking NeuroD fail to express TrkB and sufficient to inhibit Math1 expression in the chicken neural tube TrkC and, subsequently, undergo cell death. In fact, NeuroD (34). Therefore, it seems possible that Zic genes could also play mutants produce some delaminating neuroblasts capable of a role in regulating hair-cell development. forming neurons, but nearly all die after projecting axons toward the sensory epithelia (79, 100). For the purposes of Notch signaling transplantation, transfection of NeuroD into donor cells may Hair cells and supporting cells arise from common progeni- enhance survival by ensuring expression of TrkB and TrkC. tors (40, 45, 86) and are selected from a patch of equivalent Regulation of these receptors is not under the sole control of cells by a process called lateral inhibition, which is mediated by NeuroD. The POU-domain transcription factor Pou4f1 (Brn3a) Notch signaling (1, 6, 36, 41, 119, 203). Notch activation influ- regulates expression of trkC in trigeminal neurons (67) and ences the balance of the expression of Atoh1, Hes1, and Hes5. possibly in auditory neurons (66). Pou4f3 (Brn3c) regulates Specific ligands for Notch receptors, such as Delta, Jagged, or growth factor signaling in hair cells (23, 61). In Pou4f3-null Serrate, depending on the species, mediate reciprocal interac- mutant mice, hair cells are unable to complete morphological tions from hair cells and supporting cells. Although these inter- differentiation, and they degenerate by apoptosis. Subse- actions are complex (215, 216), at the simplest level, one can quently, the majority of auditory neurons also degenerate imagine that high levels of a ligand such as Delta in a hair cell because of loss of trophic support (38, 208, 209). Although the activate Notch receptors in the adjacent supporting cells. Notch organ of Corti is a main source of NT-3 and BDNF in the activates Hes genes, ensuring that the adjacent cells do not mature cochlea, auditory neurons receive neurotrophins from express Atoh1 and, thus, become supporting cells rather than several other sources, including the cochlear nucleus, Schwann hair cells (1, 15, 26, 85). Modulation of these interactions may cells, supporting cells, and even the auditory ganglion cells provide a means to stimulate hair cell regeneration from sup- themselves (55, 149, 187, 196, 213, 218). Moreover, other trophic porting cells, but they may also be an important consideration

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in the conditioning of donor cells for transplantation. One of cycle in hair cells. Rb1 is particularly interesting because its the most obvious steps might be to try to drive hair cell differ- inactivation can lead to direct proliferation of hair cells. entiation by transfection of the donor cells with Atoh1. However, cerebellar granule cells also express Atoh1, and the Cell-Transplantation Techniques cellular environment will provide an important source of A fundamental requisite is to deliver the potentially restora- extrinsic signals. In this respect, the location of cell delivery tive cells to the target, usually the site of the lesion, with mini- may be critical. mal trauma to the homeostasis of the host. This is particularly difficult in the inner ear because it has a highly specialized and Hair Cells from Supporting Cells complex anatomy. In the previously reported techniques, mate- Cell lines derived from embryonic supporting cells might rials, such as cells, viral vectors, or chemicals, have been deliv- provide an ideal source of donor cells for hair cell replacement. ered from the peripheral side of the auditory nervous system, In birds, supporting cells are able to change their phenotype namely, through the cochlea. However, we should choose the and become new hair cells (25, 27, 29, 153, 182). This might routes for cell transplantation according to the pathologies that occur in different animals by transdifferentiation, which is con- have occurred in the auditory nervous system. version of cell phenotype without cell division (2, 148) or mitotic proliferation (28, 140, 190). Mammals do not replace Cell-Transplantation Technique Using the Auditory cochlear hair cells, but there is some evidence that, in the Nerve as a Route and Host for Cell Transplantation: vestibular macular epithelia, supporting cells act as a source for Auditory Nerve Approach new hair cells (42, 101, 200). One of the pathological processes affecting the auditory Recently, an approach to restore lost hearing was reported in nervous system is typically observed in vestibular schwan- which supporting cells were converted to hair cells in mature noma or, probably, auditory neuropathy, in which the major mice (72). In this investigation, Atoh1 was delivered into the insult is in the axons of the auditory neurons (Fig. 7A, solid scala media using an adenoviral vector, and regeneration of arrow, Pathology 1). In this situation, because the hair cells are hair cells was induced, resulting in functional recovery as eval- expected to be maintained in varying degrees, a reasonable uated with auditory brainstem response recordings (72). Atoh1 approach is to replenish lost auditory neurons from the CPA was delivered to nonsensory cells in the deafened auditory side without disturbing them. epithelium 4 days after ototoxic lesion, before significant The initial site for cell placement is critical because the neu- degeneration of the sensory dendrites. In most clinical cases, rites growing from the peripheral to central direction become hair cells as well as dendrites are expected to be lost, so replace- sensitive when they encounter the astrocytes in the CNS por- ment of hair cells alone may not be sufficient. Replacement of tion of the nerves (44, 83). Actually, growing axons from the auditory neurons may also be necessary. Another point is that peripheral nerve towards the spinal cord or brainstem abruptly adenoviral vectors are potentially cytotoxic and can elicit an stop when they meet the astrocytes in the CNS (14, 19, 44). immune response. It has been reported that an adenovirus gene Thus, neurites growing from cells transplanted to the cochlear transfer into the organ of Corti via the scala media is detri- side into the portion of the auditory nerve distal to the TZ, mental to the hair cells that surround the site of inoculation such as Rosenthal’s canal, may become inhibited when they (70, 72, 77). Therefore, this method to deliver transgenes may be reach the TZ (Fig. 8A). inappropriate when the residual number of the hair cells is One method of overcoming this difficulty is to place cells to functionally significant. Further technical development of the the auditory nerve from the central side of the cochlea proximal vectors will be indispensable for clinical translation. In addition to the TZ (Fig. 8B). Recently, we confirmed the feasibility of this to these points, an ectopic production of hair cells in places approach; embryonic stem (ES) cells transplanted at the inter- other than the organ of Corti should be avoided to reestablish nal meatal portion of the auditory nerve migrated along the the proper connections between the regenerated hair cells and entire course of the auditory nerve across the TZ, and growing the auditory neurons (77, 109). neurites from ES cells easily crossed the TZ toward the cochlear side (Figs. 8B and 9) (169). In our study, migration and differen- kip1 Cell Cycle (p27 , Ink4d, Rb1) tiation of the transplanted cells depended on the damage It is possible that if supporting cells can be stimulated to imposed on the auditory nerve. ES cells were placed at the proliferate, they may naturally form a sensory epithelium in internal auditory meatal portion of the auditory nerve that had which hair cells emerge by lateral inhibition. There is evidence been previously injured and that was, therefore, nonfunction- that elimination of cell cycle inhibitors, such as p27kip1, may ing, indicating that the auditory nerve can be used as a cell- cause a reentry of supporting cells into the proliferation phase delivery route with minimal trauma (169). It is expected that (103). In transgenic mice that do not express p27kip1, there are cells transplanted proximally to the TZ may migrate and cross higher numbers of supporting cells and hair cells (21, 103). the TZ while leaving the growing neurites in the initial trans- Soon after they differentiate, hair cells do not express p27kip1, planted site and newly extending neurites peripherally toward but supporting cells continue to do so. However, the control of the residual hair cells (Fig. 9B). cell proliferation is more complex, and other genes, such as In one study, cells transplanted peripherally have been Ink4d (22) and Rb1 (108, 156), are required for regulating the cell reported to cross the peripheral nervous system–CNS bound-

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ary (64). Although this seems Auditory possible, it is not clear from cochlear nucleus cells ganglion hair cells supporting cells the results how restricted the cells delivery site was. It is quite possible that the boundary was traversed during surgery. type II cell type I cell One way to address this kind of problem is to analyze trans- Pathology 1 Pathology 2 plantation sites quantitatively within the first 0 to 24 hours, both to define the delivery site and to assess the repeata- (A) (A) bility of the surgery. From the standpoint of clin- ical translation, approaching the auditory nerve through (B) the CPA only requires remov- (B) ing a small bony plate behind the ear (retromastoid crani- ectomy). The retromastoid (C) craniectomy is currently used clinically in a variety of pro- cedures, such as microvascu- (C) lar decompression to treat (D) hemifacial spasm, trigeminal neuralgia, and resection of FIGURE 7. Pathological processes occurred in sensorineural hearing loss. In Pathology 1, the initial insult to the audi- tumors in the CPA, including tory nervous system occurs as a lesion in the axons of the nerve (A, solid arrow). In time, the degeneration of the audi- vestibular schwannomas (74, tory neurons proceeds toward the cochlea and the brainstem (A, B, and C, dotted arrows). In this pathology, the hair 81, 129, 157). cells tend to be preserved to various degrees (C). In Pathology 2, the hair cells are damaged initially (A, solid arrow), In contrast to the cochlea in and the dendrites and the auditory ganglion cells secondarily degenerate (B, C, dotted arrows). At the most advanced small experimental animals, stage of this type of pathology, the degeneration of the cochlear nucleus cells might occur (D). The cell-transplantation approach should cope with each of these pathologies properly. such as rats, mice, and guinea pigs, in which the cochlear wall is directly sighted in the tympanic bulla, the human cochlea is embedded deep in the temporal bone. Therefore, to reach the cochlear wall in humans, the thick bone around the cochlea should be removed without damaging the intra- cochlear structures. This is a difficult task to perform. Other advantages of this auditory nerve approach include its versatility. For example, when transplantation of cells into the cochlear nucleus region is planned, cells can be placed in this region under direct visual control. Increasing the number of cochlear nucleus cells is an important issue in applying ABI to the patients whose auditory nerve fibers are not suitable for a cochlear implant. From a different perspective, it can be said that it is not necessary for the transplanted cells to move, cross the TZ, and enter into the Rosenthal’s canals. In the normal anatomy FIGURE 8. TZ and neurite growth. A, growing neurites from the cell trans- of the auditory nervous system, it is only necessary for the planted distally to the TZ cannot cross the TZ because of repellent environ- ment of astrocytes in the CNS portion of the auditory nerve (x). B, on the con- neurites to provide a morphological and functional connec- trary, neurites from the cell transplanted proximally to the TZ cross the TZ. tion between the brainstem nuclei and the hair cells (Fig. Moreover, the cells themselves move across the TZ distally while leaving the 10). Transplanted cells in the region proximal or distal to neurites in the initially transplanted region, proximal to the TZ. CNS, central the TZ (Fig. 10, ① and ②) and the brainstem (Fig. 10, ③) may nervous system portion of the auditory nerve; CP, cerebellopontine; PNS, extend neurites. Even the cells transplanted outside the peripheral nervous system portion of the auditory nerve. auditory nerve trunk may extend neurites bidirectionally (Fig. 10, ④).

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Cochlear Approach for Cell Transplantation, and Its Problems In the second type of pathology affecting the auditory nerv- ous system, the initial damage is to the hair cells, as typically experienced in presbycusis, aminoglycoside ototoxicity, or noise-induced hearing loss (Fig. 7A, solid arrow, Pathology 2). At the beginning of this type of pathological process, the prox- imal structures, such as the dendrites of the auditory nerve, would be preserved (Fig. 7A), and hair cell replacement alone may accomplish hearing restoration. However, such a confined change of the inner ear is expected to be rare, and most patients with sensorineural hearing loss may be categorized as shown in Figure 7B or worse (Fig. 7, C and D) (91, 210). In these cases, an approach from the CPA side (auditory nerve approach) should be considered in addition to the cochlear approach. FIGURE 9. Cell migration through the auditory nerve. ES cells trans- In the previously reported cochlear approaches for cell trans- planted at the internal meatal portion of the auditory nerve migrated the plantation into the cochlea, the membranes sealing the perilym- entire course of the auditory nerve that had been damaged previously and phatic and endolymphatic spaces are breached (Fig. 1), disturb- profoundly degenerated (dotted and solid arrows). The transplanted cells ing the homeostasis of the inner ear fluid environment. were found most distally in the hair cell region (the scala media), implying One previously reported technique to enter into the scala that this auditory nerve approach can be used as a technique to deliver cells media is through the lateral wall of the cochlea (Fig. 1A) (72), to the entire area of the auditory nervous system. IAC, internal auditory canal; IAM, internal auditory meatus; TZ, the Schwann-glial transitional and one alternative is to deliver materials into the endolym- zone (adapted from, Sekiya T, Kojima K, Matsumoto M, Kim TS, Tamura phatic space through the vestibular aqueduct (Fig. 1B) (212). T, Ito J: Cell transplantation to the auditory nerve and cochlear duct. Exp These procedures may potentially put endolymphatic struc- Neurol 198:12–24, 2006 [169]). tures at risk of injury. Another problem with these techniques is that the injected materials may enter not only the cochlea, but also the vestibular portion of the membranous labyrinth. If these techniques are to be used, technical refinements are needed to avoid their inherent disadvantages. Various materials, such as cells, viral vectors, or pharma- cological agents, can be deliv- ered into the perilymphatic space (Fig. 1C) (65). Although direct damage to the endo- lymphatic structures may be attenuated with this tech- nique, this approach may not be totally free from hearing loss caused by perilymphatic fluid fistula (114). Another potential danger of one peri- lymphatic injection technique is that the injected materials could enter the cochlear aque- duct and travel through cere- brospinal fluid to the con- FIGURE 10. Possible rewiring of auditory neurons. A, the transplanted cells may migrate and enter into the Rosenthal’s canal as simulating the normal auditory nervous system. B, the transplanted cells may move to the region proximal and tralateral ear, where they distal to the TZ (① and ②) and the brainstem (③). Even the cells transplanted outside the auditory nerve trunk can extend could cause unintended side neurites bidirectionally (④). Under these situations, it is practically acceptable if the neurites could grow and bridge effects (Fig. 1). between the brainstem nuclei and the hair cells both morphologically and functionally, even though these rewired neurites More indirectly, the round are not the same as in the normal condition. F, fundus of the internal auditory canal; IAM, internal auditory meatus. window niche has been used

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as the placement site for diffusible materials in neuro- reported as potential candidates for hair cell replacement (51, otological research. However, diffusion of the materials is lim- 62, 76, 80, 147). Some cell types are listed below. ited to the more basal turns of the cochlea in this technique, and doses of drugs infiltrating the perilymphatic space are Hair Cells from ES Cells difficult to evaluate. Moreover, nondiffusible materials, such Hair-cell progenitors have been generated from murine ES as cells, cannot be transferred into the membranous labyrinth cells in vitro (96). They were created from murine ES cells, with this technique (16). using epidermal growth factor (EGF), insulin-like growth fac- Transplantation into the modiolus or auditory nerve trunk tor-1, and FGF-1. These progenitors were integrated into the from the cochlear side invades the membranous labyrinth developing chick otocyst, where they expressed a set of char- (Fig. 1D), thus also placing hearing at the risk (64, 143). acteristic markers for the hair-cell phenotype, including the Considering these drawbacks of the previously reported cell- transcription factors Atoh1, Pou4f3, myosin VIIA, parvalbu- transplantation techniques, there is room for these cochlear min 3, and espin. They also developed hair bundles character- approaches to be technically refined and used in such a way as istic of mature hair cells. to preserve the residual structures within the inner ear. Hair Cells from Adult Inner Ear Stem Cells Candidates for Cell Replacement and Neural Stem Cells Adult murine vestibular (utricular) sensory epithelia con- Replacement of Auditory Neurons tain cells that display the characteristic features of stem cells, There are many different types of candidate cells for the including self-renewal and multipotency. They also form replacement of the auditory neurons and cochlear hair cells spheres that can express markers for developing hair cells (80, 120, 128). To replace auditory neurons, the cells should (myosin VIIa and Pou4f3) and supporting cells (pancytoker- have the potential to extend dendritic processes peripherally atin and p27Kip1) (95), although it is not completely clear that (toward the cochlea) and axonal processes centrally (toward these stem cells were derived purely from utricular epithelial the brainstem). A conditionally immortal cell line (US-VOT- cells without including mesenchymal or vascular stem cells N33) was derived from delaminating auditory neuroblasts of in the surrounding tissue (109). Neural stem cells from the the mouse otocyst at embryonic Day 10.5 (E10.5) (88, 123), forebrain (131, 195) transplanted into the inner ear survived before formation of the cochlear-vestibular ganglion at least 4 weeks and seemed to integrate into several struc- (Fig. 5C). The cell line expresses a combination of markers tures, including the organ of Corti (71). The same neural stem found in auditory neuroblasts, including the transcription cells have been successfully grafted into the drug-injured factors GATA3, NeuroD, Pou4f1 and Islet-1, the cytoskeletal mouse inner ear and have survived for several weeks, ex- protein βIII-tubulin and the potassium channel KCNQ3. In pressing markers of mature cell types, including glia, neu- the presence of FGF-1 or FGF-2 in vitro, it forms bipolar cells rons, and hair cells, although not in the cochlea (69, 194). similar to those of normal auditory neurons (123). We found Comparison of these two types of stem cells reveals that the that US-VOT-N33 cells migrated both peripherally and cen- up-regulation of hair cell markers was observed more in the trally, projecting neuritic processes in both directions, when cells differentiated from inner ear–derived stem cells in vitro they were transplanted to a partially crushed auditory nerve than those neural stem cells taken from the forebrain (95). at its internal auditory meatus portion (Sekiya et al., unpub- These findings indicated that inner ear stem cells seem to be lished data). a plausible candidate for the source of hair cell regeneration Recently, Rask-Andersen et al. (141) cultured human audi- (78, 95, 151, 194, 200). tory ganglion cells obtained from petroclival meningioma sur- Another study demonstrated that acutely dissociated cells gery and demonstrated the presence of neural progenitor cells from the newborn rat organ of Corti developed into so-called for auditory neurons in the adult human auditory nerve. Their otospheres consisting of 98% nestin-positive cells in the pres- neurons coexpressed receptors for neurotrophic factors, such as ence of either EGF or FGF2. This work raises the hypothesis TrkB for BDNF and TrkC for NT-3, as the normal auditory that nestin-positive cells might be a source of newly generated nerve (141). They consider that the auditory ganglion progen- hair cells and supporting cells in the injured postnatal organ of itor/stem cells may be substituted and used as graft material in Corti (107). cell therapy to regenerate auditory ganglion cells and/or func- tion in patients with neurological defects, including sen- Clinical Translation and Future Trends sorineural hearing disorders (141). Maintenance of long-term Although current cochlear implant devices stimulate at cultures of characterized, renewable human auditory neurons only about 20 different sites of the cochlea, patients with remains an important challenge. cochlear implants can converse with people around them (94, 217). This indicates that the recovery of hearing might be pos- Replacement of Hair Cells sible without the complete replacement of the cochlear archi- Potential cells for hair cell replacement have been generated tecture. Actually, it might not be realistic and feasible to recre- from ES cells (96), adult inner ear stem cells (95), and neural ate the delicate and complex structure of the organ of Corti stem cells (71, 194). Besides these, many cell lines have been (94). Therefore, the tentative goal of cell-transplantation

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approaches to restore lost hearing should be set to a level ments for FGF3 and FGF10 during inner ear formation. Development above that of the current cochlear implant technologies for 130:6329–6338, 2003. effectiveness and safety. 6. Anagnostopoulos AV: A compendium of mouse knockouts with inner ear defects. Trends Genet 18:499, 2002. Clinical application of cell-transplantation techniques will 7. Araki S, Kawano A, Seldon L, Shepherd RK, Funasaka S, Clark GM: Effects depend on carefully controlled studies that take account of a of chronic electrical stimulation on spiral ganglion neuron survival and size wide range of different variables. After many experiments in deafened kittens. Laryngoscope 108:687–695, 1998. with Parkinson’s disease, this variability has made it hard to 8. Aruga J, Tohmonda T, Homma S, Mikoshiba K: Zic1 promotes the expansion judge the real benefits of this approach (205). Therefore, the of dorsal neural progenitors in spinal cord by inhibiting neuronal differen- tiation. Dev Biol 244:329–341, 2002. need for quality control in all experiments cannot be overesti- 9. Badie B, Pyle GM, Nguyen PH, Hadar EJ: Elevation of internal auditory mated. This is difficult to control because of the variability in canal pressure by vestibular schwannomas. Otol Neurotol 22:696–700, 2001. cultures of similar cell types between laboratories, but the 10. Bahr M, Andres F, Timmerman V, Nelis ME, Van Broeckhoven C, Dichgans methods within a specific laboratory should, obviously, be J: Central visual, acoustic, and motor pathway involvement in a Charcot- described fully. The surgical technique and delivery methods Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene. J Neurol Neurosurg Psychiatry 66:202–206, 1999. are also critical in terms of damage to the host tissue and ini- 11. Barald KF, Kelley MW: From placode to polarization: New tunes in inner ear tial spread of the inoculation site. These techniques are chal- development. Development 131:4119–4130, 2004. lenging, but important. 12. Benitez JT, Lopez-Rios G, Novoa V: Bilateral acoustic neuroma. A human In concrete terms, selection and preparation of donor cells is temporal bone report. Arch Otolaryngol 86:25–31, 1967. critical. The ES cells used in our laboratory are induced in 13. Bermingham NA, Hassan BA, Price SD, Vollrath MA, Ben-Arie N, Eatock RA, Bellen HJ, Lysakowski A, Zoghbi HY: Math1: An essential gene for the advance to differentiate into neuronal cells, and the possibility generation of inner ear hair cells. Science 284:1837–1841, 1999. of teratoma formation is therefore avoided (115). Generally, in 14. Berry M, Hall S, Rees L, Carlile J, Wyse JP: Regeneration of axons in the optic using ES cells or other progenitor cells, carcinogenesis should nerve of the adult Browman-Wyse (BW) mutant rat. 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219. Zheng JL, Gao WQ: Overexpression of Math1 induces robust production of is commonly encountered in our patients. The lessons learned from extra hair cells in postnatal rat inner ears. Nat Neurosci 3:580–586, 2000. hearing restoration research may provide important insight into neu- 220. Zheng JL, Shou J, Guillemot F, Kageyama R, Gao WQ: Hes1 is a negative reg- rorestoration overall. ulator of inner ear hair cell differentiation. Development 127:4551–4560, 2000. Charles Y. Liu 221. Zine A, Aubert A, Qiu J, Therianos S, Guillemot F, Kageyama R, de Rib- Los Angeles, California aupierre F: Hes1 and Hes5 activities are required for the normal develop- ment of the hair cells in the mammalian inner ear. J Neurosci 21:4712–4720, 2001. his review is unfocused, making it quite unclear what the authors 222. Zwirner P, Wilichowski E: Progressive sensorineural hearing loss in children Tare advocating. If the authors support replacing the spiral ganglion with mitochondrial encephalomyopathies. Laryngoscope 111:515–521, 2001. neurons by transplantation into the nerve, their discussion should be confined to this notion. However, the surgical route is far less important Acknowledgments than the fact that appropriate cells for such transplantation have not We are supported by the Japanese Ministry of Education, Culture, Sports, been discovered. The authors spend a significant portion of the review Science, and Technology. We thank Dr. Shinji Takebayashi, and the Departments discussing the replacement of hair cells, yet state only that transplanta- of Otolaryngology and Head and Neck Surgery, Kyoto University Graduate tion to the cochlea is problematic, with which we completely agree. It is School of Medicine, for their valuable discussion. We do not have any personal difficult to say for whom this review would be useful. The completely or institutional financial interests in any of the drugs, materials, or devices uninitiated reader will be confused because most topics are discussed described in this review. too superficially, whereas the expert will be frustrated by this superfi- ciality and the lack of useful suggestions. The main point of this review COMMENTS seems to be that if neurosurgeons want to replace spiral ganglion neu- rons, they will need to transplant these neurons to the spiral ganglion. his review describes the biology concerning the restoration of hear- Ting loss from a variety of pathologies, including those affecting the Derald E. Brackmann cochlea and those affecting the cochlear nerve itself. The authors reveal Jose N. Fayad new data indicating the depth of biological understanding that must Neuro-otologists accompany serious transplantation efforts. There seems to be little doubt Los Angeles, California that restorative surgery represents one of the most promising aspects of neurosurgery. This review indicates that restorative procedures related he authors have written a scholarly review of a myriad of important to hearing are not a distant vision but rather a clear reality. Tissues that would converge if cell transplantation were used to restore hearing. Much of the discussion is theoretical. However, in their Charles J. Hodge, Jr. elegant description of the relevant anatomy, the authors discuss the Syracuse, New York challenges that would be encountered with either axonal or cochlear repair concepts. I doubt many neurosurgeons have considered the fea- here has been a tremendous interest in restorative neurosurgery sibility of cell repair in this setting, but the research conducted to date Tusing cellular transplantation. The targets of these strategies have provides some basis that translation to clinical research may occur in largely been neurodegenerative disorders or trauma and injury to the the not-too-distant future. Obviously, any procedure directed to the central and peripheral nervous system. In addition to these patholo- inner ear structures or the auditory canal could worsen any remaining gies, loss of hearing continues to represent an ongoing challenge. In this hearing the patient may have. I would also expect that different kinds article, the authors present an extensive review of the anatomy, devel- of hearing loss may be better suited for first clinical studies. The need opment, and molecular biology of auditory neurons and the surround- for short or long-term immunosuppression in this location will also be ing structures as they relate to hearing loss. They also evaluate cellular an important consideration. transplantation therapy aimed at restoring hearing, as well as an alter- native strategy to the traditional cochlear approach. This subject is of Douglas S. Kondziolka obvious interest to neurosurgeons because sensory-neural hearing loss Pittsburgh, Pennsylvania

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COILING VERSUS CLIPPING FOR THE TREATMENT OF ANEURYSMAL SUBARACHNOID HEMORRHAGE: A LONGITUDINAL INVESTIGATION INTO COGNITIVE OUTCOME

Duncan Frazer, B.Sc., D.Psych. OBJECTIVE: Endovascular coiling has been used increasingly as an alternative to neu- Department of Clinical rosurgical clipping for treating subarachnoid hemorrhage secondary to aneurysm rup- Neuropsychology, and ture. The aim of the present study was to provide a prospective, longitudinal investiga- Therapy and Rehabilitation Services, The National Hospital for tion into cognitive function in patients with aneurysmal subarachnoid hemorrhage Neurology and Neurosurgery treated with either neurosurgical clipping or endovascular coiling. London, England METHODS: Twenty-three patients who were treated for aneurysmal subarachnoid hem- Abha Ahuja, Ph.D. orrhage at the National Hospital for Neurology and Neurosurgery in London, England, Department of Clinical were recruited prospectively. Twelve patients who underwent surgical clipping were Neuropsychology, compared with a group of 11 patients who underwent endovascular coiling. All patients The National Hospital for underwent a comprehensive, standardized neuropsychological assessment using the Neurology and Neurosurgery London, England same battery of tests at the acute stage (within 2 wk after treatment). All patients who underwent coiling and 11 of the 12 patients who underwent clipping were reassessed Laurence Watkins, M.A., at the post-acute long-term follow-up (6 mo) stage. F.R.C.S. (SN) RESULTS: Group comparisons at the acute assessment revealed a significant difference Victor Horsley Neurosurgical Unit, favoring coiling patients on only one measure of verbal recall. However, there were no The National Hospital for other significant differences between the groups at this stage. At the post-acute assess- Neurology and Neurosurgery, London, England ment, the clipped group performed better than the coiled group on measures of intellec- tual functioning (P Ͻ 0.05), although no other differences were found on a range of cog- Lisa Cipolotti, Ph.D. nitive tests. Intragroup comparisons between the acute and post-acute assessments found Department of Clinical equivocal, significant improvements in measures of intellectual functioning, memory, Neuropsychology, executive functions, and speed of information processing in both groups of patients. The National Hospital for Neurology and Neurosurgery CONCLUSION: We argue that there are minimal differences in the long-term cognitive London, England outcome between endovascular coiling and surgical clipping. In the acute phase after treatment, we suggest that coiled patients, having been spared neurosurgical interven- Reprint requests: Duncan Frazer, B.Sc., D.Psych., tion, may have a slightly better cognitive outcome than clipped patients. However, The National Hospital for these differences level off and both groups of patients ultimately experience widespread Neurology and Neurosurgery, improvement in cognitive functioning by the post-acute stage of recovery. Therapy and Rehabilitation Services, Box 90, Queen Square, KEY WORDS: Clipping, Cognitive impairment, Coiling, Subarachnoid hemorrhage London WC1N 3BG, England. Email: [email protected] Neurosurgery 60:434–442, 2007 DOI: 10.1227/01.NEU.0000255335.72662.25 www.neurosurgery-online.com

Received, August 10, 2006. Accepted, September 18, 2006. ubarachnoid hemorrhage (SAH) resulting involves the exclusion of rerupture with a cer- from ruptured aneurysms can be treated tainty of approximately 98% (8). In the past Swith either neurosurgical clipping or decade, endovascular coiling has grown in endovascular coiling. Until relatively recently, popularity as an alternative to clipping. This clipping was the most popular treatment. This procedure aims to obstruct the aneurysmal procedure, which entails a craniotomy, aims to lumen with a detachable coil, with the intent to prevent rebleeding of the aneurysm by placing provoke secondary thrombosis of the aneur- a clip across its neck, thus excluding the ysm. Coil embolization has the potential aneurysm from circulation. Surgical clipping advantage that the patient is spared intracra-

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nial surgical intervention. This results in circumventing the indicated by magnetic resonance imaging findings 1 year after damage to the brain parenchyma if no inadvertent closure of treatment. The authors concluded that their study provides perforating vessels close to the aneurysm occurs. Outcome preliminary evidence that surgical clipping may have a worse studies are required to ascertain the relative benefits of this outcome when compared with endovascular treatment and procedure over neurosurgical clipping. may result in more frontotemporal damage, as illustrated by Traditionally, the efficacy and safety of neurosurgical and neuropsychological test results and magnetic resonance imag- endovascular techniques have been evaluated by comparing ing findings (7). neurological morbidity and mortality rates associated with the More recent studies comparing cognitive outcome at the different treatments (4, 17, 26). Molyneux et al.’s (17) recent follow-up phase have only highlighted a number of similarities ongoing, multicenter International Subarachnoid Aneurysm between the clipped and coiled patients relating to the overall Trial is the only study to date to directly compare the safety and pattern and frequency of residual cognitive deficits (3, 5). efficacy of the two procedures. Their findings indicated that the However, these studies indicate a trend toward a more favorable outcome in terms of survival free of disability at 1 year is sig- outcome for coiled patients, showing greater impairments in nificantly better with endovascular coiling (24% of coiled psychomotor speed/attention and memory in the clipped group patients were dependent or dead at 1 yr versus 31% of neuro- at the 6-month follow-up examination (3) and more marked surgically clipped patients who were dependent or dead at 1 impairments on some measures of memory and executive func- yr). The long-term risks of further bleeding from the treated tions in the clipped patients at the 1-year follow-up examination aneurysm were low with both therapies. (5). To our knowledge, there has been only one study comparing However, the evaluation of neurological morbidity and mor- the neuropsychological and clinical outcomes of the two treat- tality rates, as well as cognitive outcome, are required to fully ment methods serially over time (14). The authors did not find understand the clinical outcome and relative efficacy of these any significant differences between the two groups in their neu- treatments. Many studies of reportedly good neurological ropsychological tests at the acute stage (10 d after treatment) or recovery, as determined by neurological outcome scales such as at the 3- and 12-month follow-up examinations. Both groups the Glasgow Outcome Scale (13), have revealed that a signifi- improved their performance across the three assessments. cant number of patients with treated ruptured aneurysms show However, memory functions were not assessed acutely and exec- impairments in neuropsychological functioning (9–11, 15, 21). utive functions were not evaluated in detail in this study. Neuropsychological studies examining the cognitive sequelae The aim of the present study was to explore the neuropsy- of aneurysmal SAH often report residual impairments in mem- chological outcome after clipping and coiling procedures, span- ory, executive functions, and attention (9, 10, 15, 21, 29). There ning both the acute (within 2 wk after treatment) and long- is a growing body of evidence suggesting that the most impor- term (6 mo after treatment) follow-up periods. We conducted a tant causal factor for the neuropsychological sequelae of prospective, longitudinal neuropsychological investigation into aneurysmal SAH is the hemorrhage itself and associated sec- cognitive function in aneurysmal SAH patients treated with ondary brain damage, rather than the location of the aneurysm either neurosurgical clipping or endovascular coiling using the or the surgical intervention (9, 11, 20, 21). same battery of neuropsychological tests. Particular emphasis To date, the vast majority of neuropsychological studies have was given to assessing cognitive areas known to be sensitive to focused on cognitive outcome in patients who have undergone frontal and temporal cortical region involvement, namely neurosurgical clipping. In contrast, little is known of the neu- memory and executive functions. ropsychological status of patients who have been treated with endovascular coiling. Research of this type would enable a com- parison of the acute and long-term efficacy of this procedure with PATIENTS AND METHODS that of clipping. Additionally, there is potential for such research to examine the relative contribution of neurosurgical intervention Patients itself to the cognitive deficits by comparing these patients with an A group of 23 patients who were treated for aneurysmal SAH appropriate control group, namely, coiling patients. at the National Hospital for Neurology and Neurosurgery in Few studies have systematically compared cognitive out- London, England, were recruited prospectively. Patients were come in patients with aneurysmal SAH treated by surgical clip- excluded if they experienced any other neurological or psychi- ping or endovascular coiling. Hadjivassiliou et al. (7) assessed atric condition before SAH. None of the patients had partici- 40 case-matched pairs of patients treated by clipping or coiling pated in neurorehabilitation programs in the intervening time using a battery of neuropsychological tests 1 year after the between the acute and post-acute assessment. Patients were treatment. Both groups were cognitively impaired in all graded on admission to the neurosurgical unit according to the domains (measures of intelligence, memory, executive, atten- World Federation of Neurological Surgeons grading scale (24), tion, and visual perception). Comparison of cognitive outcome age, and location of aneurysm. The ethical responsibilities between the two groups indicated a trend toward a worse out- involved in the medical care of the patients prevented the use of come in the surgical group, which had worse scores on a the preferred random trial study. Informed consent was received minority of tests sensitive to frontal and temporal functions. from all patients according to hospital procedure. Twelve Clipping was also shown to cause more structural damage, as patients who underwent surgical clipping were compared with

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a group of 11 patients who underwent endovascular coiling. A microcatheter is then introduced coaxially through the guid- Characteristics of the patient samples are provided in Table 1. ing system and is navigated into the aneurysm using a microwire. Endovascular selective occlusion of the aneurysmal Neurosurgical Clipping and sac with preservation of the parent artery is usually performed Endovascular Coiling Procedures with electrolytically detachable platinum coils. Coils of differ- All patients underwent a computed tomographic scan as part ent lengths and configurations are detached consecutively until of their original diagnosis of SAH and an angiogram before complete obliteration of the aneurysm is achieved. intervention to determine the type and location of the aneurysm. The decision about the type of treatment used was Neuropsychological Assessment not based on fixed criteria. Many aneurysms are not equally All patients were initially seen as inpatients at the National suitable for either microsurgical clipping or endovascular coil- Hospital for Neurology and Neurosurgery in the acute phase ing. In individual cases, an interventional neuroradiologist and after treatment, within 2 weeks of the treatment (see Table 1). a neurosurgeon decided on the appropriate treatment based on Eleven of the 12 clipped patients and all of the coiled patients factors such as the patient’s age and overall medical condition were also seen for neuropsychological review 6 months after and the aneurysm’s location, size, morphological features, and the initial assessment. Patients were given an identical set of relationship to adjacent vessels. tests, except for one clipped patient and two coiled patients For clipped patients, the standard surgical method of neuro- who were not administered the Wechsler Adult Intelligence surgical clipping was used. This involves an open craniotomy Scale (WAIS-R) because English was not their first language and dissection of the vessels of the circle of Willis within the (although all patients were fluent in English). basal cisterns. Having dissected the aneurysm free of the sur- Patients were administered a range of standard neuropsycho- rounding brain and vessels, a titanium clip was placed across logical tests evaluating the following cognitive domains: current the neck of the aneurysm, excluding it from the circulation. For general intellectual functioning (WAIS-R; Advanced Progressive coiled patients, the Guglielmi detachable coil (Boston Matrices) (23, 33), premorbid intellectual functioning (National Scientific/Target, Fremont, CA) was used (6). In this endovascu- Adult Reading Test [NART]) (19), and episodic verbal and visual lar procedure, a guiding catheter is maneuvered under magni- memory (Recognition Memory Test [RMT], Paired Associate fied real-time fluoroscopy into the supra-aortal artery of interest. Learning Test, Rey-Osterrieth Complex Figure Test) tests (24, 31).

TABLE 1. Patient characteristicsa Characteristic Endovascular group Surgical group No. of patients 11 12 Average NART IQ score 90.33 103.45 Female-to-male ratio 8:3 5:7 Age, mean (SD) 44.7 yr (9.4 yr) 47.5 yr (11.5 yr) No. of years of education (mean) 10.82 (1.66) 11.92(2.4) Employed-to-unemployed ratio 9:1 12:0 WFNS grade on admission 1 88 2 24 3 00 4 10 Site of aneurysm AComA 67 Right MCA 11 Right PComA 02 Left PComA 11 Left ICA 10 Basilar tip 10 Right ICA 11 No. of days from hemorrhage to treatment, mean (SD) 2.91 (2.74) 4.00 (3.87) No. of days from treatment to initial assessment, mean (SD) 11.73 (8.81) 12.27 (9.59) No. of days between initial and follow-up assessments, mean (SD) 181.82 (39.20) 190.45 (26.37)

a NART IQ, National Adult Reading Test intelligence quotient; SD, standard deviation; WFNS, World Federation of Neurological Societies; AComA, anterior communicating artier; MCA, middle cerebral artery; PComA, posterior communicating artery; ICA, internal carotid artery.

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Alternate forms of the RMT were used at the 6-month interval to neuropsychological assessment, and the number of days counter possible practice effects. The assessment also covered between the initial and follow-up neuropsychological assess- naming skills (Graded Naming Test or Oldfield Picture Naming ment between the two groups (see Table 1). There was a mar- Test) (16, 22), spelling and calculation skills (Oral Graded ginal, nonsignificant difference in the premorbid IQ scores Difficulty Spelling Test, Oral Graded Difficulty Calculation Test) between the two treatment groups as estimated by the NART, (2, 12), and perceptual functions (Visual Object and Space suggestive of a trend toward this clipped group having a higher Perception Battery: Silhouettes, Incomplete Letters, Cube premorbid intellect than the coiled group (P ϭ 0.067). However, Analysis) (32). We also assessed frontal executive functions NART scores were not obtained from three patients whose first (Modified Wisconsin Card Sorting Test, Controlled Oral Word language was not English (two patients in the coiled group and Association Test, Trail Making Test Part B, Stroop Color-Word one patient in the clipped group). Test) (1, 18, 27, 30) and speed of information processing (Trail Making Test Part A, Cancelling 0’s and Digit Copy, Symbol Digit Group Comparisons at Acute Assessment Modalities Test) (1, 25, 34). All tests were given according to standard protocols or established procedures. An entire assess- In the acute stage, the only significant difference between the two patient groups was in the WAIS-R performance IQs ment took approximately 2 hours to complete for each patient. ϭ Published age-matched normative data were used to interpret (P 0.03) (see Table 2) favoring the clipped group. Marginal dif- and compare neuropsychological test scores in these two groups. ferences were found for the Full Scale IQ, again favoring the clipped group (P ϭ 0.067), and Trial 1 of the Paired Associate The intellectual functioning score was considered to be normal if ϭ the difference between the NART and the Full Scale Intelligence Learning test, in which coiled patients performed better (P Quotient (IQ) was less than 10, mild to moderately impaired if the 0.091). However, when the difference in the premorbid NART IQ difference fell between 10 and 19, and severely impaired if there scores was accounted for by carrying out an analysis of covari- was a difference of 20 or more. On other cognitive tests, scores at ance, the differences on intellectual measures disappeared. or below the fifth percentile were taken to indicate impairment. Performance on Trial 1 of the Paired Associate Learning test sig- For each cognitive domain, the severity of the impairment was nificantly differentiated the two groups in favor of the coiling group (P ϭ 0.047). Although performance on Trial 2 did not dif- categorized as follows: normal if performance on all tests in a ϭ given cognitive domain were above the fifth percentile; mild to fer significantly, there was a marginal difference (P 0.096). moderately impaired if at least one, but not all, of the test results There were no other significant or marginal differences between in a given cognitive domain fell at or below the fifth percentile; the two groups. and severely impaired if all test results in a given cognitive domain fell at or below the fifth percentile. Performance on the Group Comparisons at Post-acute Assessment Trail Making Test (Parts A and B) and the Controlled Oral Word In the post-acute stage, significant group differences emerged Association Test were classified as impaired if performance was on measures of general intelligence, visual perception, executive below the tenth percentile because there is no normative data functions, and speed of information processing (see Table 2). available for below the fifth percentile. Any error on Trail Making Clipped patients performed better than the coiled group on all Test Part B constituted an impaired performance. Four or five WAIS-R scales of intelligence (Verbal IQ, P ϭ 0.008; Performance categories achieved on the Modified Card Sorting Test and a IQ, P ϭ 0.02; Full Scale IQ, P ϭ 0.003; Advanced Progressive score of less than 50% perseverative errors indicated mild to mod- Matrices, P ϭ 0.007), one measure of visual perception erate impairment. Less than four categories, a score at or above (Silhouette, P ϭ 0.40), two measures of executive functioning 50%, or both indicated severe impairment. (Stroop Test, P ϭ 0.053; Trail Making Test, Part B, P ϭ 0.013), and Statistical Analysis one measure of speed of information processing (Symbol Digit Modalities from WAIS-R, P ϭ 0.029) (see Table 2). However, Statistical analysis was performed using the Statistical when premorbid NART IQ scores were taken into account by Package for the Social Sciences software (version 10.0; SPSS, using an analysis of covariance, the clipped group performed Inc., Chicago, IL). The Mann-Whitney U test for continuous significantly better than the coiled group in general intellectual data was used for intergroup comparisons and the Wilcoxon functioning (Full Scale IQ, P ϭ 0.040); marginal differences were related-signed test was used for intragroup comparisons. The found on the verbal (Verbal Scale IQ, P ϭ 0.074) and nonverbal nonparametric signed test was used on variables with cutoff scales of the WAIS-R (Performance Scale IQ, P ϭ 0.063) and on scores. Raw and scaled scores were used in these analyses. Advanced Progressive Matrices (P ϭ 0.082), with a trend toward the clipped group performing better than the coiled group on RESULTS these measures. Patient Characteristics Intragroup Comparison between Acute There were no significant differences in demographic vari- and Follow-up Assessments ables (age, education, sex), grade on admission (World Federation of Neurological Surgeons), time between the rup- Significant improvements were found in measures of intelli- tured aneurysm and treatment, time between treatment and gence for both coiled (Full Scale IQ, P ϭ 0.026; Performance IQ,

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TABLE 2. Neuropsychological test scores at acute (<2 wk) and at post-acute follow-up (6 mo) after treatment for subarachnoid hemorrhagea Acute assessment Follow-up assessment Test P value P value (11 ؍ Clipping (n (11 ؍ Coiling (n (12 ؍ Clipping (n (11 ؍ Coiling (n Intelligence Verbal IQ 83 (75, 91) 92 (85, 97) 0.131 83 (78.5, 93.5) 98 (90.5, 112.5) 0.008 Performance IQ 78.5 (75.5, 95) 96.5 (83.5, 104) 0.030 88.5 (80.5, 97.5) 110 (94, 118) 0.02 Full-scale IQ 83 (76.5, 91.5) 91 (85, 100) 0.067 83 (76.5, 96.5) 105 (93.75, 115) 0.003 Advanced matrices 5 (2, 8) 5 (3.25, 8.75) 0.786 5 (4, 7) 9 (6, 9) 0.007 Memory RMT-words 43 (37, 46) 41 (33.5, 47) 0.880 46 (42, 48) 46 (41, 49) 0.949 RMT-faces 38 (32, 41) 35.5 (31.3, 43) 0.833 42 (37, 46) 44 (37, 47) 0.949 PAL trial 1 14 (11, 20) 8.5 (3, 17.75) 0.091 13 (10, 19) 15 (12, 21) 0.478 PAL trial 2 21 (19, 24) 18 (9, 23.25) 0.151 23 (19, 24) 22 (20, 24) 0.847 Figure delay recall 6 (2.5, 10) 11.5 (2.8, 15.3) 0.345 13 (9, 16) 16.5 (14, 20) 0.151 Language and literacy Graded naming test 13 (7, 21) 17.5 (11, 21.5) 0.288 14 (5, 20) 20 (14, 26) 0.065 Spelling 20 (5.5, 23.3) 23 (13, 25) 0.173 16 (5.5, 23) 23.5 (13.3, 25.3) 0.079 Calculation 8 (1.75, 11.8) 14.5 (4.3, 18.8) 0.080 8 (2, 11.5) 13 (5, 19) 0.067 Perception Silhouettesb 17 (15, 22) 20 (19, 23) 0.190 19 (16, 23) 24 (21, 25) 0.040 Cube analysisb 9 (7, 10) 10 (9, 10) 0.125b 10 (9, 10) 10 (10, 10) 0.250 Executive functions COWAT fluency 20.5 (16, 27.3) 22 (18, 41) 0.349 28.5 (18.3, 42.8) 37 (28, 60) 0.114 MCST categories 2 (2, 6) 3.5 (2, 5.6) 0.976 6 (2, 6) 6 (6, 0) 0.243 MCST errors 10 (15, 10) 8.5 (19, 4.3) 0.976 7 (9, 4) 4 (8.5, 2.8) 0.315 Stroop colors 62 (53, 101) 89.5 (45, 102.3) 0.780 82 (71, 106) 109.5 (98.8, 112) 0.053 Stroop errors 0 (6, 0) 4.5 (10, 0.8) 0.211 0 (0, 2.8) 0 (0, 1) 0.661 Trail B time 125 (162, 91.5) 106 (130, 59) 0.370 110.5 (151.8, 78) 59 (83, 51) 0.013 Trail B errors 0 (0, 1) 1 (2, 0) 0.438 0 (1, 0) 0 (0.3, 0) 0.468 Speed of information processing Trail A time 41 (60, 30) 37.5 (57, 26) 0.608 36 (44, 27) 34.1 (41, 22) 0.243 Digit copy 45 (55, 40) 47 (56, 40) 0.797 41 (38, 46) 37 (34, 51) 0.748 Number cancellation 68 (95, 44) 55 (70, 48) 0.652 48 (72, 43) 49 (61, 34) 0.519 Symbol digit modalities 32 (26, 39) 37 (30.8, 47.8) 0.190 37 (28.5, 42) 48 (40, 46) 0.029

a IQ, intelligence quotient; RMT, Recognition Memory Test; PAL, Paired Associate Learning test; COWAT, Controlled Word Association Test; MCST, Modified Card Sorting Test. Data are presented as median (interquartile range). P values in bold are significant. b Nonparametric signed test.

P ϭ 0.012) and clipped patients (Full Scale IQ, P ϭ 0.008; No other significant improvements were noted between acute Verbal Scale IQ, P ϭ 0.019; and Performance Scale IQ, and follow-up assessments in either group. P ϭ 0.011). Similarly, significant improvements were noted in both groups in tests of overall memory (coiling: RMT Level of Impairment in Each Cognitive Domain Words, P ϭ 0.015; RMT Faces, P ϭ 0.008; Rey Complex A longitudinal analysis of levels of impairment in cognitive Figure Test, P ϭ 0.008; clipping: RMT Faces, P ϭ 0.003; functioning (none, mild to moderate, and severe) indicates that Paired Associate Learning test Trial 2, P ϭ 0.018; Rey both groups improved across the range of cognitive domains Complex Figure Test, P ϭ 0.005), executive functions (coil- from the acute to the follow-up stage (see Table 3). The only ing: Controlled Oral Word Association Test, P ϭ 0.028, exception is that the coiled group did not show an improve- Stroop Test, P ϭ 0.05; Clipping: Modified Card Sorting Test ment in the verbal memory domain overall from the first to the categories, P ϭ 0.008; Stroop Test, P ϭ 0.031; Trail B time, second assessment (despite the improvement in this group on P ϭ 0.038; Trail B errors, P ϭ 0.031) and speed of information the RMT Words test), whereas the clipped group showed some processing (coiling: Digit Copy, P ϭ 0.011; Number improvement. Furthermore, clipped patients experienced a Cancellation, P ϭ 0.032; Symbol Digit Modalities Test, greater decline in intellectual functioning (relative to premorbid P ϭ 0.012; Clipping: Symbol Digit Modalities Test, P ϭ 0.005). levels) acutely when compared with the coiled patients.

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TABLE 3. Percentages of patients with no impairment, mild to moderate impairment, and severe impairment in each cognitive domain at first assessment (Time 1) and second assessment (Time 2) c,d (12 ؍ a,b Clipping (n (11 ؍ Coiling (n Cognitive domain None Mild to moderate Severe None Mild to moderate Severe Time 1 Time 2 Time 1 Time 2 Time 1 Time 2 Time 1 Time 2 Time 1 Time 2 Time 1 Time 2 Intelligence 55.6 66.7 22.2 33.3 22.2 0.0 36.4 90.0 45.5 10.0 18.2 0.0 Advanced progressive 72.7 90.9 0.0 0.0 27.3 9.1 83.3 100.0 0.0 0.0 16.7 0.0 matrices Verbal memorye 45.5 45.5 45.5 45.5 9.1 9.1 41.7 72.7 33.3 27.3 25.0 0.0 Visual memoryf 27.3 63.6 54.5 36.4 18.2 0.0 33.3 72.7 41.7 27.3 25.0 0.0 Languageg 44.4 66.6 33.3 22.2 22.2 11.2 72.7 80.0 9.1 20.0 18.2 0.0 Perceptionh 72.7 90.9 18.2 9.1 9.1 0.0 91.7 100.0 8.3 0.0 0.0 0.0 Executivei 9.1 36.4 54.5 36.4 36.4 27.3 0.0 54.5 75.0 45.5 25.0 0.0 Speedj 18.2 45.5 72.7 54.5 9.1 0.0 50.0 81.8 50.0 18.2 0.0 0.0 Other tests Spellingk 70.0 77.8 0.0 0.0 30.0 22.2 100.0 100.0 0.0 0.0 0.0 0.0 Calculationl 60.0 55.5 0.0 0.0 40.0 44.4 75.0 90.9 0.0 0.0 25.0 9.1

a At Time 1, two patients did not have complete Wechsler Adult Intelligence Scale (WAIS-R) results and three patients did not have language tests. b At Time 2, two patients did not have complete WAIS-R results or language tests. c At Time 1, one patient did not have complete WAIS-R results or language tests. d At Time 2, one patient did not have reassessment and another patient did not have complete WAIS-R results or language tests. e Recognition memory, including words, Paired Associate Learning test, Trial1, and Trial 2. f Recognition memory, including face and delay recall of the Rey-Osterrieth Complex Figure. g Graded naming test or Oldfield Naming Test and synonym test. h Silhouettes or incomplete letters subtest of the Visual Object and Space Perception Battery; Cube analysis and Trail Making Test Part B. i Controlled Oral Word Association Test, Stroop Colour-Word Test, Categories Achieved on the Modified Card Sorting Test and Trail Making Test Part B. j Digit copy, “0” Cancellation, Symbol Digit Modalities Subtest of WAIS-R and Trail Making Test Part A. k Oral graded spelling test. l Oral graded difficulty calculation test.

Importantly, however, the clipped patients showed relatively level of impairment in these domains was certainly more greater improvements in intellectual functioning than the severe in the acute phase, there was evidence for residual, coiled patients by the post-acute follow-up stage. less severe deficits in these areas in the post-acute phase, par- ticularly in memory, frontal executive functions, naming DISCUSSION skills, and speed of information processing. Analysis of cognitive test performances in the acute phase The aim of this prospective study was to compare the neu- after treatment for this series of patients shows little difference ropsychological status of patients with aneurysmal SAH who between patients who underwent clipping and those who had undergone surgical clipping with patients who had underwent coiling across a range of cognitive domains. This endovascular coiling at acute (within 2 wk after surgery) and finding is broadly consistent with the results of Koivisto et al. post-acute (6 mo after surgery) stages of recovery. The basic (14) in their neuropsychological screen of patients in which they characteristics of both treatment groups were similar in terms found no significant differences between the two groups 10 of age, education, sex, and clinical factors such as the World days after treatment. In the present study, however, there was a Federation of Neurological Surgeons grade on admission, difference between the two groups on one measure of verbal time between the ruptured aneurysm and treatment, time recall memory, in which coiled patients performed significantly between treatment and neuropsychological assessment, and better than clipped patients after NART scores were accounted the number of days between the initial and follow-up neu- for. This indicates a trend toward a more favorable outcome for ropsychological assessments. There was, however, a trend for coiled patients in memory functioning in the acute phase. clipped patients in this study to have a higher estimated pre- The present study shows significant, widespread improve- morbid intellectual level than coiled patients, although this ments in cognitive functioning from the acute to the 6-month factor has been accounted for in our analysis of the results. postacute follow-up examinations for SAH patients in both the Consistent with previous studies (9, 10, 15, 21, 29), we found clipped and coiled groups. This finding is in keeping with the significant impairments in memory, executive functioning, improvements documented by Koivisto et al. (14) across a and speed of information processing in a series of patients range of cognitive tests in both groups of patients. In our study, with SAH secondary to ruptured aneurysm. Although the a comparison of intragroup changes in cognitive test perform-

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ance between the acute and post-acute assessments showed acute phase after treatment, we suggest that coiled patients, hav- improvements in tests of general intelligence, memory, execu- ing been spared neurosurgical intervention, may have a slightly tive functions, and speed of information processing in both more favorable outcome than patients treated with clipping; groups. Interestingly, we found greater improvements in the however, both groups of patients experience improvements in clipped group, particularly in intellectual and memory func- cognitive functioning by the post-acute, long-term stage of recov- tions. One possible explanation for this finding is that clipped ery, with clipped patients perhaps having more ground to patients experienced a greater initial decline in cognition from recover cognitively during this period. In contrast to previous premorbid levels and, therefore, had further ground to recover studies, our results favor the clipped patients at the time of than coiled patients. follow-up, although this may be a function of the inherent differ- In the present study, we found residual cognitive impair- ence in intellectual level between the two groups in the present ments in both groups at the time of the follow-up examina- study. Future studies would benefit from larger samples and tions, with a significant proportion of patients continuing to inclusion of patients with unruptured intracranial aneurysms, have at least mild to moderate cognitive deficits, most notably which would allow us to further delineate the relative effects of in memory, executive, and psychomotor speed/attention func- surgery and the hemorrhage on cognitive outcome. There is no tions. Previous studies directly comparing post-acute cognitive doubt that further prospective, longitudinal research is needed in outcome in patients treated with either neurosurgical clipping this area to increase our understanding of the cognitive out- or endovascular coiling have produced a rather inconsistent comes associated with either neurosurgical clipping or endovas- picture with varying methods used. Our results most closely cular coiling as current treatment options for patients with SAH resemble the findings from Koivisto et al.’s (14) prospective secondary to ruptured aneurysms. longitudinal study in which no significant differences emerged between clipped and coiled patients between the acute stage REFERENCES and the 3- and 12-month assessments on a range of measures. After we accounted for the difference between the groups in 1. Army Individual Test Battery: Manual and Directions for Scoring. 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Q J Exp is an extremely important piece of information, and I am certain that we Psychol 17:273– 281, 1965. will be hearing more from this group regarding cognitive outcome. In 23. Raven JC: Advanced Progressive Matrices. Oxford, Psychologists Press, 1943. 24. Rey A: Psychological examination of traumatic encephalitis cases [in French], SAH, it seems that the dysfunction and survival are related to the mag- in Rey A (ed): Clinical Psychology and Neurology [in French]. Neurochatil, nitude of the hemorrhage. It will be very interesting to see larger groups Delachaux et Niestle, 1941. of patients in an analysis of the treatment of unruptured aneurysms in 25. Smith A: Symbol Digit Modalities Test (SDMT) Manual (Revised). Los Angeles, regard to cognitive outcome. The authors are to be congratulated on a Western Psychological Services, 1982. very important contribution to the neurological literature. 26. Spetzger U, Gilsbach JM: Results of early aneurysm surgery in poor-grade patients. Neurol Res 16:27–30, 1994. Robert H. Rosenwasser 27. Spreen O, Benton AL: The Neurosensory Center Comprehensive Examination for Philadelphia, Pennsylvania Aphasia. Victoria, University of Victoria Neuropsychology Laboratory, 1969. 28. Stenhouse LM, Knight RG, Longmore BE, Bishara SN: Long-term cognitive he authors have reported the results of a prospective, longitudinal deficits in patients after surgery on aneurysms of the anterior communicating Tstudy in which they explored the neuropsychological outcome after artery. J Neurol Neursurg Psychiatry 54:909–914, 1991. clipping and coiling procedures for aneurysmal SAH, spanning both 29. Tidswell P, Dias PS, Sagar HJ, Mayes AR, Battersby RD: Cognitive outcome the acute and long-term follow-up periods. Twenty-three patients after aneurysm rupture: Relationship to aneurysm site and perioperative complications. Neurology 45:875–882, 1995. treated for aneurysmal SAH at a single institution were recruited 30. Trennary MR, Crossen B, DeBoe J, Leber WR: Stroop Neuropsychological prospectively; 12 underwent surgical clip ligation and 11 were treated Screening Test (SNST). Odessa, Psychological Assessment Recourses, Inc., 1989. with endovascular therapy. Comprehensive, standardized neuropsy- 31. Warrington EK: Recognition Memory Test. Windsor, NFER-Nelson, 1984. chological testing was performed within 2 weeks of treatment and at 6 32. Warrington EK, James M: The Visual Object and Space Perception Battery. Bury months after therapy. St. Edmunds, Thames Valley Test Co., 1991. The authors demonstrated that there were minimal differences 33. Wechsler D: Wechsler Adult Intelligence Scale-Revised. New York, Psychological between endovascular coiling and surgical clipping in the long-term Corp., 1981. cognitive outcome. In the acute phase, patients undergoing endovascu- 34. Willison JR, Warrington EK: Cognitive retardation in a patient with preserva- lar coiling had a slightly better cognitive outcome than patients under- tion of psychomotor speed. Behav Neurol 5:113–116, 1992. 35. World Federation of Neurological Surgeons: Report of World federation of going craniotomy. However, these differences disappeared and both Neurological Surgeons Committee on Universal Subarachnoid Grading Scale. groups experienced significant improvement in cognitive functioning J Neurosurg 68:985–986, 1988. by 6 months after therapy. This article illustrates the likelihood that the initial SAH has far more impact on the ultimate outcome of patients than the modality of therapy. COMMENTS However, there are some important limitations of this study that may have influenced the results. Because these patients all presented with his article details a prospective neuropsychological analysis of SAH and did not have preexisting neurological or psychiatric disorders, patients with subarachnoid hemorrhage (SAH) undergoing clipping T they had not undergone premorbid neuropsychological testing to estab- or coiling. This study is well-designed and executed and examines a lish a baseline. The authors report that the group of patients undergoing highly relevant clinical question. An inherent weakness in the method- clip ligation of their aneurysms had a marginal, non-significant differ- ology is the lack of the randomization to one treatment modality or the ence in their premorbid intelligence quotient scores, as estimated by the other. Nevertheless, the clinical grades and aneurysm locations were National Adult Reading Test (NART). Furthermore, this series includes well matched between the two groups. The results suggest that the neu- a very small number of patients whose therapeutic intervention was ropsychological and cognitive morbidity noted in many SAH survivors determined by the treating physicians and not randomized, potentially is primarily caused by the hemorrhage and its sequlae rather than spe- producing some selection bias. It is also well recognized that patients will cific treatment modalities. It is important to note that the percentage of continue to improve their cognitive function for a significant period of patients with anterior communicating aneurysms was similar between time after SAH. Thus, the 6-month follow-up period may not have been the groups. Intuitively, one might have guessed that surgical manipula- long enough to determine the optimal improvement. tion in this area would have been more destructive than endovascular Despite these limitations, the authors’ results are important in demon- therapy. It would be interesting to apply this methodology to a random- strating that all patients experienced cognitive decline after SAH and ized group of patients with unruptured aneurysms. improved in the long-term follow-up period. The modality of treatment Edward Duckworth seemed to have little influence on decline in cognitive function. These H. Hunt Batjer findings reinforce my own bias that the best outcomes in managing Chicago, Illinois patients with aneurysmal SAH will occur in institutions at which both

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microsurgical and endovascular options are provided to patients based bid intellectual level when assessing scores from other neurocognitive on a multidisciplinary and collegial assessment to select the most appro- tests. Although the mean NART score between the two groups was priate therapy for the individual patient and the individual aneurysm. only marginally significant (P = 0.067), this difference was enough in this small sample that the NART score should have been used as a Daniel L. Barrow covariate in all analyses. The results summarized in the tables would Atlanta, Georgia have been easier to interpret if they included findings after controlling for NART scores. To their credit, the authors note the group differ- his article by Frazer et al. measured neurocognitive outcomes after ences that either disappeared or remained when controlling for esti- Ttwo interventions for SAH secondary to aneurysm bleed. The two mated premorbid functioning. However, appreciating the pattern and approaches were surgical clipping and endovascular coiling. The magnitude of potential group differences requires that all group com- authors noted that different medical factors determine which of these parisons be presented using a measure such as the NART to control for two interventions may be best for a particular patient. However, if dif- premorbid patient differences. ferent cognitive outcomes were associated with different interventions, Future studies should avoid combining disparate memory meas- this would be important information for the surgeon and patient when ures into a single domain and should preserve the distinction between considering treatment options. learning, recall, and recognition. Different patterns of memory deficit The current study adds to our understanding of cognitive outcomes can be associated with anatomical regions. Problems encoding and related to interventions for SAH secondary to aneurysm bleed, espe- retrieving information are frequently seen after aneurysm bleed. cially when the findings are considered in light of previous research. Therefore, exploring different patterns within functional domains may Nevertheless, the guidance that can be derived from this study is lim- be important when assessing long-term outcome after neurosurgical ited. The sample size in this study is small, with 11 patients in the intervention. coiled group and 12 in the clipped group. This is likely a function of the Despite the noted limitations, this study adds to our knowledge of phenomenon under investigation and the fact that it was a single-cen- cognitive outcomes after surgical clipping versus endovascular coiling ter study. Multicenter studies with consistent methodologies regarding for the treatment of SAH after aneurysm bleed. Hopefully this study patient selection and assessment methods to further elucidate the ques- and the other work referenced in this article will set the stage for larger, tion under study are clearly needed. multicenter investigations. Furthermore, complicating interpretation of findings from this study Robert L. Kane were differences in NART scores between the coiled and clipped Neuropsychologist groups. Appropriately, this study used the NART to control for premor- Baltimore, Virginia

442 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com CLINICAL STUDIES

EMBOLIZATION BEFORE RADIOSURGERY REDUCES THE OBLITERATION RATE OF ARTERIOVENOUS MALFORMATIONS

Yuri M. Andrade-Souza, M.D. OBJECTIVE: To evaluate the arteriovenous malformation (AVM) obliteration rate and the Division of Neurosurgery, clinical outcome after radiosurgery in patients with and without previous embolization. University of Toronto, Sunnybrook Health Sciences Centre, METHODS: Of 244 patients who underwent linear accelerator radiosurgery for AVMs Toronto Western Hospital, at the Sunnybrook Health Sciences Centre between 1989 and 2000, 61 patients had Toronto, Canada embolization before radiosurgery and complete follow-up for at least 3 years. For 47 of these 61 patients (Group A, embolization plus radiosurgery), we were able to find 47 Meera Ramani matching patients without previous embolization (Group B, radiosurgery alone). This group Division of Neurosurgery, University of Toronto, of matching patients had the same AVM volume (after embolization in Group A), loca- Sunnybrook Health Sciences Centre, tion, and marginal dose. The radiosurgery-based AVM score and the obliteration pre- Toronto Western Hospital, diction index were calculated. Toronto, Canada RESULTS: The median follow-up period was 44 months. Nidus obliteration was achieved Daryl Scora, Ph.D. in 22 patients in Group A (47%) and 33 patients in Group B (70%, P ϭ 0.036). Permanent Department of Radiation Oncology, deficit related to hemorrhage or radiation occurred in three patients (6%) in Group A University of Toronto, and three patients (6%) in Group B. During the first 3 years after radiosurgery, two Sunnybrook Health Sciences Centre, patients (4%) in Group A experienced hemorrhage; in Group B, five patients (11%) Toronto Western Hospital, ϭ Toronto, Canada experienced hemorrhage (P 0.2). In Group B, two patients (4%) died and two patients (4%) had their AVM surgically removed. Both deaths were related to hemorrhage dur- May N. Tsao, M.D. ing the latency period. The excellent outcome (obliteration plus no deficit) in Group A Department of Radiation Oncology, was 47% compared with 64% in Group B (P ϭ 0.146). There was no difference in the University of Toronto, obliteration prediction index and the radiosurgery-based AVM score between Groups Sunnybrook Health Sciences Centre, Toronto Western Hospital, A and B. The predicted rates of obliteration and excellent outcome were 55 and 62.5%, Toronto, Canada respectively, according to the obliteration prediction index and the radiosurgery-based AVM score. Karel terBrugge, M.D. CONCLUSION: Embolization before radiosurgery significantly decreases the obliter- Department of Medical Imaging, ation rate, even in AVMs with the same volume, location, and marginal dose. Although University of Toronto, Toronto Western Hospital, an excellent outcome rate was higher in the group without embolization, this was not Toronto, Canada statistically significant. KEY WORDS: Arteriovenous malformation, Dosimetry, Embolization, Outcome, Radiosurgery, Treatment Michael L. Schwartz, M.D.

Division of Neurosurgery, Neurosurgery 60:443–452, 2007 DOI: 10.1227/01.NEU.0000255347.25959.D0 www.neurosurgery-online.com University of Toronto, Sunnybrook Health Sciences Centre, Toronto Western Hospital, Toronto, Canada adiosurgery is recommended for the abnormalities that predict a high risk of hem- management of brain arteriovenous orrhage during the latency period after radio- Reprint requests: malformations (AVMs) smaller than 3 surgery. For instance, AVMs with intranidal Michael L. Schwartz, M.D., R cm in diameter when microsurgery carries a and venous aneurysms or those associated Division of Neurosurgery, Suite A129, Sunnybrook Health Sciences Centre, high risk of morbidity (2, 37). Patients with with a large arteriovenous fistula (AVF), 2075 Bayview Avenue, AVMs larger than 3 cm in diameter have been which are less sensitive to radiosurgery, are Toronto, ON, M4N 3M5-Canada. treated with embolization to reduce their size usually treated with pre-radiosurgical emboli- Email: [email protected] before radiosurgery (18, 20, 30, 34, 37, 49) zation (6, 20, 24, 29, 34). These recommenda- when microsurgery is not possible. Pre- tions for embolization and the cut-off of 3 cm Received, May 17, 2006. radiosurgical embolization is also recom- are supported by anecdotal case series and Accepted, November 1, 2006. mended for AVMs with angioarchitectural nonrandomized cohort studies.

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Overall, the rate of cure for patients receiving radiosurgery Lafayette, IN). Using dynamic subtraction fluoroscopy, the resid- for brain AVMs ranges from 53 to 86.6% (3, 4, 7, 8, 14, 17, 27, 42, ual nidus and feeders, as well as the glue cast, can be visualized. 52, 54). The incidence of radiation-related complications ranges Anticoagulation was reversed at the end of the procedure. between 2.4 and 9.4% using a gamma knife or linear accelera- tor (LINAC) system with a follow-up period of 2 to 56 months Radiosurgical Procedure (7, 8, 11, 14, 42, 51). Several factors, including the AVM volume Radiosurgery was delivered using a 6-MV LINAC system and location, the patient’s age, the conformality of the treat- and the dynamic rotation technique described by Podgorsak ment, the marginal dose, and the number of isocenters, are et al. (34) and Souhami et al. (48). Specific modifications were associated with the obliteration rate and complications after made as described by O’Brien et al. (36) and Gillies et al. (19). radiosurgery (5, 10, 12, 14, 15, 26, 27, 31, 32, 41, 46, 53, 55). During the procedure, an Olivier-Bertrand-Tipal stereotactic Likewise, some previous studies have shown a negative corre- frame (Tipal Instruments, Montreal, Canada) was applied to lation between previous embolization and the obliteration rate the patient’s head under local anesthesia (38). The patients sub- after radiosurgery (35, 41, 45). sequently underwent a dynamic enhanced computed tomo- The objective of the present study is to evaluate the obliter- graphic scan of brain, followed by stereotactic angiography. ation rate and the clinical outcome after radiosurgery in Images were transferred to the radiosurgery software, a modi- patients with and without previous embolization. Considering fied version of the CMI software (Montreal Stereotactic that other factors can be related to radiosurgical outcome, these Planning System; CMI Services, Montreal, Canada). Target def- two groups were matched by anatomic location, AVM volume inition, isocenter localization, and dose planning were per- before radiosurgery, and marginal dose. formed by a team consisting of a neurosurgeon (MLS), a radi- ation oncologist (MNT), and a physicist (DS). The dose and PATIENTS AND METHODS marginal isodose line prescribed were chosen according to the neurosurgery and radiation oncology team’s experience with LINAC radiosurgery. In general, the dose prescription was Patients 15 Gy given as a marginal dose at the 67% isodose line or 20 Gy Between October 1989 and December 2000, 244 radiosurgical at the 90% isodose line. This decision was based on the degree treatments were performed to treat brain AVMs at the of eloquence of the area treated. The AVM volume was calcu- Sunnybrook Health Sciences Centre. All patients were initially lated using the best fit isodose method (27). reviewed by the Brain Vascular Malformation Study Group, a multidisciplinary team at the University of Toronto consisting Patient Outcome of vascular neurosurgeons, endovascular radiologists, and radi- Any new or worsened neurological symptoms were consid- ation oncologists. Of these 244 patients, 61 had embolization ered to be related to radiation when not caused by hemorrhage. before radiosurgery and complete follow-up for at least 3 years. We divided the complications into permanent (duration of For 47 of these 61 patients (Group A, embolization plus radio- symptoms Ͼ 6 mo) or transient (Ͻ6 mo) deficits. These compli- surgery), we were able to find 47 matching patients without cations were assessed by our team or, in the case of patients liv- previous embolization (Group B, radiosurgery alone). The ing outside our city, by the neurologist or neurosurgeon group of matching patients had the same AVM volume involved in the patient’s management. These patients were fol- (Ͻ3 cm3, 3–10 cm3, or Ͼ10 cm3 [after embolization in Group lowed with annual magnetic resonance imaging (MRI) scans. A]), location (I, frontal and temporal; II, parietal, occipital, cor- Digital subtraction angiography (DSA) was performed as part pus callosum, and cerebellar; III, basal ganglia, thalamic, and of the 3-year follow-up evaluation. DSA diagnosis of AVM brainstem), and same marginal dose during the radiosurgical obliteration was defined by the total disappearance of the treatment. When multiple matches were found in our data- nidus, including any early filling veins on angiography; MRI base, the match was selected by choosing the patient whose last diagnosis of AVM obliteration was defined by the disappear- name was listed first alphabetically. ance of any flow-voids in the area of the previously seen AVM, as well as non-visualization of the nidus on magnetic reso- Endovascular Procedure nance angiography. An attempt was made to ensure adequate The endovascular procedure for AVM embolization was follow-up evaluation and confirmation of complete AVM oblit- described in a previous publication (22). Almost all embolization eration based on DSA. MRI-based diagnosis of AVM oblitera- procedures were performed under general anesthesia. Initially, a tion was used only in patients who refused follow-up DSA. vascular sheath was placed in the femoral artery; the patient This analysis assumes that every AVM that appears to be oblit- was subsequently anticoagulated. A 5- or 6-French guide erated on MRI would, in fact, be completely obliterated if those catheter was placed in the internal carotid or vertebral artery. patients had undergone angiography. This is likely not the case. Angiography was then performed, followed by superselective Nevertheless, assuming that the predictive value of a negative catheterization of the AVM feeders, which allowed a better post-radiosurgical MRI is 91% (43), the obliteration rate would understanding of the AVM angioarchitectural findings. Nidal not be reduced significantly (1). On the other hand, if we had glue deposition was performed using an admixture of included only those patients who had undergone angiography, N-butyl cyanoacrylate and Lipiodol (Lafayette Pharmacal, this would have spuriously increased the obliteration rate (23).

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Regardless, the same criteria of obliteration were applied for RESULTS the three two groups compared in this study. Patient outcomes were classified as excellent (complete oblit- Patients, AVM Characteristics, and Treatment eration and no new or worsened deficits related to radiation or The median follow-up period was 44 months (range, 18–122 hemorrhage), good (complete obliteration with minor deficits), mo; mean, 48 mo). Patients with follow-up periods shorter than fair (complete obliteration with major deficits), unchanged 3 years either died or had their AVMs removed surgically dur- (residual AVM and no new or worsened deficits), poor (persist- ing the latency period (n ϭ 4). There were 38 women (40%) and ent AVM and new or worsened deficits related to radiation or 56 men (59%) with a median age of 39 years (range, 5–70 yr; hemorrhage), or death at the time of the last follow-up exami- mean, 39 yr). Clinical presentation, previous surgery, AVM nation. This classification was previously proposed by Pollock location and side, venous drainage, eloquence, the initial and Flickinger (40) to describe the radiosurgical outcome in Spetzler-Martin grade, and the grade during the radiosurgery AVMs. In this system of classification, a deficit that does not are summarized in Table 1. The maximum diameter during interfere with a patient’s normal level of activities is considered diagnosis and radiosurgery, treatment volume, marginal doses, minor and a deficit that results in a decline in a patient’s level of functioning is considered major. Good and fair results were con- sidered together because no objective quality of life assessment TABLE 1. Clinical characteristics of 94 patients included in was used in this study. The outcome was classified as poor and this studya the AVM was deemed unobliterated in any patient who had the AVM removed before the end of the 3-year follow-up period. Group A, Group B, no. (%) no. (%) An AVM was also deemed unobliterated in any patient who died during the first 3 years after treatment. The determination Previous hemorrhage 25 (53.2) 18 (38.3) of outcome was blinded to the study hypothesis that emboliza- Previous surgery 8 (17) 4 (8.5) tion alters obliteration, morbidity, and hemorrhage. AVM side Left 22 (46.8) 27 (57.4) Radiosurgery-based AVM Score and the Midline 9 (19.1) 3 (6.4) Obliteration Prediction Index Right 16 (34.0) 17 (36.2) Location The radiosurgery-based AVM score (RBAS) was calculated as Frontal or temporal 18 (38.3) 18 (38.3) described by Pollock and Flickinger (40). Briefly, the RBAS is Parietal, occipital, 18 (38.3) 18 (38.3) 3 ϩ calculated as follows: 0.1 (volume of the lesion in cm ) 0.02 intraventricular, corpus ϩ (patient’s age in yr) 0.3 (location of the lesion: frontal or tem- callosum, cerebellar poral, 0; parietal, occipital, intraventricular, corpus callosum, Basal ganglia, thalamic, 11 (23.4) 11 (23.4) cerebellar, 1; basal ganglia, thalamic, brainstem, 2). When an brainstem AVM involves multiple sites, fractional values were used Volume according to the number of sites. The RBAS was used to con- <3 cm3 18 (38.3) 18 (38.3) firm that the expected excellent outcome rate is the same for 3–10 cm3 11 (23.4) 11 (23.4) Groups A and B because patients were matched according to >10 cm3 18 (38.3) 18 (38.3) AVM volume and location. Although the RBAS was initially Eloquence described using data from gamma knife radiosurgery, we have No 10 (21.3) 10 (21.3) recently confirmed its use as a predictor for outcome in LINAC Yes 37 (76.6) 37 (76.6) radiosurgery (1). Venous drainage The obliteration prediction index (OPI) was calculated by Superficial 16 (34) 19 (40.4) dividing the marginal dose (Gy) by the lesion diameter (cm), Deep and superficial/deep 31 (66) 28 (59.6) as described by Schwartz et al. (46). The OPI was used to con- Spetzler-Martin Grade at diagnosis firm that the expected obliteration rate was the same for I 2 (4.3) 2 (4.3) Groups A and B. II 8 (17) 17 (36.2) III 25 (53.2) 24 (51.1) Statistical Analyses IV 12 (25.5) 4 (8.5) The outcome and all data pertinent to the treatment were col- V —— lected using SPSS software (version 9.0 for Windows; SPSS, Spetzler-Martin Grade at radiosurgery Inc., Chicago, IL). Comparisons of nominal measurements were I 2 (4.3) 2 (4.3) made using the χ2 test. Linear regression and logarithmic II 13 (27.7) 17 (36.2) regression were performed using the same software. Alpha III 26 (55.3) 24 (51.1) error, power, and sample size were calculated using Primer of IV 6 (12.8) 4 (8.5) Biostatistics statistical software (version 5.0; McGraw-Hill a Group A, embolization ϩ radiosurgery; Group B, radiosurgery alone. Medical, New York, NY).

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dose line and 16 patients (34%) in each group were treated TABLE 2. Arteriovenous malformation maximum diameter before with 20 Gy given as the marginal dose at the 90% isodose line. and after embolization, radiosurgical treatment volume, mar- ginal dose, obliteration prediction index, and radiosurgery-based Obliteration Rate, Radiation-induced Complications, arteriovenous malformation score for 94 patients included in Hemorrhage, and Death a this study Nidus obliteration was achieved in 22 patients (47%) in Group A Group B Group A and 33 patients (70%) in Group B (P ϭ 0.036). Based Initial AVM maximum diameter (cm) only on angiographically-confirmed obliteration, 18 out of 47 Mean 3.17 2.42 AVMs (39%) in Group A and 28 out of 47 AVMs (60%) in Group ϭ Minimum 0.9 1.00 B were obliterated (P 0.06). Permanent deficit induced by Maximum 4.8 5.8 radiation or related to hemorrhage was observed in three Median 3.2 2.5 patients (6%) in Group A and three patients (6%) in Group B. AVM maximum diameter during During the first 3 years after radiosurgery, two patients (4%) radiosurgery (cm) in Group A experienced hemorrhage, one of whom had hemor- Mean 2.49 2.30 rhage as a initial presentation. In Group B, five patients (11%) ϭ Minimum 0.8 1.0 experienced hemorrhage (P 0.2). Among these five patients, Maximum 4.4 4.2 two had history of hemorrhage as the initial presentation. Two Median 2.5 2.3 Group B patients (4%) died as a result of hemorrhage during Radiosurgical treatment volume (cm3) the latency period and two (4%) had the AVM surgically Mean 7.42 6.66 removed after bleeding. There was no death or surgical Minimum 0.35 0.35 removal in Group A during the first 3 years. Excluding the four Maximum 18.3 18.3 patients who did not complete 3 years of follow-up evalua- Median 6.42 4.8 tion, 68 out of 94 patients (72%) underwent final assessment of Marginal dose (Gy) their AVMs by angiography. Mean 16.7 16.7 The clinical outcomes for Groups A and B are shown in Minimum 15 15 Figure 1. The outcome was also examined based on the pres- Maximum 20 20 ence of hemorrhage as an initial presentation of the AVM. Median 15 15 Interestingly, the same outcome was observed for patients with OPI and without hemorrhage before the treatment (Fig. 2). Mean 8.4 8.7 The obliteration rate in Group A was 42% for patients treated Minimum 3.16 3.57 with a marginal dose of 15 Gy compared with 56% in patients ϭ Maximum 22.99 22.99 treated with 20 Gy (P 0.3). In Group B, the obliteration rate Median 7.06 8.37 was 65% for patients treated with a marginal dose of 15 Gy ϭ RBAS compared with 81% for patients treated with 20 Gy (P 0.3). Mean 1.71 1.76 RBAS and OPI Minimum 0.64 0.75 Maximum 3.34 3.53 The median RBASs for Groups A and B were 1.55 (range, Median 1.55 1.66 0.64–3.34; mean, 1.71) and 1.66 (range, 0.75–3.53; mean, 1.76),

a AVM, arteriovenous malformation; OPI, obliteration prediction index, RBAS, radiosurgery-based AVM score.

OPI, and RBAS for the two groups are shown in Table 2. There was no difference in volume, minimal dose, and location between Groups A and B because they were matched based on these three factors. In Group A, the mean AVM diameter was 3.17 cm (range, 0.9–4.8 cm; median, 3.2 cm) before embolization and 2.49 cm (range, 0.8–4.4 cm; mean, 2.5 cm) after embolization. The aver- age maximum reduction in diameter among Group A patients was 22%. Seven patients showed no reduction in diameter, 28 patients had a reduction of less than 30%, and 12 patients had a reduction greater than 30% in the maximum diameter after embolization. Thirty-one patients (66%) in each group were FIGURE 1. Bar graph showing the clinical outcome for Groups A and B. treated with 15 Gy given as the marginal dose at the 67% iso-

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FIGURE 3. Line graph showing the expected rate of AVM obliteration according to AVM volume in patients with and without previous embolization. This information is derived from the results of 94 patients matched by volume, location, and marginal dose. Rsq, R2.

In the group of patients with previous embolization, the risk of hemorrhage during the first 3 years 4% (two patients) com- pared with an 11% risk in the group with no previous embolization. Although the rate of hemorrhage was more than twice as high in the group without embolization compared with the group with embolization, this was not statistically sig- nificant. Assuming that this was a β error and considering this percentage difference (4.3 versus 10.6%), the study would have required 505 patients to achieve a P value of 0.05 considering a power of 0.8. FIGURE 2. Bar graph showing the clinical outcome for Groups A and B taking the effect of hemorrhage as the initial presentation of the AVM into consideration. DISCUSSION

Previous Studies of Embolization Followed respectively. The median OPIs for Groups A and B were 7.06 by Radiosurgery (range, 3.16–22.99; mean, 8.42) and 8.37 (range, 3.57–22.99; In the present study, previous embolization was associated mean, 8.79), respectively. There were no differences in RBAS or with a lower rate of obliteration when comparable AVMs (same OPI between Groups A and B (t test, P ϭ 0.72 and 0.68, respec- volume and location) were treated with the same marginal tively). According to the OPI and the RBAS, the expected oblit- dose. This finding has been described in previous studies using eration and excellent outcome rates for both groups are 55 and linear regression. Pollock et al. (41) studied the results of 220 63%, respectively (40, 46). In Group A, the results found for patients after gamma knife radiosurgery. Forty patients (18%) obliteration and excellent outcome were 47 and 47%, respec- had previous embolization. A univariate linear regression and tively. In Group B, the obliteration and excellent outcome rates a multivariate linear regression with 11 other factors and a P were 70 and 64%, respectively. Logarithmic regression was value less than identified previous embolization as a negative used to calculate new curves to predict obliteration using the predictor of obliteration (P Ͻ 0.001 and P ϭ 0.02). OPI and taking previous embolization into consideration Schlienger et al. (45) studied 169 patients with AVMs treated (Fig. 3). The same was performed with the RBAS using linear with LINAC radiosurgery, 61 (36%) of whom had previous regression to predict excellent outcome with consideration of embolization. The obliteration rate for patients with previous previous embolization (Fig. 4). The relation between volume embolization was 54% compared with 71% for patients with no and obliteration is displayed in Figure 5. embolization (P ϭ 0.03). This factor was independently associ- The excellent outcome in Group A was 47% compared with ated with a lower obliteration rate in a multivariate analysis. 64% in Group B (P ϭ 0.146). This was not a significant differ- Miyawaki et al. (35) reported the results of 73 patients with ence in our study. The sample size necessary to show a signif- intracranial AVMs treated with LINAC radiosurgery. Forty- icant difference with an equivalent mix of patients would be three patients (59%) had previous embolization. Obliteration 255 patients with alpha equals 0.05 and power equals 0.08. was negatively associated with previous embolization. The

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FIGURE 5. Line graph showing the expected rate of excellent outcome (obliteration with no deficits related to radiation or hemorrhage during the latency period) taking the RBAS into consideration. Rsq, R2.

Although the risk of complications associated with radiation and hemorrhage was smaller in the group with previous embolization (seven versus 12 complications), this was counter- balanced by the complications associated with the embolization (eight complications). Based on our data, which is consistent with the findings of previous publications, we concluded that using embolization to decrease the volume of AVMs before radiosurgery significantly decreases the obliteration rate. In our experience, this is true for AVMs with volumes up to 15 cm3, regardless of the maximum AVM diameter. Other authors have inferred that AVMs with 3 FIGURE 4. Line graphs showing the expected rate of obliteration for volumes smaller than 30 cm can be treated effectively with an patients with (A) and without (B) embolization according to the OPI. acceptably low complication rate (53). The risk of radiosurgical complications is not significantly changed by decreasing the AVM volume with embolization. In obliteration rate was 26 and 76% for patients with and without fact, the slight decrement in risk achieved in most cases is over- previous embolization, respectively. AVMs with previous balanced by the complication rate of embolization. The mortal- embolization had a larger median volume than those that were ity rate during brain AVM embolization ranges from 1 to 3.7%; not embolized (12.2 versus 4.2 cm3). In multivariate analysis, the permanent morbidity rate ranges from 3.8 to 14% (9, 16, 21, however, embolization was an independent factor for oblitera- 22, 33, 50). Embolization that targets the nidus for subsequent tion after radiosurgery. radiosurgery, rather than targeting the feeders for subsequent Söderman et al. (47) described a clinical hypothetical model microsurgery, is more challenging, and has higher rates of mor- to compare the results of AVMs treated with embolization plus bidity and mortality (22). Of note, a higher concentration of radiosurgery and radiosurgery alone. Eighty patients had lipiodol is used in our center for better nidus penetration dur- stereotactic angiography performed before and after emboliza- ing pre-radiosurgery embolization. We could not find evidence tion. Using these images, the two strategies were hypothetically in the literature indicating that partial embolization before compared based on previously described outcome models. For radiosurgery decreases the risk of hemorrhage during the radiosurgery, obliteration was predicted as a function only of latency period. the minimum radiation dose (26) and the complications were Some patients are cured by embolization. For those patients, based on previous hemorrhage or irradiation, nidus location, the latency period and its risk of hemorrhage is obviated. and the dose distribution (25). The risk of hemorrhage during Vigorous efforts should be made to clarify the factors that iden- the latency period and the complications that arose during tify those patients likely to have successful obliteration of their embolization were also considered. There were no differences AVMs by embolization. Radiosurgery should be administered in the predicted obliteration and complication rates for either to those patients who, despite prediction of likely endovascu- strategy, even when comparing AVMs larger than 10 cm3. lar obliteration, fail to follow the expected course. However, the predicted obliteration rate did not take into At best, reducing the AVM volume by embolization will not account the negative impact of embolization on obliteration. improve the probability of obliteration by radiosurgery if the

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theoretical calculations of Söderman et al. (47) are correct. If, as manifestation was hemorrhage and for AVMs with angioarchi- we have found, the prediction algorithm curves for embolized tectural features suggesting that an endovascular cure is possi- and non-embolized patients are different and there is no bene- ble, embolization has usually been preferred. Taking the archi- fit to embolized patients such as protection from hemorrhage in tecture of the AVM into account, the risk of embolization is the latency period after radiosurgery before obliteration, also considered. embolization should not be offered to these patients. The AVMs were matched according to the volume after embolization. This was done because stereotactic angiography Predicting Radiosurgical Results in AVMs with was not available before embolization. However, considering and without Previous Embolization the decrease in the maximum diameter of AVMs after In this study, we have used two predictors of radiosurgery embolization, this would not change the conclusions of this outcome, the RBAS (40) and the OPI (46), to confirm that the study. For example, in Group A, the mean maximum diameter expected outcome was comparable in both the embolization was 3.17 cm before embolization and 2.49 cm after. For a spher- 3 plus radiosurgery and the radiosurgery alone groups. ical shape, this translates to 16 and 8 cm , respectively. The 3 However, the RBAS overestimated the excellent outcome in expected obliteration rate for a 16 cm AVM without previous 3 patients with previous embolization in this cohort. On the other embolization is 55% compared with 45% for an 8 cm AVM hand, the OPI averaged the obliteration in patients with and with previous embolization (Fig. 3). This is a “best case” analy- without previous embolization. This probably reflects the pro- sis for embolization. In fact, most AVMs do not have a uniform file of the initial series from which the RBAS and OPI were decrease in the volume, even when there is a decrease in the derived. In the RBAS initial series, just 5% of the patients had maximum diameter. previous embolization compared with 34% in the OPI series (54). Neither prediction algorithm considers embolization in CONCLUSION the prediction of outcome. We conclude that the role of pre-radiosurgery embolization is Radiosurgical Plan in Previously Embolized AVMs problematic. Embolization before radiosurgery significantly decreases the obliteration rate, even considering the AVM vol- The lower radiosurgical obliteration rate in patients with pre- ume, location, and marginal dose. Although the rate of excel- vious embolization has been attributed to two main factors, lent outcome was higher in the group without embolization, namely recanalization of the embolized AVM compartments this was not statistically significant and a larger number of (17, 28, 30, 44) and increased difficulty in AVM delineation for patients must to be studied. Based on the results of this study, radiosurgical planning (28, 30, 35, 44). It is known that patients however, we can no longer support the practice of planned embolized with particles have a higher recanalization rate than pre-radiosurgery embolization. patients embolized with liquid material. In the present study, all patients were embolized with liquid material, which prob- REFERENCES ably precludes recanalization and, hence, an effect on the oblit- eration rate. The embolized part of the AVMs of some patients 1. Andrade-Souza YM, Zadeh G, Ramani M, Scora D, Tsao MN, Schwartz ML: were included in the radiosurgical plan, but we do not have Testing the radiosurgery-based arteriovenous malformation score and the reliable data concerning this. We have recently conducted an modified Spetzler-Martin grading system to predict radiosurgical outcome. J experiment from which we concluded that the glue admixture Neurosurg 103:642–648, 2005. 2. Anonymous: Arteriovenous malformations of the brain in adults. N Engl J can attenuate the dose delivered to the AVM by as much as 10 Med 340:1812–1818, 1999. to 15% (unpublished data). 3. Aoki Y, Nakagawa K, Tago M, Terahara A, Kurita H, Sasaki Y: Clinical eval- The obliteration rate was higher in patients treated with a uation of gamma knife radiosurgery for intracranial arteriovenous malforma- marginal dose of 20 Gy compared with a marginal dose of 15 Gy tion. Radiat Med 14:265–268, 1996. 4. 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Coffey RJ, Nichols DA, Shaw EG: Stereotactic radiosurgical treatment of cere- Limitations of this Study bral arteriovenous malformations. Gamma Unit Radiosurgery Study Group. Mayo Clin Proc 70:214–222, 1995. The analysis of the outcome of treatment for these patients 8. Colombo F, Pozza F, Chierego G, Francescon P, Casentini L, De Luca G: Linear was performed retrospectively and not all of the embolized accelerator radiosurgery of cerebral arteriovenous malformations: Current patients could be matched with similar non-embolized radio- status. Acta Neurochir Suppl (Wien) 62:5–9, 1994. 9. Debrun GM, Aletich V, Ausman JI, Charbel F, Dujovny M: Embolization of the surgery patients. We have no truly objective criteria for choos- nidus of brain arteriovenous malformations with n-butyl cyanoacrylate. ing embolization. Nevertheless, for AVMs in which the initial Neurosurgery 40:112–121, 1997.

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10. Ellis TL, Friedman WA, Bova FJ, Kubilis PS, Buatti JM: Analysis of treatment 31. Mavroidis P, Theodorou K, Lefkopoulos D, Nataf F, Schlienger M, Karlsson failure after radiosurgery for arteriovenous malformations. J Neurosurg B, Lax I, Kappas C, Lind BK, Brahme A: Prediction of AVM obliteration after 89:104–110, 1998. stereotactic radiotherapy using radiobiological modelling. Phys Med Biol 11. Flickinger JC, Kondziolka D, Lunsford LD, Pollock BE, Yamamoto M, 47:2471–2494, 2002. Gorman DA, Schomberg PJ, Sneed P, Larson D, Smith V, McDermott MW, 32. Meder JF, Oppenheim C, Blustajn J, Nataf F, Merienne L, Lefkoupolos D, Miyawaki L, Chilton J, Morantz RA, Young B, Jokura H, Liscak R: A multi- Laurent A, Merland JJ, Schlienger M, Fredy D: Cerebral arteriovenous malfor- institutional analysis of complication outcomes after arteriovenous malforma- mations: The value of radiologic parameters in predicting response to radio- tion radiosurgery. 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Miyawaki L, Dowd C, Wara W, Goldsmith B, Albright N, Gutin P, Halbach V, 14. Friedman WA, Bova FJ, Bollampally S, Bradshaw P: Analysis of factors pre- Hieshima G, Higashida R, Lulu B, Pitts L, Schell M, Smith V, Weaver K, dictive of success or complications in arteriovenous malformation radio- Wilson C, Larson D: Five year results of LINAC radiosurgery for arteriove- surgery. Neurosurgery 52:296–308, 2003. nous malformations: Outcome for large AVMS. Int J Radiat Oncol Biol Phys 15. Friedman WA, Bova FJ, Mendenhall WM: Linear accelerator radiosurgery 44:1089–1106, 1999. for arteriovenous malformations: The relationship of size to outcome. 36. O’Brien PF, Gillies BA, Schwartz M, Young C, Davey P: Radiosurgery with J Neurosurg 82:180–189, 1995. unflattened 6-MV photon beams. Med Phys 18:519–521, 1991. 16. Frizzel RT, Fisher WS 3rd: Cure, morbidity, and mortality associated with 37. Ogilvy CS, Stieg PE, Awad I, Brown RD Jr, Kondziolka D, Rosenwasser R, embolization of brain arteriovenous malformations: A review of 1246 patients Young WL, Hademenos G; Special Writing Group of the Stroke Council, in 32 series over a 35-year period. Neurosurgery 37:1031–1040, 1995. American Stroke Association: AHA Scientific Statement: Recommendations 17. Gallina P, Merienne L, Meder JF, Schlienger M, Lefkopoulos D, Merland JJ: for the management of intracranial arteriovenous malformations: A state- Failure in radiosurgery treatment of cerebral arteriovenous malformations. ment for healthcare professionals from a special writing group of the Stroke Neurosurgery 42:996–1004, 1998. Council, American Stroke Association. Stroke 32:1458–1471, 2001. 18. Gentili F, Schwartz M, TerBrugge K, Wallace MC, Willinsky R, Young C: A 38. Olivier A, Bertrand G: Stereotaxic device for percutaneous twist-drill insertion multidisciplinary approach to the treatment of brain vascular malformations. of depth electrodes and for brain biopsy. Technical note. J Neurosurg Adv Tech Stand Neurosurg 19:179–207, 1992. 56:307–308, 1982. 19. Gillies BA, O’Brien PF, McVittie R, McParland C, Easton H: Engineering mod- 39. Podgorsak EB, Olivier A, Pla M, Lefebvre PY, Hazel J: Dynamic stereotactic ifications for dynamic stereotactically assisted radiotherapy. Med Phys radiosurgery. Int J Radiat Oncol Biol Phys 14:115–126, 1988. 20:1491–1495, 1993. 40. Pollock BE, Flickinger JC: A proposed radiosurgery-based grading system for 20. Gobin YP, Laurent A, Merienne L, Schlienger M, Aymard A, Houdart E, arteriovenous malformations. J Neurosurg 96:79–85, 2002. Casasco A, Lefkopoulos D, George B, Merland JJ: Treatment of brain arteri- 41. Pollock BE, Flickinger JC, Lunsford LD, Maitz A, Kondziolka D: Factors asso- ovenous malformations by embolization and radiosurgery. J Neurosurg ciated with successful arteriovenous malformation radiosurgery. 85:19–28, 1996. Neurosurgery 42:1239–1247, 1998. 21. Hartmann A, Pile-Spellman J, Stapf C, Sciacca RR, Faulstich A, Mohr JP, 42. Pollock BE, Gorman DA, Coffey RJ: Patient outcomes after arteriovenous Schumacher HC, Mast H: Risk of endovascular treatment of brain arteriove- malformation radiosurgical management: Results based on a 5- to 14-year nous malformations. Stroke 33:1816–1820, 2002. follow-up study. Neurosurgery 52:1291–1297, 2003. 22. Haw CS, terBrugge K, Willinsky R, Tomlinson G: Complications of 43. Pollock BE, Kondziolka D, Flickinger JC, Patel AK, Bissonette DJ, Lunsford embolization of arteriovenous malformations of the brain. J Neurosurg LD: Magnetic resonance imaging: An accurate method to evaluate arteriove- 104:226–232, 2006. nous malformations after stereotactic radiosurgery. J Neurosurg 85:1044– 23. Heffez DS, Osterdock RJ, Alderete L, Grutsch J: The effect of incomplete 1049, 1996. patient follow-up on the reported results of AVM radiosurgery. Surg Neurol 44. Pollock BE, Kondziolka D, Lunsford LD, Bissonette D, Flickinger JC: Repeat 49:373–384, 1998. stereotactic radiosurgery of arteriovenous malformations: Factors associated 24. Inoue HK, Ohye C: Hemorrhage risks and obliteration rates of arteriovenous with incomplete obliteration. Neurosurgery 38:318–324, 1996. malformations after gamma knife radiosurgery. J Neurosurg 97 [Suppl 45. Schlienger M, Atlan D, Lefkopoulos D, Merienne L, Touboul E, Missir O, 5]:474–476, 2002. 25. Karlsson B, Lax I, Soderman M: Factors influencing the risk for complications Nataf F, Mammar H, Platoni K, Grandjean P, Foulquier JN, Huart J, following Gamma Knife radiosurgery of cerebral arteriovenous malforma- Oppenheim C, Meder JF, Houdart E, Merland JJ: Linac radiosurgery for cere- tions. Radiother Oncol 43:275–280, 1997. bral arteriovenous malformations: Results in 169 patients. Int J Radiat Oncol 26. Karlsson B, Lax I, Soderman M: Can the probability for obliteration after Biol Phys 46:1135–1142, 2000. radiosurgery for arteriovenous malformations be accurately predicted? Int J 46. Schwartz M, Sixel K, Young C, Kemeny A, Forster D, Walton L, Franssen E: Radiat Oncol Biol Phys 43:313–319, 1999. Prediction of obliteration of arteriovenous malformations after radiosurgery: 27. Karlsson B, Lindquist C, Steiner L: Prediction of obliteration after gamma The obliteration prediction index. Can J Neurol Sci 24:106–109, 1997. knife surgery for cerebral arteriovenous malformations. Neurosurgery 47. Soderman M, Rodesch G, Karlsson B, Lax I, Lasjaunias P: Gamma knife out- 40:425–431, 1997. come models as a reference standard in the embolisation of cerebral arteriove- 28. Kwon Y, Jeon SR, Kim JH, Lee JK, Ra DS, Lee DJ, Kwun BD: Analysis of the nous malformations. Acta Neurochir (Wien) 143:801–810, 2001. causes of treatment failure in gamma knife radiosurgery for intracranial arte- 48. Souhami L, Olivier A, Podgorsak EB, Pla M, Pike GB: Radiosurgery of cere- riovenous malformations. J Neurosurg 93 [Suppl 3]:104–106, 2000. bral arteriovenous malformations with the dynamic stereotactic irradiation. 29. Marks MP, Lane B, Steinberg GK, Fabrikant JI, Levy RP, Frankel KA, Phillips Int J Radiat Oncol Biol Phys 19:775–782, 1990. MH: Endovascular treatment of cerebral arteriovenous malformations fol- 49. Surdell DL Jr, Bhattacharjee S, Loftus CM: Pros, cons, and current indica- lowing radiosurgery. AJNR Am J Neuroradiol 14:297–305, 1993. tions of open craniotomy versus gamma knife in the treatment of arteriove- 30. Mathis JA, Barr JD, Horton JA, Jungreis CA, Lunsford LD, Kondziolka DS, nous malformations and the role of endovascular embolization. Neurol Res Vincent D, Pentheny S: The efficacy of particulate embolization combined 24:347–353, 2002. with stereotactic radiosurgery for treatment of large arteriovenous malforma- 50. Valavanis A, Yasargil MG: The endovascular treatment of brain arteriovenous tions of the brain. AJNR Am J Neuroradiol 16:299–306, 1995. malformations. Adv Tech Stand Neurosurg 24:131–214, 1998.

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51. Yamamoto M, Hara M, Ide M, Ono Y, Jimbo M, Saito I: Radiation-related In this study, Andrade-Souza et al. have carefully examined the adverse effects observed on neuro-imaging several years after radiosurgery question of whether or not preradiosurgical AVM embolization affects for cerebral arteriovenous malformations. Surg Neurol 49:385–398, 1998. obliteration or clinical outcomes. Although they found that emboliza- 52. Yamamoto M, Jimbo M, Hara M, Saito I, Mori K: Gamma knife radiosurgery tion reduced the obliteration rate and outcomes were slightly better in for arteriovenous malformations: Long-term follow-up results focusing on the non-embolized group, the difference was not statistically signifi- complications occurring more than 5 years after irradiation. Neurosurgery cant. This supports earlier studies reporting that preradiosurgical AVM 38:906–914, 1996. embolization adversely affects outcome. Possible factors that could 53. Yamamoto Y, Coffey RJ, Nichols DA, Shaw EG: Interim report on the radio- surgical treatment of cerebral arteriovenous malformations. The influence of explain this discrepancy are patient selection bias (e.g., worse patients size, dose, time, and technical factors on obliteration rate. J Neurosurg are more likely to undergo embolization), morbidity from the 83:832–837, 1995. embolization procedures, conversion of a compact nidus into a more 54. Young C, Summerfield R, Schwartz M, O’Brien P, Ramani R: Radiosurgery for diffused and difficult-to-target nidus, and delayed recanalization. The arteriovenous malformations: The University of Toronto experience. Can J authors also introduce the concept that embolization materials them- Neurol Sci 24:99–105, 1997. selves may attenuate the radiation dose to adjacent tissue, thereby 55. Zipfel GJ, Bradshaw P, Bova FJ, Friedman WA: Do the morphological charac- effectively reducing the radiation dose to the AVM. Overall, I strongly teristics of arteriovenous malformations affect the results of radiosurgery? J agree with the authors’ conclusions that planned preradiosurgical Neurosurg 101:393–401, 2004. embolization is rarely beneficial to the patient. COMMENTS Bruce E. Pollock Rochester, Minnesota he authors report a retrospective, matched cohort study designed Tto provide additional information about the potential value or ndrade-Souza et al. report detailed obliteration and complication lack of value for preradiosurgical arteriovenous malformation (AVM) Adata on 61 patients with pretreatment embolization and radio- embolization. In summary, obliteration rates and overall outcomes surgery. Forty-seven of the patients had retrospectively matched con- seem to be better in patients who did not have embolization. The trols. The authors conclude that embolization substantially reduces the study’s weakness is the difficulty for matching a complex group of chances of successful radiosurgical treatment. This certainly agrees patients retrospectively; AVM obliteration rates are related to vol- with our experience at the University of Florida. Embolization con- ume, dose, angioarchitecture (diffuse versus well demarcated), and verts a fairly uniform geometric target into a more poorly defined tar- age. In our study, pediatric patients respond more completely and get, usually with multiple irregular components. The result is signifi- quickly for comparable volumes; in some studies, however, the cantly greater difficulty defining the target and greater error in reverse seems to be true. designing the radiosurgical treatment plan. In addition, some Using the technology at this center, many patients received doses embolized malformations at least partially recanalize. In general, we using the linear acceleration technique of 15 Gy at the margin, often think embolization before radiosurgery adds the risk but does not add with a higher isodose, which means the overall volume of AVM receiv- any benefits to the results of radiosurgery. We prefer other strategies for ing a high dose was significantly less than a comparable plan using the larger AVMs, including staged radiosurgical treatments. 50% isodose at the margin. In regard to subsequent success with oblit- eration, we have observed a sharp decline at the 16 Gy edge dose. William A. Friedman We also think that magnetic resonance imaging (MRI) scans pro- Gainesville, Florida vide superior three-dimensional morphology of the AVM and the brain itself when compared with computed tomographic (CT) scans because n this study, Andrade-Souza et al. evaluate the effect of AVM obliter- risk is related to the dose and volume of brain included outside the tar- Iation and clinical outcome after radiosurgery in patients with and get. Despite these concerns, I agree with the final analysis in this study. without preoperative embolization. They use a case match controlled Embolization, reducing the flow and feeders, and outlining the nidus methodology based on AVM volume, location, and prescription dose. to be removed are important before surgical excision in many cases. Obliteration was achieved in 70% of the patients receiving radiosurgery Before radiosurgery, embolization may distort the nidus and fail to alone and in 47% of the patients treated with embolization before radio- completely and permanently eliminate a volume of AVM, thereby surgery. Permanent neurological deficits from either radiation-induced reducing the target volume for subsequent radiosurgery. Whether or injury or hemorrhage were comparable in both groups. not new agents, such as Onyx (Microtherapeutics, Inc., Irvine, CA), In general, embolization before radiosurgery may have a role in will improve embolization remains unclear. The agent that is needed to reducing a very large nidus to a smaller one (2). It is clear, however, benefit radiosurgery is not better filling of the vascular channels, but that the ability of the embolization procedure to improve obliteration rather an agent that either potentiates the radiosurgical dose delivery rates with radiosurgery depends on shrinking the size of the nidus (e.g., a sensitizer) or protects the brain. and allowing the delivery of an optimal prescription dose to the L. Dade Lunsford remaining nidus. If the embolization only decreases flow or splits the Pittsburgh, Pennsylvania AVM into multiple portions, it seems unlikely to improve the outcome of radiosurgery and could potentially worsen it. here are several management options for patients diagnosed with As embolization technology improves, there may be a role for the Tlarge-volume AVMs who are considered poor candidates for surgi- use of emobilization alone in the treatment of AVMs (3). Encouraging cal excision. These include observation, embolization, embolization fol- results with newer embolic agents (e.g., Onyx) and improvements in lowed by radiosurgery, radiosurgery with low radiation doses and catheter technology (e.g., break-away catheters) may further expand planned repeat radiosurgery for the expected residual, staged-volume the indications for embolization. In addition, there has been renewed radiosurgery, and fractionated radiation therapy. Each of these interest in magnetic resonance-guided focused ultrasound for intracra- approaches has the theoretical advantage of never being proven clearly nial applications such as AVMs (1). Before choosing gamma rays, Lars superior to the other options. Leksell initially tried other energy sources, including focused ultra-

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sound, which was abandoned because of technological hurdles that could not be cleared at that time. 1. Ram Z, Cohen ZR, Harnof S, Tal S, Faibel M, Nass D, Maier SE, Hadani M, The current study questions the routine use of embolization before Mardor Y: Magnetic resonance imaging-guided, high-intensity focused ultra- sound for brain tumor therapy. Neurosurgery 59:949–956, 2006. radiosurgery in small to moderately sized AVMs. More detailed stud- 2. Sirin S, Kondziolka D, Niranjan A, Flickinger JC, Maitz AH, Lunsford LD: ies should be performed to better define the indications of current Prospective staged volume radiosurgery for large arteriovenous malforma- embolization techniques in the treatment of AVMs. Currently, micro- tions: Indications and outcomes in otherwise untreatable patients. surgery and radiosurgery remain the best methods to afford patients a Neurosurgery 58:17–27, 2006. desirable result. 3. Yu SC, Chan MS, Lam JM, Tam PH, Poon WS: Complete obliteration of intracranial arteriovenous malformation with endovascular cyanoacrylate Jason P. Sheehan embolization: Initial success and rate of permanent cure. AJNR Am J Charlottesville, Virginia Neuroradiol 25:1139–1143, 2004.

Atomic-force microscopy of natural amyloid fibrils from the heart of a patient with a familial form of apolipoprotein A-I amyloidosis. Courtesy of Dr. Annalisa Relini, Department of Physics, University of Genoa, Genoa, Italy and Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. N Engl J Med 349:583–596, 2003.

452 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com CLINICAL STUDIES

RADIOSURGERY TO REDUCE THE RISK OF FIRST HEMORRHAGE FROM BRAIN ARTERIOVENOUS MALFORMATIONS

Keisuke Maruyama, M.D., Ph.D. OBJECTIVE: It remains unclear whether or not and to what extent stereotactic radiosurgery Department of Neurosurgery, can reduce the risk of first intracranial hemorrhage from brain arteriovenous malfor- University of Tokyo Hospital, mations. Tokyo, Japan METHODS: We performed a retrospective observational investigation of 500 patients Masahiro Shin, M.D., Ph.D. with arteriovenous malformations who were treated with gamma knife radiosurgery. Department of Neurosurgery, The risk of first hemorrhage was analyzed using the Cox proportional-hazards model with University of Tokyo Hospital, age at radiosurgery and angiographic obliteration included as time-dependent covari- Tokyo, Japan ates. Three periods were defined: from birth to radiosurgery (before radiosurgery); from Masao Tago, M.D., Ph.D. radiosurgery to angiographic obliteration (latency period); and from angiographic oblit- eration to end of the follow-up period (after obliteration). Department of Radiology, University of Tokyo Hospital, RESULTS: Hemorrhage was documented before radiosurgery in 318 patients (median Tokyo, Japan observation period, 30.0 yr), during the latency period in 11 patients (median observa- tion period, 2.2 yr), and after obliteration in two patients (median observation period, Junji Kishimoto, M.A. 5.5 yr). Compared with the period before radiosurgery, the risk of hemorrhage decreased Department of Clinical Bioinformatics, University of Tokyo Hospital, by 86% after obliteration (hazard ratio, 0.14; 95% confidence interval, 0.03–0.55; Tokyo, Japan P ϭ 0.005), whereas the reduction observed during the latency period was not statis- tically significant (hazard ratio, 0.56; 95% confidence interval, 0.31–1.04; P ϭ 0.07). Akio Morita, M.D., Ph.D. Irrespective of obliteration, the risk of hemorrhage decreased by 62% after radiosurgery Department of Neurosurgery, (hazard ratio, 0.38; 95% confidence interval, 0.22–0.67; P ϭ 0.001). Similar results University of Tokyo Hospital, were observed when the 33 patients who had undergone previous therapy were excluded Tokyo, Japan from the analysis. Nobutaka Kawahara, M.D., CONCLUSION: Stereotactic radiosurgery significantly reduces the risk of first hemor- Ph.D. rhage from brain arteriovenous malformations. The extent of the decrease might be Department of Neurosurgery, greater if angiography indicates the evidence of obliteration. University of Tokyo Hospital, Tokyo, Japan KEY WORDS: Arteriovenous malformation, Gamma knife, Hemorrhage, Radiosurgery, Risk

Reprint requests: Neurosurgery 60:453–459, 2007 DOI: 10.1227/01.NEU.0000255341.03157.00 www.neurosurgery-online.com Keisuke Maruyama, M.D., Ph.D., Department of Neurosurgery, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, rteriovenous malformations (AVMs) of embolization are the current treatment options Tokyo 113–8655, Japan. the brain are congenital cerebrovascu- for achieving this objective (6, 11, 28, 32). Email: [email protected] Alar disorders that can cause disabling or Radiosurgery provides angiographic evidence fatal intracranial hemorrhage, especially in of cure (obliteration) in 80 to 90% of AVMs at 3 Received, May 30, 2006. younger patients (11, 32). Hemorrhage is the to 5 years (7, 11, 14, 26, 36, 37). A risk of bleed- Accepted, November 7, 2006. most common clinical presentation of AVMs ing remains in 1.8 to 5% of patients per year and the lifetime risk of hemorrhage from until obliteration (13, 21, 34). In our large retro- untreated AVMs is relatively high when esti- spective observational study, we recently mated using the following formula: percent reported that radiosurgery significantly lifetime risk of hemorrhage ϭ 105 Ϫ age in decreased the risk of hemorrhage from previ- years (2, 23). The main therapeutic goal is elim- ously ruptured AVMs, even before angio- inating or reducing the risk of hemorrhage graphic obliteration (27). However, significant from these lesions. Microsurgical resection, reduction in risk of hemorrhage from unrup- stereotactic radiosurgery, and endovascular tured AVMs was not proven and it is unclear

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whether or not the risk of first hemorrhage from unruptured AVMs can be reduced after radiosurgery. One option to prove this issue might be a randomized controlled trial comparing a group undergoing radiosurgery with a group receiving no treat- ment for their unruptured AVMs. Such a study needs a suffi- ciently large cohort of patients and a sufficiently long observa- tion period. Practically, it is very difficult to accomplish such a large-scale study with a potentially devastating disease affecting young populations. One ongoing study, A Randomized Trial of Unruptured Brain AVMs, in which patients diagnosed with unruptured AVMs are being followed for 5 years after random- ization for any treatments or conservative management (http://www.arubastudy.org), seems unlikely to be sensitive enough to detect the effect of radiosurgery in reducing the risk of hemorrhage. Thus, to investigate whether or not and to what extent radiosurgery can reduce the risk of first hemorrhage from brain AVMs by using currently available data, we performed further analyses of the cohort investigated in our previous study (27), which comprised 531 patients who were treated with stereotactic radiosurgery using gamma knife at the University of Tokyo Hospital.

PATIENTS AND METHODS

Patients FIGURE 1. Flow diagram showing the study population. The observation Selection criteria for radiosurgery, details of the study pop- period was divided into three intervals: from birth to radiosurgery (before ulation, and the radiosurgical technique used have been radiosurgery); from radiosurgery to angiographic obliteration (latency reported previously (27). Briefly, radiosurgery was indicated period); and from angiographic obliteration to the end of the follow-up for small AVMs with general high surgical risks. Between period (after obliteration). AVMs, arteriovenous malformations. 1990 and 2004, 531 patients were treated with gamma knife radiosurgery. Our institutional review board did not require informed consent for participation in this study because the Information on all patients was prospectively entered into a analysis relied on information obtained as part of the routine computer database at the time of treatment and at each clinical clinical care of patients. Details of the follow-up evaluations follow-up visit thereafter. The database used in our previous have been described previously (27). Clinical and neuroimag- study was used here. Data including the patient’s date of birth, ing follow-up assessment, including computed tomographic the radiosurgical procedure, previous or new hemorrhages, or magnetic resonance imaging scans, were performed every angiographic obliteration, and final follow-up visits were 6 months after the procedure. If these less invasive imaging included in the analyses, along with treatment histories. The studies suggested obliteration of the AVMs, cerebral angiog- observation period was divided into the following three inter- raphy was performed to confirm cure (angiographic oblitera- vals: before radiosurgery, the period between birth and radio- tion) (36). Angiographic obliteration was defined as the surgery; the latency period, the period between radiosurgery absence of abnormal vessels in the former nidus of the AVM, and angiographic obliteration or cure; and after obliteration, the disappearance or normalization of draining veins from the period between angiographic obliteration and the end of the area, and a normal circulation time on angiography (25). the follow-up period (Fig. 1). A second radiosurgical treatment was generally recom- mended if obliteration was not observed 3 years after the ini- Statistical Analysis tial treatment. Intracranial hemorrhage was defined as a clin- The cumulative incidence of first hemorrhage and oblitera- ically symptomatic event (i.e., sudden onset headache, tion was calculated using the Kaplan-Meier method (20). The seizure, focal deficits, death, or a combination of these) annual incidence of hemorrhage was calculated with the num- accompanied by signs of fresh bleeding from AVMs detected ber of hemorrhages divided by the sum of the observation peri- using computed tomographic or magnetic resonance imag- ods of the patients. A Cox proportional-hazards model with ing scans (30). A previous history of hemorrhage was diag- time-dependent covariates was used to analyze the effect of nosed with a clinically symptomatic event and/or signs of radiosurgery on the incidence of intracranial hemorrhage. SPSS past bleeding from AVMs detected using these imaging meth- software (version 11; SPSS, Inc., Chicago, IL) (8, 10) was used ods at the time of radiosurgery. under the following two assumptions: the risk of first hemor-

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rhage from AVMs remains constant throughout the patient’s lifetime since birth and the risk of first hemorrhage in patients TABLE 1. Characteristics of 500 patients treated with radio- without hemorrhage at the time of presentation is similar to the surgerya risk in patients who presented with hemorrhage. We defined a Characteristic Value set of three time-dependent covariates: “1” for the period No. of female patients (%) 213 (42.6) before radiosurgery, “Ϫ1” for the latency period, and “0” for No. of patients presenting with hemorrhage (%) 310 (62.0) the period after obliteration. The primary endpoint was the Diameter of AVMs (cm; mean Ϯ SD) 2.1 Ϯ 0.9 first hemorrhage since birth. For patients presenting with hem- No. of AVMs with small size (Ͻ3 cm) (%) 417 (83.4) orrhage, censoring data dated back to the time of initial hem- No. of AVMs in the eloquent brain location (%) 316 (63.2) orrhage. For patients who had experienced previous therapy, No. of AVMs with deep venous drainage (%) 282 (56.4) data from the period after the previous treatment was included No. of accompanying aneurysms (%) 10 (2.0) in the overall analysis. There is always a delay in confirming Maximum dose during radiosurgery (Gy) 40.9 Ϯ 5.0 obliteration by cerebral angiography, which makes it difficult to Margin dose during radiosurgery (Gy) 21.0 Ϯ 2.4 accurately define the time of occurrence of angiographic oblit- Observation period eration. Therefore, to analyze the change in the risk of hemor- From birth to radiosurgery (yr) 32.3 Ϯ 15.8 rhage before and after radiosurgery, irrespective of angio- From radiosurgery to obliteration (yr) 3.0 Ϯ 2.4 graphic obliteration, we reanalyzed the data, defining the After obliteration (yr) 4.8 Ϯ 3.7 covariates as “1” for the period before radiosurgery and “0” for Whole period (yr) 34.3 Ϯ 16.7 the period between radiosurgery and the end of the follow-up period; the latter period was defined as “after radiosurgery.” a AVMs, arteriovenous malformations; SD, standard deviation. Plus-minus Ϯ We performed additional analyses to adjust for several poten- values are means SD. tial biases. To exclude the effect of previous therapy on the risk of hemorrhage, we reanalyzed the data and excluded patients who had undergone previous treatments. TABLE 2. The annual incidence of hemorrhagea The reduction in the hazard of intracranial hemorrhage com- Annual incidence No. of pared with the period before radiosurgery was calculated as No. of Interval of hemorrhage patients 100 ϫ (1 Ϫ hazard ratio [HR]). A two-sided P value less than hemorrhages (95% CI) analyzed 0.05 was considered statistically significant. Before radiosurgery 2.0 (1.8–2.2) 500 318 Latency period 2.0 (1.0–3.6) 182 11 RESULTS After obliteration 0.5 (0.06–1.8) 89 2

Of the 531 patients, 31 were unable to return for serial follow- a CI, confidence interval. up examination after radiosurgery for personal reasons and were, therefore, excluded from the analyses. Among this group, 18 patients had a history of hemorrhage before radiosurgery, radiosurgery, 11 reported hemorrhage during the latency eight patients were confirmed not to have experienced clini- period. Of the 89 patients whose AVMs were obliterated, two cally significant hemorrhage through subsequent communica- experienced their first hemorrhage after obliteration (Table 2) tions by telephone or mail, and no information was available (35). Clinical information regarding these two patients was for the remaining five patients, three of whom lived overseas. described in detail in our previous report (35). The annual inci- Therefore, the final study group included 500 patients (Table 1). dence of hemorrhage decreased only after obliteration (Table 2). The obliteration and complication rates of these patients were Of the 169 patients who did not experience any hemorrhage, reported previously (27). The median observation period was 125 reached the latest cut-off point for our data set. The reasons 31.7 years. Based on a follow-up period shorter than 3 years, for censoring the data regarding patients without complete AVMs were not obliterated by radiosurgery in 123 out of the follow-up were loss to follow-up (33 patients), refusal to 500 patients. The cumulative rates of obliteration were 81% at undergo angiography to confirm obliteration (three patients), 4 years and 91% at 6 years (27). undergoing a second radiosurgical procedure (six patients), or Previous therapy had been performed in 137 patients, 104 of death from lung cancer (two patients). whom had experienced hemorrhage before their previous treat- The cumulative risk of first hemorrhage during the period ments. In the remaining 33 patients, the previous therapy con- before radiosurgery was 21% at 20 years of age, 40% at 30 years sisted of partial resection (four patients), several sessions of of age, and 62% at 50 years of age. This risk seemed to be con- endovascular embolization (25 patients), or both (four patients). stant with respect to age, although it was slightly higher in the Hemorrhage was documented before radiosurgery in 318 of third to fifth decades of life (Fig. 2). the 500 patients, 310 of whom initially presented with hemor- Compared with the period before radiosurgery, the risk of rhage and eight of whom experienced their first hemorrhage hemorrhage was reduced by 86% after obliteration (HR, 0.14; between the time of diagnosis and radiosurgery. Of the 182 95% confidence interval [CI], 0.03–0.55; P ϭ 0.005) (Table 3). patients who had not experienced their first hemorrhage before Although the risk of hemorrhage also showed a tendency to

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previous therapy were excluded from the analysis (Table 3). None of the factors, including deep venous drainage, accompa- nying aneurysm, and small size, was significantly associated with the reduction of hemorrhagic risk (data not shown).

DISCUSSION

Among patients selected for radiosurgery, we found that radiosurgery reduced the risk of first hemorrhage from brain AVMs after angiographic evidence of obliteration. Based on an analysis in which the latency period and the period after oblit- eration were combined, the risk was reduced after radiosurgery regardless of obliteration. This study was based on the follow- ing two assumptions: the risk of first hemorrhage from AVMs remains constant throughout the patient’s lifetime since birth and the risk of first hemorrhage in patients without hemor- rhage at the time of presentation is similar to the risk in patients who presented with hemorrhage. There is no evidence that completely contradicts our assumption; rather, several facts support our assumptions. Regarding the first assumption, many previous studies have suggested that AVMs are congen- FIGURE 2. Line graph illustrating the cumulative incidence of first hem- orrhage before radiosurgery. The gray line indicates the line of best fit. ital lesions and that the majority of patients have harbored AVMs since birth (11, 32). Evidence of growth or de novo for- mation is extremely rare and few cases have been reported (1, decrease during the latency period, the reduction compared 5, 16, 24, 31). Therefore, it seems reasonable to define the obser- with the period before radiosurgery was not statistically signif- vation period for studies of this condition as starting at the icant (HR, 0.56; 95% CI, 0.31–1.04; P ϭ 0.07). time of birth (11, 32). If a substantial portion of AVMs devel- Regardless of angiographic obliteration, the risk of hemor- oped after birth because of some growth and/or stress requir- rhage decreased by 62% in the period after radiosurgery (HR, ing multiple decades, the result of our study would be more 0.38; 95% CI, 0.22–0.67; P ϭ 0.001) compared with the period significant because the observation period before treatment before radiosurgery, based on analysis in which the latency would be shorter. In our previous study, the observation period period and the period after obliteration were combined. Similar started at the time of diagnosis of AVM (27). Thus, the col- results were obtained when the 33 patients who had undergone lected data were based on direct observation during the period

TABLE 3. Risk of first hemorrhage from brain arteriovenous malformations compared with before radiosurgerya

No. of hemorrhages Latency period After obliteration After radiosurgery No. of Type of analysis Before Latency After Hazard ratio P value Hazard ratio P value Hazard ratio P value patients radiosurgery period obliteration (95% CI) (95% CI) (95% CI) Overall All patients with follow-up data 500 318 11 2 0.56 0.07 0.14 0.005 — — (0.31–1.04) (0.03–0.55) — All patients with follow-up data 500318112 ————0.38 0.001 — — (0.22–0.67) Secondary Excluding 33 patients with previous 467 318 10 2 0.60 0.12 0.17 0.01 — — treatments (0.32–1.15) (0.04–0.70) — Excluding 33 patients with previous 467318102 ————0.43 0.005 treatments ——(0.24–0.77)

a CI, confidence interval.

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after diagnosis; although, in a sense, the time of diagnosis was angiography shows evidence of obliteration, whereas the risk artificially determined a posteriori for this congenital disorder. of hemorrhage during the period between radiosurgery and Considering the congenital nature of this disease, commencing obliteration was not significantly reduced. This was probably the observation period at the time of birth seems appropriate caused by the small number of patients analyzed because the for our current study. In addition, the cumulative incidence of risk would have been significantly reduced if the number of first hemorrhage before radiosurgery in our cohort was rela- patients had been doubled (P ϭ 0.010). Although further study tively constant according to the Kaplan-Meier method (Fig. 2), is needed to directly confirm our results, our study suggests the although some authors have previously reported that the efficacy of radiosurgery in reducing the risk of bleeding from annual risk of hemorrhage increases with age (22). Therefore, unruptured brain AVMs. our data were suitable for analyses using the Cox proportional- hazards model and any change of hemorrhagic risk according to age would be expected to have little, if any, effect on our REFERENCES results. 1. Akimoto H, Komatsu K, Kubota Y: Symptomatic de novo arteriovenous mal- A limitation of our study is the validity of the second formation appearing 17 years after the resection of two other arteriovenous assumption that the risk of first hemorrhage in patients without malformations in childhood: Case report. Neurosurgery 52:228–232, 2003. hemorrhage at the time of presentation is similar to the risk in 2. 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Young WL, Hademenos G; Special Writing Group of the Stroke Council, There was not a significant reduction in the hemorrhage rate during the American Stroke Association: AHA Scientific Statement: Recommendations latency period alone. Statistically, the risk of reduction in hemorrhage for the management of intracranial arteriovenous malformations: A state- after GKR seems to be dominated by the effect of obliteration. At the ment for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Stroke 32:1458–1471, 2001. University of Virginia, I have never observed a hemorrhage after angio- 33. Ondra SL, Troupp H, George ED, Schwab K: The natural history of sympto- graphic confirmation of gamma knife-induced AVM obliteration. matic arteriovenous malformations of the brain: A 24-year follow-up assess- A confounding factor with analyzing the effect of hemorrhage reduc- ment. J Neurosurg 73:387–391, 1990. tion during the latency period is the variability in timing and detection 34. Pollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, Kondziolka D: of AVM obliteration after radiosurgery. Without neuroimaging studies Hemorrhage risk after stereotactic radiosurgery of cerebral arteriovenous more often than every 6 months and a larger study population that pro- malformations. Neurosurgery 38:652–661, 1996. vides greater statistical authority, early, undetected obliteration may 35. Shin M, Kawahara N, Maruyama K, Tago M, Ueki K, Kirino T: Risk of hem- present a false appearance of protection during the latency period, orrhage from an arteriovenous malformation confirmed to have been obliter- whereas the patient should be classified in the obliteration group. ated on angiography after stereotactic radiosurgery. J Neurosurg 102:842–846, 2005. Angiographically-confirmed obliteration continues to be the objective 36. Shin M, Maruyama K, Kurita H, Kawamoto S, Tago M, Terahara A, Morita A, for all AVM patients after radiosurgery. Ueki K, Takakura K, Kirino T: Analysis of nidus obliteration rates after Jason P. Sheehan gamma knife surgery for arteriovenous malformations based on long-term Charlottesville, Virginia follow-up data: The University of Tokyo experience. J Neurosurg 101:18–24, 2004. 37. Steiner L, Lindquist C, Adler JR, Torner JC, Alves W, Steiner M: Clinical out- he authors have retrospectively reviewed their data to glean addi- come of radiosurgery for cerebral arteriovenous malformations. J Neurosurg Ttional perspectives on the potential benefit of radiosurgery to 77:1–8, 1992. reduce bleed rates of AVMs. For a significant number of patients who are selected because of volume and location, treated with an appropri- Acknowledgments ate dose and technique, and managed by an experienced team, success- We thank Hiroki Kurita, M.D., Ph.D., Department of Neurosurgery, Kyorin ful AVM radiosurgery can be expected. The data does not support the University School of Medicine and Shunsuke Kawamoto, M.D., Ph.D., Depart- concept that bleed rates are reduced during the latency interval until ment of Neurosurgery, Dokkyo University School of Medicine for their help obliteration occurs, although a larger number of patients might assist with data collection and their valuable advice in writing this article. This study in resolving this quandary. The authors also reconfirm their observation

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that angiographic obliteration does reduce the risk to zero. This retro- assumptions necessary for a retrospective, observational study, the spective report provides additional outcome data related to a prime authors determined that the annual risk of first hemorrhage before determinant of the benefit of radiosurgery. The question of whether or radiosurgery for all patients (n ϭ 500) was 2.0%, the annual risk of first not radiosurgery reduces the risk of a bleed, as best can be determined hemorrhage after radiosurgery for patients without previous bleeding using current clinical experience, remains. The answer seems to con- (n ϭ 182) was 2.0%, and the annual risk of first hemorrhage after oblit- firm the observations of other studies over the past 20 years. eration (n ϭ 89) was 0.5%. A significant reduction in bleeding risk was noted after angiographic obliteration and in the entire group after L. Dade Lunsford radiosurgery. There was no significant reduction noted during the Pittsburgh, Pennsylvania latency interval. This study provides further support for the concept that radiosurgery does not change quiescent lesions into more aggres- aruyama et al. from the University of Tokyo have reanalyzed sive malformations owing to the blood flow alterations in the nidus their prospective database of AVM patients who underwent M before obliteration. Moreover, although the observation of AVM bleed- radiosurgery between 1990 and 2004, asking whether or not radio- ing after angiographic obliteration remains provocative and their esti- surgery reduces the risk of first AVM hemorrhage. Although some may mated risk seems high (0.5%/year), I suspect this figure will decline as consider this a matter of semantics, previous studies examining hem- they accumulate more patients with angiographic obliteration. orrhage risk after radiosurgery included patients with and without previous bleeding, thereby raising the question of whether or not radio- Bruce E. Pollock surgery reduces the risk of any AVM hemorrhage. Based on several Rochester, Minnesota

Structural features of amyloid illustrated: three-dimensional polypeptide chain models of transthyretin, apolipoprotein A-I, lysozyme and immunoglobulin κ light chain shown on left combine, creating a protofilament structure. Several of these protofilaments wind around one another to form the amyloid fibril shown on the right, illustrated and in microscopy images (fibril diameter 7.5 to 10 nm). Courtesy of Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. N Engl J Med 349:583–596, 2003.

NEUROSURGERY VOLUME 60 | NUMBER 3 | MARCH 2007 | 459 David Mathieu, M.D. CLINICAL STUDIES Department of Neurological Surgery, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania TEREOTACTIC ADIOSURGERY FOR ESTIBULAR Douglas Kondziolka, M.D. S R V Departments of Neurological Surgery SCHWANNOMAS IN PATIENTS WITH and Radiation Oncology, University of Pittsburgh School of Medicine, NEUROFIBROMATOSIS TYPE 2: AN ANALYSIS University of Pittsburgh Medical Center, OF TUMOR CONTROL, COMPLICATIONS, AND Pittsburgh, Pennsylvania HEARING PRESERVATION RATES John C. Flickinger, M.D. Department of Radiation Oncology, University of Pittsburgh OBJECTIVE: Vestibular schwannomas present significant management challenges in School of Medicine, patients with neurofibromatosis Type 2 (NF2). We evaluated the results of gamma knife University of Pittsburgh radiosurgery for the management of these tumors, focusing on tumor response, hearing Medical Center, Pittsburgh, Pennsylvania preservation, and other factors affecting outcomes. METHODS: Stereotactic radiosurgery was performed to manage 74 schwannomas in 62 Ajay Niranjan, M.Ch. patients. Ipsilateral serviceable hearing was present in 35% of tumors before the pro- Department of Neurological Surgery, 3 University of Pittsburgh cedure. The mean tumor volume was 5.7 cm . The mean margin and maximum dose School of Medicine, used were 14 and 27.5 Gy, respectively. Cox regression analyses were performed to University of Pittsburgh identify factors affecting outcomes. Medical Center, Pittsburgh, Pennsylvania RESULTS: The median follow-up period was 53 months, and two patients were lost to follow-up. Actuarial local control rates at were 85, 81, and 81% at 5, 10, and 15 years, Richard Williamson, B.S. respectively. Tumor volume was significant as a predictor of local control. Since 1992, Department of Neurological Surgery, using current radiosurgery techniques (magnetic resonance imaging scan targeting and University of Pittsburgh School of Medicine, reduced margin dose to 14 Gy or less), the actuarial serviceable hearing preservation University of Pittsburgh rate is 73% at 1 year, 59% at 2 years, and 48% at 5 years after radiosurgery. Facial neu- Medical Center, ropathy occurred in 8% of tumors, trigeminal neuropathy occurred in 4%, and vestibu- Pittsburgh, Pennsylvania lar dysfunction occurred in 4%. Radiation dose and tumor volume were predictive of Juan J. Martin, M.D. development of new deficits. No radiosurgery-associated secondary tumors or atypical Department of Neurological Surgery, or malignant changes were noted. University of Pittsburgh CONCLUSION: Stereotactic radiosurgery is a safe and effective management modal- School of Medicine, University of Pittsburgh ity for neurofibromatosis Type 2 vestibular schwannomas. Although results do not seem Medical Center, to be as good as for patients with sporadic unilateral tumors, gamma knife radiosurgery Pittsburgh, Pennsylvania results seem favorable and indicate that radiosurgery should be strongly considered for L. Dade Lunsford, M.D. primary tumor management in selected patients. Departments of Neurological Surgery KEY WORDS: Acoustic neuromas, Gamma knife, Hearing preservation, Local control, Neurofibromatosis and Radiation Oncology, type 2, Stereotactic radiosurgery, Vestibular schwannomas University of Pittsburgh School of Medicine, Neurosurgery 60:460–470, 2007 DOI: 10.1227/01.NEU.0000255340.26027.53 www.neurosurgery-online.com University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania eurofibromatosis Type 2 (NF2) is an has been microsurgical removal of tumors that Reprint requests: autosomal dominant genetic disorder grew over time (6). However, surgical resec- Douglas Kondziolka, M.D., Ncaused by mutations on chromosome tion is associated with a high rate of hearing Department of Neurological Surgery, 22 (7). The hallmark of this disease is the bilat- loss because the tumor tends to engulf or even UPMC Presbyterian, eral development of Schwann cell tumors on infiltrate the cochlear nerve. In contrast, spo- 200 Lothrop St., Suite B-400 Pittsburgh, PA, 15213. the vestibular portions of the VIIth cranial radic tumors more commonly displace and Email: [email protected] nerve. Most patients afflicted by this disorder compress the nerve (34). In recent years, stereo- lose hearing over time and may become com- tactic radiosurgery has emerged as a first-line Received, June 19, 2006. pletely deaf. The traditional management of management for small- to medium-sized VS. Accepted, November 2, 2006. NF2-associated vestibular schwannomas (VS) This approach provides long-term growth con-

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trol, hearing preservation, morbidity rates superior to micro- surgery, and eliminates traditional open surgical risks (10, 19, TABLE 1. Patient and individual tumor characteristicsa 21, 28, 36). This study expands the long-term outcome analysis No. of patients (%) of patients with NF2-associated VS managed with gamma Sex knife radiosurgery and focuses on tumor control, hearing Female 33 (53) preservation, and complication management. Male 29 (47) Family history of NF2 13 (21) PATIENTS AND METHODS Presence of other CNS tumors Meningiomas 39 (63) Patient Population Schwannomas 35 (57) Oculomotor 3 (5) This retrospective study was approved by the Institutional Trigeminal 12 (19) Review Board of the University of Pittsburgh Medical Center, Jugular foramen 5 (8) Pittsburgh, PA. Between 1987 and 2005, 62 patients with NF2 Spinal 22 (36) underwent radiosurgery for the management of 74 VS (62 uni- Spinal ependymoma 11 (18) lateral procedures and 12 bilateral staged procedures). All Previous microsurgical resection (tumors) patients were diagnosed on the basis of the presence of bilateral One 13 (18) VS (57 patients) or unilateral tumors (five patients) with mul- Two 3 (4) tiple other central nervous system (CNS) tumors (multiple Three 3 (4) meningiomas, schwannomas, and spinal cord tumors). There Four 2 (3) were 29 men (47%) and 33 women (53%). The mean age at the VP shunt 5 (8) time of the first procedure was 36 years (median, 33 yr; range, Gardner-Robertson hearing grade (ears, tumors) 11–79 yr). Family history of NF2 was present in 13 patients 1 23 (32) (21%). The majority of patients had multiple other CNS tumors. 2 3 (4) Table 1 summarizes patient and tumor characteristics. 3 13 (18) Twenty-one tumors (28%) in 17 patients (27%) had at least 4 3 (4) one microsurgical resection before radiosurgery. Among those 5 32 (43) cases, radiosurgery was performed because of progressive Other symptoms (tumors) growth of 17 residual tumors and for the recurrence of four Tinnitus 20 (27) tumors after previous gross total resection. One patient had Ataxia 36 (49) failed fractionated radiation therapy for a previous recurrence. Incoordination 2 (3) At the time of radiosurgery, 32 (43%) out of 74 schwannomas Facial neuropathy 15 (20) were associated with complete deafness and 42 (57%) had some As postop deficit 12 remaining hearing in the affected ear. Hearing was serviceable Trigeminal neuropathy 14 (19) (Gardner-Robertson Grade 1 or 2, corresponding to pure tone As postop deficit 9 average less than 50 dB and speech discrimination score of 50% Lower cranial neuropathies 13 (18) or more) in 26 tumors (35%). In 20 tumors, deafness had been As postop deficit 13 a consequence of previous resection. Only one previously Oculomotor neuropathy 4 (5) resected tumor had some measurable hearing remaining As postop deficit 3 (Grade 3). a NF2, neurofibromatosis Type 2; CNS, central nervous system; VP Radiosurgery Procedures ventriculoperitoneal; postop, postoperative. The decision to perform gamma knife radiosurgery was made after documentation of progressive tumor growth or better define the intracanalicular portion of the tumors. The declining hearing status over time (Table 2). Informed consent images were then transferred via Ethernet to the planning was obtained from the patients and/or their caregivers. computer, after which, the radiosurgery team agreed on a con- Patients were admitted on the morning of the procedure. The formal dose plan. An average of seven isocenters of radiation Leksell model G stereotactic frame (Elekta AB, Atlanta, GA) were used (range, 1–16 isocenters). The 50% isodose line was was applied to the patient’s head after appropriate administra- used in most cases. The dose delivered to the margin of the tion of conscious sedation and local anesthesia. Before 1992, tumors varied from 11 to 20 Gy (mean, 14 Gy). However, since contrast-enhanced computed tomographic scans were used 1992, no tumor received more than 14 Gy at the margin. The for dose planning. Since 1992, magnetic resonance imaging maximum dose varied from 21.8 to 40 Gy (mean, 27.5 Gy). (MRI) scanning has been used exclusively, unless contraindi- The mean tumor volume was 5.7 cm3 (range, 0.2–21.1 cm3). cated. Axial contrast-enhanced spoiled gradient recalled acqui- After the procedure, the patients received a bolus of 40 mg of sition in steady state images of the tumors were obtained. A intravenous methylprednisolone. The patients were observed volumetric axial T2-weighted sequence was also obtained to for a few hours in the gamma knife suite and were then either

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RESULTS TABLE 2. Details of radiosurgery proceduresa No. of tumors (%) Follow-up information was available for 72 tumors in 60 patients. Two patients who had unilateral procedures were lost Imaging modality to follow-up. The median duration of the follow-up period was CT 20 (27) 53 months (mean, 64 mo; range 4–196 mo). MRI 54 (73) Isodose line used Local Control 40% 1 (1) At the latest evaluation, 28 tumors (39%) had decreased in 50% 63 (85) size, 32 tumors (44%) were stable in size, and 12 tumors (17%) 55% 7 (10) had increased in size. Repeat surgical intervention was per- 60% 2 (3) formed in nine tumors (12%), consisting of microsurgery in 70% 1 (1) seven tumors, radiosurgery in one tumor (using a margin dose Margin dose of 12 Gy administered to the 50% isodose line), and resection <12 Gy 4 (6) followed by radiosurgery in one tumor (11 Gy to the 50% iso- 12–14 Gy 50 (67) dose line). The median time to a new intervention was 34 15–17 Gy 8 (11) months (range, 5–84 mo). Thus, local control, as defined by the 18–20 Gy 12 (16) absence of repeat surgical intervention on the tumor, was 88% Maximum dose for the entire series. Actuarial local control rates were 85, 81, <24 Gy 8 (11) and 81% at 5, 10, and 15 years, respectively. However, among 24–28 Gy 45 (60) the tumors that had a later resection, two (with tumor volumes 29–34 Gy 14 (19) of 4 and 21.1 cm3 at the time of radiosurgery) were performed 35–40 Gy 7 (10) in other institutions at 5 and 8 months after radiosurgery Gamma knife model used because of a minimal increase in size associated with central U 34 (46) loss of contrast enhancement. These two tumors likely did not B 16 (22) require a resection. Two other tumors (with volumes of 5.8 and C/4C 24 (32) 14.8 cm3 at the time of radiosurgery) were resected because of a CT, computed tomographic scan; MRI, magnetic resonance imaging scan. persistent symptoms of brainstem compression at 6 and 11 months after radiosurgery despite stable tumor size. All four discharged or kept overnight in the hospital, depending on tumors were originally deemed appropriate for radiosurgery their clinical condition. and the patients were referred from other institutions because of recurrence after previous microsurgical resection. When Follow-up and Postradiosurgery Clinical Evaluation including only tumors with documented growth, the actuarial Follow-up evaluations were scheduled with the patients progression-free survival rate was 84% at 5 years, 80% at 10 every 6 months for the first year and annually thereafter if their years, and 67% at 15 years after radiosurgery. Three patients condition was stable. Audiological evaluations (in case of had a ventriculoperitoneal shunt inserted to relieve hydro- remaining hearing) and MRI scans were obtained at the time of cephalus from increased fourth ventricle compression at 10, 22, the follow-up examination. On the MRI scans, measurements and 169 months after radiosurgery. Shunting reversed the of the extracanalicular and intracanalicular portions of the symptoms and no further growth warranting new surgical tumor were taken in all three dimensions and used to assess intervention was observed on subsequent follow-up evalua- tumor size. A 25% change in dimension was necessary for the tions. On univariate Cox regression analysis, increasing age recognition of progression or regression. Otherwise, the tumor (P 0.032) and smaller tumor volume (P 0.0005) were found was deemed to be stable. Hearing scores were based on the to be significant predictors of local tumor control, as continuous Gardner-Robertson classification (9). Facial nerve grading was variables. The margin and maximum radiation dose, imaging performed using the House-Brackmann grading system (11). modality used for planning, patient sex, and previous surgical resection did not impact local control. On multivariate analysis, Data Analysis only tumor volume remained a significant variable (P For outcome analyses, every tumor irradiated was consid- 0.0005). Figures 1 and 2 exemplify typical follow-up MRI scans ered as a separate entity, even if more than one occurred in the in patients after undergoing radiosurgery. Figure 3 summarizes same patient. Tumor control, hearing status, and complications local control data based on previous therapy and radiation were compiled for each tumor. Stepwise forward conditional dose used for radiosurgery. Table 3 summarizes the details of analyses were performed using the Cox proportional hazards univariate and multivariate analyses. model to determine factors significantly influencing each out- come endpoint. These factors were also compared using the Hearing Preservation Kaplan-Meier method. All statistical analyses were performed Before radiosurgery, 41 tumors were associated with measur- using SPSS 13.0 software (SPSS Inc., Chicago, IL). able hearing on audiological testing. Among those, hearing

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AB A B

C D

FIGURE 1. This 45-year-old man had total resection of a left VS 2 years before radiosurgery. He experienced postoperative permanent trigeminal neu- ropathy, facial neuropathy, and deafness. He subsequently developed a right VS the following year, which led to the diagnosis of NF2. Progressive growth of the right tumor was documented with preserved Grade 1 hearing, at which point it was decided to perform radiosurgery. These axial contrast-enhanced T1-weighted MRI scans at the time of radiosurgery (A) and after 39 months (B) demonstrate a stable tumor size. Hearing status remains Grade 1, with normal trigeminal, facial, and vestibular function on the right side.

FIGURE 2. This young woman had family history of NF2 involving her was serviceable in 25 patients. At the time of latest follow-up mother and grandmother. She presented with subjective hearing loss in the examination, 17 of the patients with tumors with measurable right ear at the age of 22 years. Audiological evaluation revealed bilateral preradiosurgery hearing had remaining hearing and 24 of the Grade 1 hearing. MRI scans demonstrated bilateral VS, with the right side patients had progressed to deafness in the affected ear. The larger than the left, prompting radiosurgery of the right tumor. Sequential measurable hearing preservation rate was 42% for the entire axial contrast-enhanced T1-weighted MRI scans obtained at the time of series, which included tumors managed early in our experience gamma knife radiosurgery (A), at 25 months (B), at 50 months (C), and at using higher doses. The hearing dropped a median of two 81 months (D) after surgery demonstrate stable tumor size after the proce- dure. Unfortunately, serviceable hearing was lost after 50 months. Despite grades on the Gardner-Robertson scale after a median interval early enlargement of the left tumor at 25 months, further therapy has been of 10 months (mean, 23.2 mo; range, 1–99 mo). Serviceable deferred because it has subsequently remained stable and is still associated hearing was preserved in 10 (40%) out of 25 tumors. Univariate with Grade 1 hearing. She remains employed and has normal facial function analysis revealed that better preradiosurgery hearing grade and good balance. (P 0.033), margin dose of 14 Gy or less (P 0.001), and max- imum dose of 28 Gy or less (P 0.003) were predictors of Radiosurgical management of NF2 schwannomas hearing preservation. On N=72 tumors in 60 patients multivariate analysis, only the margin dose remained a Following resection Primary radiosurgery significant factor (P 0.002) N=20 N=52 (Table 3). However, the serviceable Progression of residual tumor Recurrent tumor Dose 14 Gy Dose 14 Gy N=16 N=4 N=35 N=17 hearing preservation rate was 53% for tumors that received a Dose 14 Gy Dose 14 Gy Dose 14 Gy Dose 14 Gy Tumor control Tumor control margin dose of 14 Gy or less, N=14 N=2 N=3 N=1 N=31 (88.6%) N=15 (88.2%) whereas no tumor receiving a higher dose retained servicea- Tumor control Tumor control Tumor control Tumor control N=12 (85.7%) N=2 (100%) N=2 (66.7%) N=1 (100%) ble hearing (Fig. 4). The actu- arial serviceable hearing preservation rate was 73% at FIGURE 3. Summary of local control data for tumors with available follow-up data, based on previous therapy and radiation dose used for radiosurgery. No statistically significant difference was observed between subgroups relative 1 year, 59% at 2 years, and to tumor control rates. 48% at 5 years after radio-

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TABLE 3. Variables used in univariate and multivariate analyses of local control, hearing loss and complicationsa Local control Hearing loss Complications Variable Univariate Multivariate Univariate Multivariate Univariate Multivariate HRR HRR P value P value HRR P value P value P value P value Sex 0.417 0.718 NA 0.071 0.186 NA 0.505 0.409 NA Age (yr) 0.032 0.112 NA 0.505 0.346 NA 0.259 0.205 NA Previous resection 0.646 0.973 NA 0.295 0.316 NA 0.212 0.114 NA Hearing grade NT NT NT 0.033 0.085 NA NT NT NT Imaging modality 0.452 0.308 NA 0.071 0.243 NA 0.002 0.343 NA Margin dose 0.411 0.953 NA 0.001 0.002 1.251 0.001 0.138 NA Maximum dose 0.949 0.719 NA 0.003 0.618 NA 0.001 0.001 1.162 Tumor volume 0.005 0.005 1.355 0.665 0.976 NA 0.103 0.036 1.132

a HRR, hazard rate ratio (estimate of relative risk); NA, not available; NT, not tested.

degree of facial weakness occurred in 12 tumors (17%). According to the House-Brackmann scale, Grade 2 weakness was observed in one tumor (permanent), Grade 3 in six tumors (three cases permanent), Grade 4 in one tumor (permanent), Grade 5 in two tumors (one case permanent), and Grade 6 in two tumors (both permanent). Trigeminal neuropathy occurred in eight tumors (11%). Worsened vestibular function, mani- fested clinically by ataxia and vertigo, was observed in five patients (7%). Among tumors with radiation-induced neuro- pathy, facial function returned to baseline in four (33%) out of 12 patients, trigeminal function in two (25%) out of eight patients, and vestibular function in two (40%) out of five patients. Hemifacial spasm, trigeminal neuralgia, and abducens palsy each complicated one case. The use of computed tomo- graphic scanning for dose planning (P 0.002), margin dose greater than 14 Gy (P 0.001), and maximum dose greater than 28 Gy (P 0.001) were associated with greater odds of FIGURE 4. Kaplan-Meier plot illustrating serviceable hearing preserva- complication on univariate analysis. On multivariate analysis, tion rates according to margin dose used for irradiation. The solid line maximum dose greater than 28 Gy (P 0.001) and tumor vol- represents a margin dose of 14 Gy or less and the dotted line represents ume greater than 5 cm3 (P 0.036) were predictors of compli- a margin dose of greater than 14 Gy. cations (Table 3). Since 1992, all tumors have been irradiated using MRI scans for planning and with margin and maximum doses no higher than 14 and 28 Gy, respectively. The adverse surgery for tumors irradiated with 14 Gy or less. There was a effect rate lessened accordingly since that time. Complication trend toward better hearing preservation with the use of MRI rates using current planning strategies compared with our scans rather than computed tomographic scans for dose plan- early experience are reported in Table 4. ning, although this did not reach statistical significance Sixteen patients died during the follow-up period after a (P 0.064). Patient sex, age, and previous microsurgical resec- median of 91.5 months (range, 24–182 mo). Two patients died tion had no influence on hearing preservation. Figure 5 summa- from causes unrelated to NF2. The cause of death for the other rizes the hearing preservation data according to initial hearing patients is presumed to be related to complications from pro- grade and radiation dose used for radiosurgery. gression of other NF2-associated tumors. No patient developed Complications atypical or malignant changes in irradiated tumors. For the entire series, adverse radiation effects other than hearing loss occurred in 18 (25%) out of 72 tumors. Symptoms DISCUSSION became apparent after a median of 5.5 months after radio- surgery (range, 1–18 mo). The radiation effect was transient in Surgical Resection of NF2 Schwannomas seven tumors (39%), with the clinical condition returning to NF2 is an autosomal dominant disorder caused by muta- normal after a median of 7 months (range, 3–33 mo). Some tions on the long arm of chromosome 22. The gene product, a

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radic unilateral tumors (6). Hearing results for NF2 schwannomas Samii et al. (32) have reported N=72 tumors a 36% hearing preservation rate after microsurgical resec- tion of 120 VS in patients Deaf at radiosurgery Measureable hearing present before radiosurgery with NF2 using the suboccip- N=31 N=41 ital approach. The facial nerve was preserved anatom- Secondary to Secondary Serviceable hearing Non serviceable hearing ically in only 85% of the cases (GR 1-2) (GR 3-4) microsurgery to tumor and 67% of those retained N=19 N=12 N=25 N=16 normal facial function. Complete resection was Dose 14 Gy Dose 14 Gy Dose 14 Gy Dose 14 Gy achieved in 87.5% of the N=19 N=6 N=10 N=6 tumors. In comparison, the same authors reported that Serviceable hearing Serviceable hearing Hearing Hearing total resection was achieved preservation preservation preservation preservation in 99.3% of 880 patients with N=10 (52.6%) N=0 (0%) N=4 (40%) N=0 (0%) unilateral tumors, with hear- ing preservation in 40% and FIGURE 5. Summary of hearing preservation data for tumors with available follow-up data, on the basis of initial anatomic continuity of the hearing grade and radiation dose used for radiosurgery. Using doses of 14 Gy or less resulted in significant improve- facial nerve maintained in ment in hearing preservation rates. GR, Gardner-Robertson grade. 95% of the patients (31, 32). Data regarding long-term tumor control was not reported in those studies. Using the TABLE 4. Postradiosurgery complication rates using early versus cur- middle fossa approach, Doyle and Shelton (5) have reported a rent radiosurgery techniques serviceable hearing preservation rate of 44% for 13 small- to Early experience Current technique medium-sized tumors operated at the House Ear Institute. (1987–1992): (1993–2005): Three (23%) of those 13 tumors were noted to recur during the Complications 20 tumors 52 tumors long-term follow-up period, including two tumors that were Total No. perm- Total No. perm- completely removed, after 10, 13, and 18 years. Slattery et al. no. (%) anent (%) no. (%) anent (%) (33) subsequently reported that 48% of 23 NF2 VS resected Facial weakness 7 (35) 4 (20) 5 (10) 4 (8) through the middle fossa approach (all with small tumors) Hemifacial spasm 1 (5) 0 (0) 0 (0) 0 (0) retained hearing within 15 dB of the preoperative pure-tone Trigeminal neuropathy 5 (25) 4 (20) 3 (6) 2 (4) average and within 15% of the preoperative speech discrimina- Trigeminal neuralgia 1 (5) 0 (0) 0 (0) 0 (0) tion score. Moffat et al. (23) reported the outcome of 15 patients Vestibular dysfunction 2 (10) 1 (5) 3 (6) 2 (4) in whom total resection was accomplished. No patient had pre- Abducens palsy 1 (1) 1 (1) 0 (0) 0 (0) served hearing after surgery. No tumor recurrence was noted Total 9 (45) 5 (25) 9 (17) 6 (12) during the long-term follow-up period (length not specified). Recent articles have reported some success with auditory rehabilitation of deaf NF2 patients with auditory brainstem protein called merlin, is postulated to act as a tumor suppres- implantation (4, 15). The implant is usually inserted at the time sor through inhibition of several signal transduction pathways of surgical resection in the lateral recess of the fourth ventricle (6). The incidence of NF2 is approximately one for every 35,000 with the goal of stimulating the cochlear nuclei. No added mor- live births (7). As many as 50% of the cases are acquired as bidity from the implantation was reported, and improvement new somatic mutations (7). The hallmark of NF2 is the devel- in auditory function was noted with time in most patients. opment of bilateral VS. However, depending on the severity of However, as was stated by the authors of these studies, this the underlying mutation, multiple other CNS tumors can also technique rarely provides independent auditory function and be found, notably multiple meningiomas and schwannomas mostly serves as an adjunct to lip reading. Therefore, preserva- involving other cranial nerves (6). Pathologically, VS occurring tion of native audition should still be the goal with NF2 in NF2 differ from sporadic tumors in that they are more lobu- patients whenever possible. lar, less vascularized, and have an increased growth rate (17). They also tend to engulf the surrounding cochlear and facial Stereotactic Radiosurgery of NF2 VS nerves, whereas sporadic schwannomas usually compress and Because therapeutic options are more likely to result in mor- displace the nerves (14, 34). This might explain why complica- bidity in NF2 VS than in sporadic tumors and because patients tions and hearing preservation rates are reported to be poor will often experience consequences of the development of mul- after resection of VS in the context of NF2 compared with spo- tiple other CNS tumors, the management paradigm for VS in

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the context of NF2 has recently focused mostly on the preser- patients managed using gamma knife radiosurgery. They irra- vation of function and the maintenance of quality of life over diated 122 tumors in 96 patients between 1986 and 2000. No complete tumor elimination (6). Our current management of other therapeutic intervention was necessary in 79% of the NF2-associated VS consists of the observation of newly diag- cases. Using current radiation doses, 38% of the tumors had nosed asymptomatic tumors. Treatment is only offered in cases hearing preservation at 3 years after radiosurgery. Facial func- of documented progressive tumor growth, progressive hearing tion worsened in 8% of the patients and trigeminal function in loss, or large symptomatic tumors. This approach ensures that 2% of the patients. Tumor volume was found to be the only normal neurological and audiological function is preserved for factor predictive of local control, with worse outcome associ- as long as possible. ated with larger tumors (29). Table 5 summarizes the main With that goal in mind, stereotactic radiosurgery has series focusing on radiosurgery of NF2 VS. proven its efficacy as a minimally invasive management option for unilateral VS, with reported long-term results at Malignant Transformation Risks least equivalent to, if not better than, microsurgical resection. Despite superior outcome and a lower complication profile Tumor control varies from 92 to 98%, with follow-up intervals compared with microsurgery, reticence to use radiosurgery in up to 10 years (10, 19, 21, 24, 27, 28). Using current dose- NF2 patients remains because of concerns of secondary malig- planning techniques (MRI planning, margin dose no higher nant transformation. Because the initial mutation in NF2 results than 14 Gy), hearing preservation ranges from 52 to 83.4% in the loss of one allele of a tumor suppressor gene, it has been and the risk of permanent facial weakness has been reduced postulated that radiation might act as a second “hit” and pre- to less than 1% (8, 10, 13, 21, 24, 28, 37). To our knowledge, not dispose these patients to late secondary malignant transforma- many articles have focused on the results of stereotactic radio- tion, both in existing schwannomas and surrounding regions, surgery specifically for NF2-associated VS (16, 20, 28–30, 35). according to the ”two-hit hypothesis” of oncogenesis (25). VS Kida et al. (16) reported the results of unilateral gamma knife are generally regarded as benign tumors that rarely undergo radiosurgery procedures to manage 20 patients. Using 10 to malignant transformation in the general population. Only four 15 Gy as a margin dose, they achieved 100% tumor control cases of spontaneous malignant VS have been reported in non- after a mean follow-up period of 33.6 months. Hearing was NF2 patients, with four more occurring after radiosurgery (1). preserved in 33.3% of the cases. Transient radiation-induced However, only one of the latter had resection before radio- facial paresis and ataxia occurred in two patients each, but surgery with demonstration of initial benign histology. The resolved completely. Roche et al. (28) reported the outcome of pre-irradiation histology was unknown in the other three cases, 37 patients with NF2 in whom gamma knife radiosurgery was so whether or not this represents true malignant degeneration used to manage 50 tumors. Five- and 10-year local control is unknown. rates were 90 and 85%, respectively. Serviceable hearing was On the basis of a survey of North American and European preserved in 36% of the patients at 5 years. Permanent facial centers with experience in the management of NF2 patients, palsy complicated 2% of the procedures. Irradiation with mar- Baser et al. (2) tried to establish the rates of CNS malignancy gin dose greater than 12 Gy was a risk factor for hearing dete- in 1348 NF2 patients. Among this group, five patients had rioration. Rowe et al. (30) reported a large series of NF2 VS malignant transformation of a tumor managed with radio-

TABLE 5. Summary of series focusing on stereotactic radiosurgical management of vestibular schwannomas in the context of NF2

Series Patients/ Follow-up Serviceable hearing Local control Complications (ref. no.) tumors length (range) preservation Kida et al., 20 patients/ 34 mo 100% 33.3% 2 facial paresis 2000 (16) 20 tumors (18–84 mo) 2 facial spasm 2 ataxia all transient Roche et al., 27 patients/ 62 mo 74% 57% 3 facial deficits 2000 (28) 35 tumors (27–123 mo) (2 transient) Rowe et al., 96 patients/ 50 mo 79% 38% 8% facial neuropathy 2003 (30) 122 tumors (4–154 mo) 2% trigeminal neuropathy Present series 60 patients/ 64 mo 88% 53% 17% total 72 tumors (4–196 mo) 12% permanent 8% facial paresis 4% trigeminal neuropathy

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surgery, whereas nine non-irradiated patients developed a ing preservation rate has risen to 53% and the morbidity rate malignant tumor spontaneously. In the absence of data has decreased to 17%, with only 12% remaining permanent. regarding the exact denominator (the number of patients who Other than radiation dose, univariate analysis has revealed had radiosurgery) a valid incidence of malignant transforma- that better preradiosurgery auditory function was predictive tion related to radiation could not be estimated. Bari et al. (1) of hearing preservation, as has been shown after microsurgery reported an NF2 patient with malignant histological features (32). Overall, these results are not as good as those attained at resection 42 months after gamma knife radiosurgery. This with radiosurgery for sporadic VS, which reflects the ten- patient was included in the series reported by Rowe et al. dency for NF2 tumors to invade adjacent cranial nerves, ren- (29). However, this patient’s previous histology was unknown dering functional preservation more difficult (14, 34). and radiosurgery was performed for rapid tumor growth; However, our results compare favorably with the best pub- therefore, it is possible that this tumor was already malignant lished data from microsurgical resection of NF2-associated at the time of radiosurgery. No such case has been reported in tumors (5, 32, 33). The avoidance of exposure to risks such as other radiosurgery series focusing on NF2 and none of our cerebrospinal fluid leak, meningitis, hemorrhage, pulmonary patients developed malignant changes after radiosurgery (16, embolism, and other problems associated with resection 28). Thus, there is no conclusive evidence in the literature that makes radiosurgery an important therapeutic choice for NF2 NF2 patients are more prone to malignant neoplastic degen- patients and their families. eration after undergoing radiosurgery than patients with spo- radic VS. Disclosure Local Experience Douglas Kondziolka, M.D., Ajay Niranjan, M.Ch., and L. Dade Lunsford, M.D., are consultants for Elekta AB. Our experience with gamma knife radiosurgery for the management of NF2-associated VS now includes 60 patients for whom follow-up information was available, accounting REFERENCES for 72 tumors. To our knowledge, our results compare favor- 1. Bari ME, Forster DM, Kemeny AA, Walton L, Hardy D, Anderson JR: ably with other published series. Only nine tumors had a Malignancy in a vestibular schwannoma. Report of a case with central neu- repeat intervention targeting the schwannoma specifically, rofibromatosis, treated by both stereotactic radiosurgery and surgical exci- which corresponds to a local control rate of 88% after a sion, with a review of the literature. Br J Neurosurg 16:284–289, 2002. median follow-up period of 53 months. This rate might have 2. Baser ME, Evans DG, Jackler RK, Sujansky E, Rubenstein A: Neuro- been higher because two tumors were resected at other insti- fibromatosis 2, radiosurgery and malignant nervous system tumours. Br J Cancer 82:998, 2000. tutions early after radiosurgery because of slight tumor cap- 3. Baser ME, Makariou EV, Parry DM: Predictors of vestibular schwannoma sule expansion associated with central loss of contrast growth in patients with neurofibromatosis Type 2. J Neurosurg enhancement. This is now known to be a common occurrence 96:217–222, 2002. after VS radiosurgery and is usually a transient phenomenon 4. Colletti V, Carner M, Miorelli V, Guida M, Colletti L, Fiorino F: Auditory that may predict subsequent tumor response (18, 19, 26, 27). brainstem implant (ABI): New frontiers in adults and children. Otolaryngol Head Neck Surg 133:126–138, 2005. Repeat procedures occurred from 5 to 84 months after pri- 5. Doyle KJ, Shelton C: Hearing preservation in bilateral acoustic neuroma sur- mary radiosurgery. The reported experience with unilateral gery. Am J Otol 14:562–565, 1993. VS suggested that tumor progression usually occurs within 4 6. Evans DG, Baser ME, O’Reilly B, Rowe J, Gleeson M, Saeed S, King A, Huson years after radiosurgery (10, 12, 19, 21). However, this might SM, Kerr R, Thomas N, Irving R, MacFarlane R, Ferner R, McLeod R, Moffat not be applicable to VS in the context of NF2, which are D, Ramsden R: Management of the patient and family with neurofibromato- sis 2: A consensus conference statement. Br J Neurosurg 19:5–12, 2005. known to have more aggressive growth rates than sporadic 7. Evans DG, Huson SM, Donnai D, Neary W, Blair V, Teare D, Newton V, tumors (17). Our results suggest that continued close imaging Strachan T, Ramsden R, Harris R: A genetic study of type 2 neurofibromatosis surveillance is necessary for these tumors because late pro- in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation gression leading to repeat intervention occurred as late as 7 of maternal transmission effect on severity. J Med Genet 29:841–846, 1992. 8. Flickinger JC, Kondziolka D, Niranjan A, Maitz A, Voynov G, Lunsford LD: years after radiosurgery. Age and tumor volume were pre- Acoustic neuroma radiosurgery with marginal tumor doses of 12 to 13 Gy. Int dictors of local control in our study. Age was reported to J Radiat Oncol Biol Phys 60:225–230, 2004. influence tumor growth rates in two longitudinal NF2 studies, 9. Gardner G, Robertson JH: Hearing preservation in unilateral acoustic neu- with younger patients having growth rates that were signifi- roma surgery. Ann Otol Rhinol Laryngol 97:55–66, 1988. cantly more elevated (3, 22). Radiation dose had no impact on 10. Hasegawa T, Fujitani S, Katsumata S, Kida Y, Yoshimoto M, Koike J: Stereotactic radiosurgery for vestibular schwannomas: Analysis of 317 tumor control, but it did impact hearing preservation and patients followed more than 5 years. Neurosurgery 57:257–265, 2005. complication rates. In our early experience, using margin 11. House JW, Brackmann DE: Facial nerve grading system. Otolaryngol Head doses greater than 14 Gy and maximum doses greater than 28 Neck Surg 93:146–147, 1985. Gy, the total new cranial nerve complication rate was 45%. No 12. Inoue HK: Low-dose radiosurgery for large vestibular schwannomas: Long- patient with preradiosurgery serviceable hearing retained term results of functional preservation. J Neurosurg 102 [Suppl]:111–113, 2005. 13. Iwai Y, Yamanaka K, Shiotani M, Uyama T: Radiosurgery for acoustic neuro- useful auditory function among this subgroup. Using current mas: Results of low-dose treatment. Neurosurgery 53:282–288, 2003. techniques of reduced prescription doses and improved 14. Jääskeläinen J, Paetau A, Pyykko I, Blomstedt G, Palva T, Troupp H: Interface tumor targeting with MRI scanning, the total serviceable hear- between the facial nerve and large acoustic neurinomas. Immunohisto-

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chemical study of the cleavage plane in NF2 and non-NF2 cases. J Neurosurg Acknowledgment 80:541–547, 1994. We thank Charlene Baker for assistance with data collection. 15. Kanowitz SJ, Shapiro WH, Golfinos JG, Cohen NL, Roland JT Jr: Auditory brainstem implantation in patients with neurofibromatosis type 2. Laryngo- scope 114:2135–2146, 2004. COMMENTS 16. Kida Y, Kobayashi T, Tanaka T, Mori Y: Radiosurgery for bilateral neurinomas associated with neurofibromatosis type 2. Surg Neurol 53:383–390, 2000. atients with vestibular schwannomas (VS) have clear goals regard- 17. Kishore A, O’Reilly BF: A clinical study of vestibular schwannomas in type 2 ing the management of their tumors. They do not want to worry neurofibromatosis. Clin Otolaryngol Allied Sci 25:561–565, 2000. P about tumor growth or regrowth after treatment. They want to main- 18. Kondziolka D, Lunsford LD, Flickinger JC: Gamma knife radiosurgery for vestibular schwannomas. Neurosurg Clin N Am 11:651–658, 2000. tain normal facial movement, preserve their hearing, and improve 19. Kondziolka D, Lunsford LD, McLaughlin MR, Flickinger JC: Long-term out- tumor-related symptoms such as tinnitus, imbalance, and headache. comes after radiosurgery for acoustic neuromas. N Engl J Med 339: They also want the chosen treatment to be as safe and simple as possi- 1426–1433, 1998. ble. Consequently, the management of these patients must balance 20. Linskey ME, Lunsford LD, Flickinger JC: Tumor control after stereotactic these different goals to maximize outcomes. radiosurgery in neurofibromatosis patients with bilateral acoustic tumors. With radiosurgery, it is possible that higher radiation doses may Neurosurgery 31:829–839, 1992. translate to higher tumor growth control rates; however, the attendant 21. Lunsford LD, Niranjan A, Flickinger JC, Maitz A, Kondziolka D: Radio- morbidity on adjacent cranial nerves would be unacceptable. Likewise, surgery of vestibular schwannomas: Summary of experience in 829 cases. tumor resection that sacrifices the adjacent cranial nerves would ensure J Neurosurg 102 [Suppl]:195–199, 2005. 22. Mautner VF, Baser ME, Thakkar SD, Feigen UM, Friedman JM, Kluwe L: that tumor recurrence rates would be negligible. Fortunately, both Vestibular schwannoma growth in patients with neurofibromatosis Type 2: A radiosurgical and microsurgical management of patients with VS has longitudinal study. J Neurosurg 96:223–228, 2002. advanced, tumor growth and progression are rare, cranial nerve preser- 23. Moffat DA, Quaranta N, Baguley DM, Hardy DG, Chang P: Management vation is high, and treatment-associated complications are low. Most strategies in neurofibromatosis type 2. Eur Arch Otorhinolaryngol 260:12–18, neurosurgeons would agree that radiosurgery is associated with better 2003. cranial nerve outcomes than microsurgical resection when considering 24. Paek SH, Chung HT, Jeong SS, Park CK, Kim CY, Kim JE, Kim DG, Jung HW: the management of patients with small to moderate-sized unilateral VS Hearing preservation after gamma knife stereotactic radiosurgery of vestibu- and has less effect on a patient’s daily quality of life (1). lar schwannoma. Cancer 104:580–590, 2005. In this study, Mathieu et al. from the University of Pittsburgh thor- 25. Plowman PN, Evans DG: Stereotactic radiosurgery XI. Acoustic neuroma therapy and radiation oncogenesis. Br J Neurosurg 14:93–95, 2000. oughly document their 18-year experience with 60 patients with neu- 26. Pollock BE: Management of vestibular schwannomas that enlarge after stereo- rofibromatosis Type 2 (NF2). Compared with the results of radiosurgery tactic radiosurgery: Treatment recommendations based on a 15 year experi- for patients with unilateral VS, the results reported in this study are evi- ence. Neurosurgery 58:241–248, 2006. dently worse. Nonetheless, a permanent facial weakness rate of 8% and 27. Prasad D, Steiner M, Steiner L: Gamma surgery for vestibular schwannoma. a hearing preservation rate of almost 50% compare favorably with any J Neurosurg 92:745–759, 2000. series on the microsurgical resection of these tumors. Moreover, 28. Roche PH, Regis J, Pellet W, Thomassin JM, Gregoire R, Dufour H, Peragut although the follow-up period in this study (318 patient years) does not JC: Neurofibromatosis type 2. Preliminary results of gamma knife radio- permit a meaningful analysis on the chance of malignant transformation surgery of vestibular schwannomas [in French]. Neurochirurgie 46:339–354, after radiosurgery, the anecdotal reports thus far are not sufficient to 2000. conclude that radiosurgery significantly increases the chance of malig- 29. Rowe JG, Radatz M, Walton L, Kemeny AA: Stereotactic radiosurgery for type 2 neurofibromatosis acoustic neuromas: Patient selection and tumour size. nant transformation for NF2 patients. It seems that radiosurgery accom- Stereotact Funct Neurosurg 79:107–116, 2002. plishes the management goals for the majority of VS patients, both those 30. Rowe JG, Radatz MW, Walton L, Soanes T, Rodgers J, Kemeny AA: Clinical with unilateral tumors and patients with NF2. experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas secondary to type 2 neurofibromatosis. J Neurol Bruce E. Pollock Neurosurg Psychiatry 74:1288–1293, 2003. Rochester, Minnesota 31. Samii M, Matthies C: Management of 1000 vestibular schwannomas (acoustic neuromas): Hearing function in 1000 tumor resections. Neurosurgery 40:248–262, 1997. 1. Pollock BE, Driscoll CL, Foote RL, Link MJ, Gorman DA, Bauch CD, 32. Samii M, Matthies C, Tatagiba M: Management of vestibular schwannomas Mandrekar JN, Krecke KN, Johnson CH: Patient outcomes after vestibular (acoustic neuromas): Auditory and facial nerve function after resection of schwannoma management: A prospective comparison of microsurgical resec- 120 vestibular schwannomas in patients with neurofibromatosis 2. tion and stereotactic radiosurgery. Neurosurgery 59:77–85, 2006. Neurosurgery 40:696–706, 1997. 33. Slattery WH 3rd, Brackmann DE, Hitselberger W: Hearing preservation in neurofibromatosis type 2. Am J Otol 19:638–643, 1998. he management of VS in NF2 is a vexing problem in neurosurgery. 34. Sobel RA: Vestibular (acoustic) schwannomas: Histologic features in neurofi- TThis report of 62 patients treated with gamma knife stereotactic radio- bromatosis 2 and in unilateral cases. J Neuropathol Exp Neurol 52:106–113, surgery (SRS) is an important contribution to the literature and reveals the 1993. limitations of using radiosurgery to treat aggressive tumors. This report 35. Subach BR, Kondziolka D, Lunsford LD, Bissonette DJ, Flickinger JC, Maitz criticizes microsurgical results as an argument for choosing radiosurgery. AH: Stereotactic radiosurgery in the management of acoustic neuromas asso- However, the ultimate goals in NF2 are long-term tumor control and ciated with neurofibromatosis Type 2. J Neurosurg 90:815–822, 1999. hearing preservation. Even unilateral permanent hearing preservation is 36. Unger F, Walch C, Papaefthymiou G, Eustacchio S, Feichtinger K, an accomplishment in this patient group. It is not clear from this report Quehenberger F, Pendl G: Long term results of radiosurgery for vestibular schwannomas. Zentralbl Neurochir 63:52–58, 2002. whether or not radiosurgery can deliver either of these goals. 37. van Eck AT, Horstmann GA: Increased preservation of functional hearing Similar to much of the radiosurgery literature, the short follow-up after gamma knife surgery for vestibular schwannoma. J Neurosurg 102 period (median, 5 yr) is a weakness in this series. In addition, the [Suppl]:204–206, 2005. change in dosing schemes since 1992 makes a vague follow-up study.

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The longest follow-up period is for tumors treated with the highest alternative, as the authors show in their illustrative case of a growing doses. By lowering doses below 14 Gy and reducing complications, we tumor left untreated. At our institution, we see a disproportionate share expect decreased long-term control rates. Although the numbers are of younger NF2 patients with aggressive disease progression and con- small, Figure 3 shows failures in the tumors treated with lower doses. sider SRS to be a last resort treatment. We recommend early surgery for The authors perpetuate the radiosurgical practice of defining local con- small to moderate-sized tumors hoping for single-side hearing preser- trol as the absence of repeat surgical intervention. In tumor studies, vation. In patients with larger tumors, we consider observation until radiographic progression is the same as progression of the disease. hearing is lost, at which time we will surgically intervene to preserve Although tumors may grow sporadically, a treated tumor that enlarges the facial nerve, relieve mass effect, and for placement of an auditory cannot be considered to be under control. Moreover, three patients brain stem implant. underwent shunt placement for hydrocephalus from increased fourth John G. Golfinos ventricle compression. At the very least, this should be considered a J. Thomas Roland morbidity, if not poor local control. Ash Narayana Finally, these tumors can progress many years after radiosurgery. In Philip H. Gutin this series, one patient’s tumor progressed 7 years after treatment. We New York, New York have had the unfortunate experience of resecting a rapidly progressing, previously irradiated tumor in a patient with NF2 10 years after irradi- ation. In this series, younger patients had worse control rates. This 1. Baser ME, Makariou EV, Parry DM: Predictors of vestibular schwannoma growth reflects a population with more aggressive mutations and clinical in patients with neurofibromatosis Type 2. J Neurosurg 96:217–222, 2002. course of the disease. As the authors cited, tumors in these patients 2. Doyle KJ, Shelton C: Hearing preservation in bilateral acoustic neuroma sur- seem to grow faster in younger patients (1). This is the same patient gery. Am J Otol 14: 562–565, 1993. group that will have more years to fail and more years to develop radi- 3. Evans DG, Birch JM, Ramsden RT, Sharif S, Baser ME: Malignant transforma- tion and new primary tumours after therapeutic radiation for benign disease: ation-induced malignancy. Substantial risks in certain tumour prone syndromes. J Med Genet 43: The hearing preservation data from this study are encouraging. 289–294, 2006. However, an important question remains regarding how durable hearing will be after radiation. The steady decline in actuarial hearing preserva- RS has contributed to improved results in the treatment of NF2 tion rates from 72.6% at the first year to only 47.5% at the fifth year brings Spatients with bilateral VS. It is no longer common to see patients the 10 and 20-year hearing preservation rates into question. This is espe- with bilateral complete deafness, bilateral facial paralysis, bilateral facial cially important for younger patients with more aggressive tumors. hypesthesia, severe ataxia, and swallowing problems that are the result The other interesting conclusion of this study is that tumor volume of multiple bilateral resections. However, there are still issues to be did not predict hearing preservation. Although this was likely a conse- addressed. Even though a serviceable hearing preservation rate of quence of the study’s small numbers, it raises the concern that no 52.6%, as noted in this study, is not bad, there is clearly room for tumor can be selected as particularly favorable for hearing preservation improvement. Surprisingly, some NF2 patients have unaffected hearing using radiosurgery. and the tumors may reach a size of 2 to 3 cm before they are diagnosed. As far as the question of increased malignancy rates, it is clear it will Currently, there is not much we can do with the available open surgical happen given enough time. The only unanswered questions are what the and radiation-based methods to avoid loss of hearing in that situation. actual risk is and whether or not the NF2 mutation increases that risk or decreases the time to induction of a second malignancy. A careful review Georg Noren of the literature and the experience of Evans et al. (3) reveal an increased Providence, Rhode Island relative risk of new tumors (18.8 relative risk for new schwannomas) and a real risk of malignant transformation of treated schwannomas. hether treated with microsurgery or radiosurgery, the surgical Whereas the authors reported no instances of atypical changes in their Wremedy of NF2-associated acoustic neuroma is accompanied by resected patients, we have resected a tumor 4 years after gamma knife far greater risk than in the setting of sporadic acoustic neuroma. Facial treatment with an MIB-1 labeling index greater than 5%. In our institu- nerve paresis rates and loss of hearing are higher because of the tion, this tumor was considered an atypical schwannoma. propensity of these lesions to diffusely infiltrate the nerve. The bilateral Determining the better technique for treating VS in patients with nature of this disease compounds the risk of profound deafness NF2 should not be questioned. Instead, patients should be treated by whether treatment is instituted or not. Furthermore, the risk of recur- surgeons who have significant experience in both microsurgical resec- rence or progression is higher for tumors associated with NF2 regard- tion and stereotactic radiosurgery so that therapy can be tailored to the less of whether surgery or radiosurgery is chosen as the primary treat- individual patient. This report provides that tumor volume predicts ment. Given the perspective of these data and their personal experience, the authors have wisely advocated a conservative approach local control and morbidity. Therefore, the best tumors for radiosurgery for these patients, recommending treatment only in the presence of are small tumors in patients with good hearing. Unfortunately, these progressive symptoms or documented enlargement of tumor to pre- are also the best cases for microsurgical resection and hearing preser- serve useful hearing as long as possible. vation. At least 12% of tumors will fail radiation in the first 5 years, and This is a well-written and comprehensive review of the Pittsburgh probably more in young patients with aggressive forms of the disease. group’s experience with acoustic neuromas associated with NF2. The This is the most compelling reason in favor of surgical resection, espe- results of this study set a very high standard to which other treatments cially in young patients. Otherwise, surgery will eventually occur in the must be compared. This article currently represents the most definitive setting of a previously radiated field with little chance of facial nerve statement on the topic and should be referred to when evaluating and preservation. The best chance for durable hearing preservation in a counseling patients with NF2-associated acoustic neuromas. young patient may still be surgical resection of a small tumor (2). In larger tumors with little chance of surgical hearing preservation or Joseph C.T. Chen radiosurgical hearing preservation, observation remains a reasonable Los Angeles, California

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athieu et al. present their experience with gamma knife SRS for with magnetic resonance imaging, resulted in an improved hearing MVS in patients with NF2. The management of this group is a chal- preservation rate of 53% and a decrease in other complications. The lenge to all who treat these patients. The authors make a convincing authors do not define the cause for the delayed loss of hearing for case for serious consideration of SRS as a primary treatment for this which direct nerve injury and axonal damage and/or vascular compro- group of patients. mise have been suggested. It might be interesting to study the dose to The delayed loss of hearing after gamma knife radiosurgery is of the cochlear and whether or not there is a relationship to hearing loss interest. The authors note that a margin dose more than 14 Gy and a in patients treated with stereotactic radiosurgery for VS. maximum dose more than 28 Gy were associated with loss of useful auditory function. However, using a reduced prescription dose (margin Robert Goodkin dose, ≤14 Gy; maximum dose, ≤28 Gy) and improved tumor targeting Seattle, Washington

Amyloid Proteins and Their Precursors.* Amyloid Precursor Distribution Type Syndrome or Involved Tissues Protein

Aβ Aβ protein precursor Localized Acquired Sporadic Alzheimer’s disease, aging Localized Hereditary Prototypical hereditary cerebral amyloid angiopathy, Dutch type

APrP Prion protein Localized Acquired Sporadic (iatrogenic) CJD, new variant CJD (alimentary?) Localized Hereditary Familial CJD, GSSD, FFI

ABri ABri protein precursor Localized or systemic? Hereditary British familial dementia

ACys Cystatin C Systemic Hereditary Icelandic hereditary cerebral amyloid angiopathy β A 2M Beta2-microglobulin Systemic Acquired Chronic hemodialysis

AL Immunoglobulin light chain Systemic or localized Acquired Primary amyloidosis, myeloma-associated

AA Serum amyloid A Systemic Acquired Secondary amyloidosis, reactive to chronic infection or inflammation including hereditary periodic fever (FMF, TRAPS, HIDS, FCU, and MWS)

ATTR Transthyretin Systemic Hereditary Prototypical FAP Systemic Acquired Senile heart, vessels

AApoAI Apolipoprotein A-I Systemic Hereditary Liver, kidney, heart

AApoAII Apolipoprotein A-II Systemic Hereditary Kidney, heart

AGel Gelsolin Systemic Hereditary Finnish hereditary amyloidosis

ALys Lysozyme Systemic Hereditary Kidney, liver, spleen

AFib Fibrinogen Aα chain Systemic Hereditary Kidney

*Data were adapted from Westermark et al. The following proteins may also cause amyloidosis: immunoglobulin heavy chain, calcitonin, islet- amyloid polypeptide, atrial natriuretic factor, prolactin, insulin, lactadherin, keratoepithelin, and Danish amyloid protein (which comes from the same gene as ABri and has an identical N-terminal sequence). CJD denotes Creutzfeldt–Jakob disease, GSSD Gerstmann–Sträussler–Scheinker disease, FFI fatal familial insomnia, FMF familial Mediterranean fever, TRAPS tumor necrosis factor receptor–associated periodic syndrome, HIDS hyper-IgD syndrome, FCU familial cold urticaria, MWS Muckle–Wells syndrome, and FAP familial amyloidotic polyneuropathy.

Courtesy of Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. N Engl J Med 349:583-596, 2003 and Westermark P, Benson MD, Buxbaum JN: Amyloid fibril protein nomenclature – 2002. Amyloid 9:197–200, 2002.

470 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com David Mathieu, M.D. CLINICAL STUDIES Department of Neurological Surgery, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Douglas Kondziolka, M.D. Departments of Neurological Surgery GAMMA KNIFE RADIOSURGERY IN THE MANAGEMENT and Radiation Oncology, University of Pittsburgh OF MALIGNANT MELANOMA BRAIN METASTASES School of Medicine, University of Pittsburgh Medical Center, OBJECTIVE: Radiosurgery is increasingly used to manage malignant melanoma brain Pittsburgh, Pennsylvania metastases. We reviewed our series of patients who underwent radiosurgery for melanoma Patrick B. Cooper, M.D. brain metastases to assess clinical outcomes and identify prognostic factors for survival Department of Neurological Surgery, and cerebral disease control. University of Pittsburgh School of Medicine, METHODS: Two hundred forty-four patients had radiosurgery for the management of University of Pittsburgh 754 metastatic tumors. A mean of 2.6 tumors were irradiated per procedure. The median Medical Center, 3 Pittsburgh, Pennsylvania tumor volume was 4.4 cm . The median margin and maximum doses used were 18 and 32 Gy, respectively. John C. Flickinger, M.D. Department of Neurological Surgery, RESULTS: The median survival was 5.3 months after radiosurgery (mean, 10 mo; range, University of Pittsburgh 0.2–114.3 mo). Patients survived a median of 7.8 months (mean, 13.4 mo) from the School of Medicine, University of Pittsburgh diagnosis of brain metastases and 44.9 months (mean, 69 mo) after the diagnosis of the Medical Center, primary tumor. Survival was better in patients with controlled systemic disease (12.7 mo), Pittsburgh, Pennsylvania single brain metastasis (6.8 mo), and a Karnofsky performance score of 90 or 100% Ajay Niranjan, M.Ch. (6.3 mo). Sustained local control was achieved in 86.2% of tumors. Increased tumor vol- Department of Neurological Surgery, ume and previous evidence of hemorrhage increased the risk of local failure. Multiple University of Pittsburgh lesions and failure to provide systemic immunotherapy were predictors for the occur- School of Medicine, University of Pittsburgh rence of new brain metastases, which developed in 41.7% of the patients. Symptomatic Medical Center, radiation changes occurred in 6.6% of the patients. Overall, 71.4% of the patients Pittsburgh, Pennsylvania improved or remained clinically stable. Brain disease was the cause of death in 40.5% Sanjiv Agarwala, M.D. of the patients, usually from the development of new metastases. Division of Medical Oncology, University of Pittsburgh CONCLUSION: Gamma knife radiosurgery for malignant melanoma brain metastases School of Medicine, is safe and effective and provides a high rate of durable local control. Improved sur- University of Pittsburgh vival can be achieved in patients with single metastasis, controlled systemic disease, and Medical Center, Pittsburgh, Pennsylvania a high Karnofsky performance score. John Kirkwood, M.D. KEY WORDS: Brain metastases, Gamma knife, Malignant melanoma, Prognostic factors, Stereotactic radio- Division of Medical Oncology, surgery University of Pittsburgh School of Medicine, Neurosurgery 60:471–482, 2007 DOI: 10.1227/01.NEU.0000255342.10780.52 www.neurosurgery-online.com University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania fter lung and breast cancer, melanoma tionated WBRT for metastatic cancer. Radio- L. Dade Lunsford, M.D. is the third most common primary surgery provides high local tumor control rates Departments of Neurological Surgery tumor associated with central nervous in cancers that are often considered radioresis- and Radiation Oncology, A University of Pittsburgh system (CNS) metastasis (5, 46, 47). Cerebral tant, such as sarcomas, renal cell carcinomas, School of Medicine, metastases occur in 10 to 40% of patients diag- and melanomas (7, 9). To better understand the University of Pittsburgh nosed with Stage IV melanoma (5, 46). factors that influence survival and tumor Medical Center, Survival usually varies from 2.75 to 4 months, response, we reviewed our experience with Pittsburgh, Pennsylvania with the majority of patients dying from com- gamma knife surgery for melanoma brain Reprint requests: plications of CNS disease (30). For years, the metastases. Douglas Kondziolka, M.D., management of melanoma brain metastases Department of Neurological Surgery, UPMC Presbyterian, consisted of resection of symptomatic surgi- 200 Lothrop Street, Suite B-400, cally accessible lesions followed by whole- PATIENTS AND METHODS Pittsburgh, PA, 15213. brain radiation therapy (WBRT) or WBRT Email: [email protected] alone (5, 30, 46). Stereotactic radiosurgery has Data Collection Received, June 8, 2006. emerged as a minimally invasive adjunct or This retrospective study was approved by Accepted, October 18, 2006. alternative to microsurgical resection and frac- the University of Pittsburgh Institutional

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Review Board. Follow-up imaging studies, when available, 200 patients (82%) were in Class II, and 16 patients (6.6%) were were used to assess tumor response. If no clinical follow-up in Class III. Table 1 summarizes the characteristics of the was available, the referring oncologist was contacted to obtain patient population. the required information. The internet-based Social Security Death Index (http://ssdi.genealogy.rootsweb.com) was used Radiosurgery Procedures to obtain survival data when it was not available from our A total of 291 radiosurgery procedures were performed to records. When no autopsy information was available, the pre- manage 754 tumors. Only one procedure was required in sumed cause of death was decided according to the clinical 207 patients, and 37 patients had multiple procedures (two pro- evolution (neurological and systemic) and with the imaging cedures in 32 cases, three procedures in two cases, four proce- information available from the last follow-up visit. The data dures in one case, and five procedures in two cases). A mean of was collected by two neurosurgeons (DM, PC) who had not 2.6 tumors per patient were irradiated at each procedure participated in patient management. (range, 1–14 tumors). Six hundred twelve tumors (81.2%) were located in the cerebral hemispheres, 47 tumors (6.2%) in deep Patient Population supratentorial parenchyma (thalamus, basal ganglia, and cor- Between August 1987 and September 2005, 244 patients pus callosum), 67 tumors (8.9%) in the cerebellum, 14 tumors underwent gamma knife radiosurgery for the management of (1.9%) in the brainstem, and 14 tumors (1.9%) in the cranium melanoma brain metastases at the University of Pittsburgh (vault or base). Medical Center. The population consisted of 79 (32.4%) women Informed consent was obtained from the patients and their and 165 (67.6%) men aged between 16 and 87 years (mean age, families before the procedure. Using conscious sedation and 54.2 yr). Ninety-eight patients (40.2%) had a single metastasis local anesthesia, the Leksell G frame (Elekta AB, Atlanta, GA) and 146 patients (59.8%) had multiple metastases (range, was applied to the patient’s head. A 2-mm-thick axial spoiled 2–14 patients). The mean interval from primary diagnosis to gradient recalled acquisition in steady state sequence with brain metastases diagnosis was 49.4 months (range, 0–49.8 yr). double-dose contrast covering the entire head was obtained. A In 119 patients (48.8%), the metastases were asymptomatic but fluid-attenuated inversion recovery sequence was performed to were revealed on staging imaging studies. Thirty patients identify additional lesions if necessary. (12.3%) presented with seizures, 21 patients (8.6%) presented Using the Kula or GammaPlan software (Elekta AB), the with a brain hemorrhage, and 74 patients (30.3%) presented attending neurosurgeon, radiation oncologist, and medical with symptoms of focal mass effect from the tumors without physicist designed a dose plan that conformed closely to the imaging evidence of hemorrhage. Previous treatment of the tumor shape using an average of 4.9 isocenters (range, 1–18 systemic disease involved immunotherapy in 124 patients isocenters). The isodose line used to deliver radiation varied (54%), chemotherapy in 105 patients (43%), and extracranial from 30 to 90% (median, 50%). The median margin dose deliv- radiation therapy in 32 patients (14.1%). ered was 18 Gy (mean, 17.4 Gy; range, 10–22 Gy) and the For the management of their brain disease, radiosurgery median maximum dose was 32 Gy (mean, 33.3 Gy; range, was used as the primary management modality in 115 patients 20–50 Gy). The doses were selected based on tumor size, loca- (within 1 mo of brain metastasis diagnosis with no other pre- tion, and previous irradiation status of the patients. Individual vious therapy). One hundred ten patients (45.1%) had received tumor volume (largest tumor in case of multiple metastases) previous WBRT, usually 30 Gy in 10 or 12 fractions (range, varied from 0.1 to 37.2 cm3 (median, 3.4 cm3; mean, 6.0 cm3), 21–60 Gy). Radiosurgery was performed as a planned boost to whereas the total tumor volume (including all lesions in cases WBRT (within 4 wk) in 37.7% of the patients. Two patients of multiple metastases) varied from 0.1 to 44.8 cm3 (median, had previous radiosurgery (one linear accelerator-based and 4.4 cm3; mean, 7.7 cm3). Radiosurgery was performed using a one with a gamma knife) at other institutions. Fifty-three Leksell Gamma Knife model U, B, or C (Elekta AB). patients (21.7%) had previous surgery (craniotomy in After the procedure, as an institutional protocol, 40 mg of 42 patients, stereotactic biopsy in eight patients, and needle methylprednisolone was administered to most patients. The aspiration of tumor cyst in three patients). At the time of radio- first clinical and radiological follow-up assessments were surgery, 131 patients (53.7%) were asymptomatic, 23 patients scheduled at 8 weeks (earlier if a new symptom developed), (9.4%) had headaches only, 14 patients (5.7%) had seizures and then every 3 months for the first year. Further evaluations only, 63 patients (25.8%) had focal neurological deficits, and were dictated by the status of the patients. A tumor was 13 patients (5.3%) had cognitive disturbances. Evidence of pre- deemed stable on follow-up magnetic resonance imaging (MRI) vious tumor hemorrhage, either clinical or radiological, was scans if it remained within 25% of its initial size. Progression present in 37 cases (15.2%). The median Karnofsky perform- was recognized if the tumor increased by more than 25% com- ance score (KPS) was 90% (range, 50–100%). According to the pared with size at the time of radiosurgery, whereas tumor referring oncologist evaluation, the systemic cancer was con- regression occurred in cases of shrinkage of more than 25%. In sidered controlled in 48 patients (19.7%) and active in addition to patients with increased tumor size, those who 196 patients (80.3%). When stratified according to the recursive needed additional intervention on an irradiated lesion because partitioning analysis (RPA) devised by the Radiation Therapy of worsening symptoms, even without change in size, were Oncology Group (13), 28 patients (11.5%) were in Class I, classified as having progression.

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TABLE 1. Demographics and clinical data of the patient popula- tiona Characteristic No. of patients Sex Female 79 (32.4%) Male 165 (67.6%) Initial cerebral presentation Staging imaging (no symptoms) 119 (48.8%) Seizure 30 (12.3%) Tumor hemorrhage 21 (8.6%) Mass effect (without bleed) 74 (30.3%) Number of metastases 1 98 (40.2%) 2–3 85 (34.8%) 4–6 41 (16.8%) 7 or more 20 (8.2%) FIGURE 1. Kaplan-Meier plot showing overall survival from the time of Metastases location radiosurgery for the entire patient series. Lobar supratentorial 219 (89.8%) Deep supratentorial 37 (15.2%) Cerebellum 39 (16%) Statistical Analysis Brainstem 13 (5.3%) Statistical analysis was performed using the SPSS 13.0 soft- Cranium 6 (2.5%) ware (SPSS Inc., Chicago, IL). Kaplan-Meier analyses were per- Previous systemic therapy formed to assess survival and freedom from local and distant Chemotherapy 105 (43%) failure after radiosurgery. Univariate and stepwise forward Immunotherapy 124 (50.8%) conditional multivariate analyses were performed with the Cox Extracranial radiation 32 (13.1%) proportional hazards model to assess the prognostic value of Previous cerebral therapy different variables relative to tumor response, distant failure, Surgery 53 (21.7%) survival, and complications. WBRT 110 (45.1%) Radiosurgery 2 (0.8%) Extent of systemic disease RESULTS CNS only 7 (2.9%) Primary site only 21 (8.6%) Survival Primary + one lymph node chain 25 (10.2%) At the time of the analysis, 212 patients were deceased and Primary + more than 1 lymph chain 49 (20.1%) 18 survived. Fourteen patients were presumed deceased (with- or visceral metastases out confirmation) and were censored from survival analysis. Disseminated (more than 2 visceral sites) 142 (58.2%) The median survival after radiosurgery was 5.3 months (mean, Systemic disease status 10 mo; range, 0.2–114.3 mo). The median survival was 7.8 Active 196 (80.3%) months (mean, 13.4 mo) from the diagnosis of brain metastases Controlled 48 (19.7%) and 44.9 months (mean, 69 mo) from the diagnosis of the pri- Main neurological symptomatology mary tumor. Actuarial survival rates were 67.6 Ϯ 3.1% at at radiosurgery 3 months, 42.8 Ϯ 3.3% at 6 months, 20.2 Ϯ 2.7% at 12 months, Asymptomatic 131 (53.7%) Ϯ Headaches only 23 (9.4%) and 9.3 2.1% at 24 months after radiosurgery (Fig. 1). One Seizures only 14 (5.7%) hundred eight patients (50.9%) were thought to have died from Focal deficits 63 (25.8%) progression of the systemic disease and 86 patients (40.5%) Cognitive deficits 13 (5.3%) from CNS disease. In the latter group, 77 patients died from KPS increased cerebral tumor burden (most with multiple new 90–100% 163 (66.8%) metastases) and nine patients died as a consequence of brain Below 80% 81 (33.2%) hemorrhage. Six patients (2.8%) died from causes not related to RPA class their neoplastic disease. The exact cause of death remained 1 28 (11.5%) unknown in 12 patients (5.7%). 2 200 (82%) In univariate analysis, increased age (P ϭ 0.014), active 3 16 (6.6%) extracranial disease (P Ͻ 0.0005), presence of neurological symp- ϭ a WBRT, whole-brain radiation therapy; CNS, central nervous system; KPS, toms at radiosurgery (P 0.002), increased RPA class Karnofsky performance score; RPA, recursive partitioning analysis. (P Ͻ 0.0005), KPS of 80% or below (P Ͻ 0.0005), increased num- ber of metastases (P Ͻ 0.0005), increased tumor volume (either as

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TABLE 2. Univariate and multivariate analyses of survival after radiosurgerya Univariate Multivariate Hazard rate Variable P value P value ratio (relative risk) Age 0.014 0.149 NA Sex 0.990 0.986 NA Primary to brain metastasis interval 0.062 0.071 NA Extracranial disease status Ͻ0.0005 Ͻ0.0005 2.153 RPA class Ͻ0.0005 0.225 NA KPS Ͻ0.0005 Ͻ0.0005 2.043 Number of metastases Ͻ0.0005 0.275 NA Single or multiple metastases Ͻ0.0005 0.005 1.544 Initial brain metastasis presentation (symptomatic or not) 0.267 0.125 NA Neurological status at time of radiosurgery (symptomatic or not) 0.002 0.685 NA WBRT at any time 0.055 0.316 NA Chemotherapy 0.114 0.539 NA Immunotherapy 0.761 0.897 NA Total radiosurgery volume 0.001 0.571 NA Total radiosurgery volume (Ϯ 8 cm3) 0.003 0.041 1.379 Presence of deep cerebral metastasis 0.328 0.241 NA Presence of cerebellar metastasis 0.004 0.021 1.604 Presence of brainstem metastasis 0.798 0.406 NA

a NA, not available; RPA, recursive partitioning analysis; KPS, Karnofsky performance score; WBRT, whole-brain radiation therapy. a continuous variable [P ϭ 0.001] or dichotomized to less than or whereas, for patients with active disease, the median survival to greater than 8 cm3 [P ϭ 0.003]), and cerebellar metastases was only 3.9 months (P Ͻ 0.0005; log-rank test). Patients with (P ϭ 0.004) were associated with decreased survival. In multi- a KPS of 90 or 100% at the time of radiosurgery survived a variate analysis, only active extracranial disease (P Ͻ 0.0005), median of 6.3 months compared with 2.9 months for patients KPS 80% or below (P Ͻ 0.0005), multiple metastases (P ϭ 0.005), with scores of 80% or below (P Ͻ 0.0005; log-rank test). Median tumor volume greater than 8 cm3 (P ϭ 0.041), and cerebellar survivals were 12.7 months, 4.9 months, and 2.3 months for metastases (P ϭ 0.021) remained predictors of decreased sur- patients in RPA Classes 1, 2, and 3, respectively (Fig. 3). vival (Table 2). There was no difference in survival for patients managed with radiosurgery as primary therapy of the brain Local Control metastases compared with patients who had radiosurgery as Follow-up imaging was available for 175 patients after 208 salvage after previous failed therapy. On Cox regression procedures (total, 507 metastases). The median follow-up inter- analysis, being exposed to WBRT was not a significant predic- val was 4.3 months (mean, 8.1 mo; range, 0.3–114.3 mo). The tor of survival, nor were treatment with chemotherapy or best response obtained was complete disappearance of immunotherapy. However, using Kaplan-Meier analysis, 31 tumors (6.1%), regression of 162 tumors (32%), and no patients who had WBRT before radiosurgery had a slightly change in 268 tumors (52.8%). Early progression occurred in worse median survival than patients without WBRT (4.7 mo 46 tumors (9.1%) and delayed progression after previous with and 5.7 mo without WBRT; P ϭ 0.01; log-rank test). When regression or stabilization was noted in 24 tumors. Thus, a total measured from the time of diagnosis of brain metastasis, of 70 tumors (13.8% of all metastases) eventually progressed. median survival was 8.6 months for patients previously Overall, 54 patients (30.9%) had progression of at least one exposed to WBRT and 7.2 months for patients who never had metastasis after radiosurgery. The median time to progression WBRT (P ϭ 0.853; log-rank test). was 2.9 months (mean, 5.5 mo; range, 0.1–30.9 mo). For all The median survival for patients having radiosurgery for a patients with follow-up imaging, actuarial freedom from pro- single brain metastasis was 6.8 months; the median survival gression was 83.1 Ϯ 2.8% at 3 months, 74.6 Ϯ 3.6% at 6 months, was 3.6 months for patients with multiple tumors (P Ͻ 0.0005; 58.9 Ϯ 5.2% at 12 months, and 42.8 Ϯ 7.1% at 24 months (Fig. 4). log-rank test). When patients were grouped according to the Figure 5 exemplifies typical follow-up MRI scans in a patient number of metastases present, the median survival was with tumor response after radiosurgery. 4.5 months for those with two or three tumors, 3.2 months for Univariate analysis demonstrated the following variables as those with four to six tumors, and 2.4 months for those with predictors of local failure: increased volume of largest irradi- more than seven metastases (Fig. 2). The median survival for ated lesion (P Ͻ 0.0005), increased total irradiation volume patients with controlled extracranial disease was 12.7 months, (P Ͻ 0.0005), decreased margin (P ϭ 0.001), maximum radi-

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FIGURE 2. Kaplan-Meier plot showing overall survival from the time of FIGURE 4. Kaplan-Meier plot depicting radiological control rate after radiosurgery for patients categorized according to the total number of brain radiosurgery. metastases. Squares represent patients with single metastasis, triangles represent patients with two to three metastases, circles represent patients with four to six metastases, and plus signs represent patients with seven or A B more metastases.

C D

FIGURE 3. Kaplan-Meier plot showing overall survival after radiosurgery according to RPA stratification. Circles represent Class 1, triangles rep- resent Class 2, and the straight line represents Class 3. ation doses (P ϭ 0.024), and hemorrhagic metastasis (P Ͻ 0.0005). In multivariate testing, only increased total vol- FIGURE 5. Contrast-enhanced T1-weighted MRI scans at the time of radio- ume (P Ͻ 0.0005) and hemorrhagic metastasis (P ϭ 0.002) surgery (A and B) and 1 year after radiosurgery (C and D) in a patient in remained predictors of failure (Table 3). There were no differ- whom radiosurgery was used as the primary management of two brain metas- tases. This demonstrates complete disappearance of the right parietal metasta- ences in local control rates for metastases managed with pri- sis and significant regression of the left temporal metastasis. This patient sur- mary radiosurgery compared with tumors that had previous vived a total of 42 months after radiosurgery. Neither brain lesion recurred therapy. Having previous WBRT had no influence on local during the follow-up period. control after radiosurgery. time was 4.2 months after radiosurgery (mean, 5.9 mo; range Distant Control 0.5–41.1 mo). Actuarial freedom from distant failure was Of 175 patients with follow-up imaging, 73 (41.7%) were 78.6 Ϯ 3.2% at 3 months, 57.5 Ϯ 4.3% at 6 months, 32.5 Ϯ 4.9% found to have new lesions on subsequent studies. The median at 12 months, and 17.1 Ϯ 4.6% at 24 months (Fig. 6).

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TABLE 3. Univariate and multivariate analyses of local control after radiosurgerya Univariate Multivariate Hazard Variable P value P value rate ratio Age 0.014 0.149 NA Number of brain metastases 0.363 0.481 NA Neurological status at treatment (symptomatic or not) 0.058 0.723 NA KPS 0.063 0.901 NA RPA class 0.115 0.176 NA Hemorrhagic metastasis Ͻ0.0005 0.002 2.528 Irradiation of cavity postresection of brain metastasis 0.323 0.370 NA Superficial brain metastasis 0.933 0.989 NA Deep brain metastasis 0.478 0.471 NA Cerebellar metastasis 0.596 0.274 NA Brainstem metastasis 0.940 0.854 NA Volume of largest metastasis Ͻ0.0005 0.669 NA Total radiosurgery volume Ͻ0.0005 Ͻ0.0005 1.055 Margin dose used 0.001 0.482 NA Maximum dose used 0.024 0.421 NA WBRT 0.838 0.937 NA Radiosurgery as a boost to WBRT 0.323 0.425 NA

a NA, not available; KPS, Karnofsky performance score; RPA, recursive partitioning analysis; WBRT, whole-brain radiation therapy.

Leptomeningeal dissemination, demonstrated on MRI scans or cerebrospinal fluid analysis, occurred in nine patients. In univariate analysis, multiple metastases (P ϭ 0.003), increased number of metastases (P Ͻ 0.0005), use of previous WBRT (P ϭ 0.003), and absence of subsequent immunotherapy (P ϭ 0.002) were predictors of distant brain failure. In multi- variate testing, only multiple metastases (P Ͻ 0.0005) and absence of immunotherapy after radiosurgery (P ϭ 0.002) remained predictors of new brain metastases (Table 4).

Morbidity and Clinical Outcome Clinical follow-up data was available for 206 patients (range, 0.2–114.3 mo). Sixteen patients (6.6%) had sympto- matic radiation effects demonstrated by increased contrast uptake with signal changes around the lesion on long repeti- tion time MRI scans. These imaging changes, as well as symp- toms, were completely reversed with a temporary course of FIGURE 6. Kaplan-Meier plot demonstrating the proportion of patients corticosteroids in 12 patients. Two patients required a cran- without new brain metastases after radiosurgery. iotomy; one of whom had fourth ventricle compression with hydrocephalus and the other had a worsening level of con- sciousness and hemiparesis. The remaining two patients had WBRT), radiation dose, or tumor location had no impact on partial resolution of radiation-induced motor deficits with the occurrence of radiation changes. steroids. Asymptomatic radiation-induced long repetition Imaging-confirmed hemorrhage from a metastasis occurred time changes were noted in eight patients (3.9%). Thus, in 46 patients (22.3%). The source was a tumor managed with radiation-induced changes were found on imaging in 10.5% of radiosurgery in 38 patients and a new metastasis in eight patients. The median occurrence time of radiation changes patients. Twenty-seven of these patients had sudden neurolog- was 2.2 months (mean 2.8 mo; range, 0.1–9.5 mo). No variable ical deterioration, whereas 19 remained asymptomatic. The was found to predict the occurrence of complications on Cox median time to hemorrhage was 1.8 months after radiosurgery regression analysis, although increased total radiosurgery vol- (mean, 3.7 mo; range, 0.1–18 mo). Thirteen patients required a ume approached statistical significance on univariate analysis craniotomy for evacuation of the blood clot. Nine patients (P ϭ 0.07). Age, previous irradiation (either radiosurgery or eventually died as a direct consequence of the brain hemor-

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TABLE 4. Univariate and multivariate distant control analysesa Univariate Multivariate Hazard Variable P value P value rate ratio Time interval from diagnosis of primary to brain metastasis 0.492 0.656 NA Extracranial disease status 0.209 0.214 NA RPA class 0.381 0.240 NA Previous chemotherapy treatment 0.229 0.420 NA Previous immunotherapy treatment 0.811 0.515 NA Number of brain metastases Ͻ0.0005 0.070 NA Single or multiple metastases Ͻ0.0005 Ͻ0.0005 2.629 Total radiosurgery volume 0.738 0.085 NA WBRT 0.003 0.061 NA Subsequent chemotherapy 0.555 0.974 NA Subsequent immunotherapy 0.002 0.002 0.380

a NA, not available; RPA, recursive partitioning analysis; WBRT, whole-brain radiation therapy. rhage. On univariate analysis, previous hemorrhage in a tic melanoma patients (11, 14, 22, 24, 37). Stereotactic radio- metastasis (P ϭ 0.01), increased size of the largest tumor surgery is a surgical procedure that allows single-session (P ϭ 0.007), and increased total radiosurgery volume closed-cranium delivery of radiation in a conformal fashion. Its (P ϭ 0.003) were associated with postradiosurgery intratu- efficacy in the management of brain metastases has been moral hemorrhage. On multivariate analysis, only increased proven in numerous publications (20, 31, 48). Recent articles radiosurgery volume remained significant (P ϭ 0.004). Age, have also reported success using stereotactic radiosurgery to previous irradiation, and radiosurgery dose had no impact on manage metastatic tumors from primary cancers that are often the occurrence of hemorrhage. considered “radioresistant” (sarcoma, renal carcinoma, and Overall, the clinical condition improved in 17 patients (8.3%) melanoma) (7, 9). The present series is, to our knowledge, the after radiosurgery, remained stable in 130 patients (63.1%), and largest reported series focusing on radiosurgery for patients worsened in 59 patients (28.6%). In worsened patients, adverse with melanoma brain metastases. Table 5 summarizes data radiation effects were the cause in 16 patients (27.1%), brain gathered from the main cerebral melanoma radiosurgery series. hemorrhage in 27 patients (45.8%), and increased lesion burden (either local or distant progression) in 16 patients (27.1%). Survival Corticosteroids were unnecessary or discontinued after radio- The median reported survival after radiosurgery for mela- surgery in 108 patients (52.4%). noma brain metastases varies between 4.8 and 10.6 months (7, After radiosurgery, 27 patients (13.1%) required a cran- 8, 10, 15–17, 21, 25, 27, 29, 32, 33, 35, 36, 38, 41–43, 49). The iotomy. Local progression was the cause in nine patients, brain median survival in the present series (5.3 mo) is worse than hemorrhage in 13 patients, radiation injury in two patients, that reported in our previous experience (7 mo) (35, 43). This and new metastases in three patients. Forty-two patients difference can be explained by the change that has progres- (20.4%) required at least one repeat radiosurgery procedure for sively occurred in our management paradigm of melanoma the management of new brain metastases (33 patients), pro- brain metastases. Early on, radiosurgery was preferentially gression of a previously irradiated lesion (five patients), or both offered to patients in good clinical condition with limited (four patients). Fifty-one patients (24.8%) underwent WBRT intracranial disease (most had solitary tumors), as a boost to after radiosurgery because of the development of multiple new WBRT. Increased evidence of the efficacy of radiosurgery has brain lesions. In addition, further systemic therapy involved led us to offer this approach as palliative management to chemotherapy in 72 patients, immunotherapy in 33 patients, patients with more extensive CNS disease and more active and extracranial radiation therapy in 21 patients. extracranial disease. We are now participating in the care of increasingly challenging patients. In the present study, 59.8% of DISCUSSION patients had multiple metastases, which were found to nega- tively impact survival. When further analyzing survival in mul- The diagnosis of a cerebral metastasis is usually associated tiple metastases patients, it was difficult to establish a cutoff with a dismal prognosis in melanoma patients because a signif- number of tumors over which patients did not benefit from icant proportion will die as a direct consequence of the neuro- radiosurgery. Because of the grim prognosis of patients with logical disease (39). In currently used dose schedules, WRBT extensive cerebral disease, many centers only offer radio- has been demonstrated to be relatively ineffective at achieving surgery to patients presenting with three metastases or fewer local control and significantly prolonging survival for metasta- (9, 29). Recent articles, however, have reported the benefit of

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TABLE 5. Summary of malignant melanoma brain metastases radiosurgical seriesa

Single/ Survival (from Series (ref. no.) Modality Cases Tumor control Survival prognostic factors Multiple radiosurgery)

Gieger et al., 1997 (15) LINAC 12 pts 50% single Median 8 mo 57% local Increased with longer interval 21 mets 66% at 6 mo control, New from primary to brain diagnosis 36% at 12 mo mets in 6 pts

Grob et al., 1998 (17) GK 35 pts 17/35 single Median 7 mo Local: Increased with single lesions 70 mets 100% at 6 mo 87.5% at 12 mo

Mingione et al., GK 45 pts 23/45 single Median 10.4 mo 24% disappear Increased with: 2002 (33) 92 mets 35% shrink Single mets 23% stable No visceral mets 18% increase KPS 80 or more New mets in 13 pts

Yu et al., 2002 (49) GK 122 pts 50% single Median 7 mo 26% at 12 mo Volume Ͼ3 cm3 and active systemic 332 mets 90% local control disease associated with decreased survival and occurrence of new mets Gonzalez-Martinez GK 24 pts 33% single Median 5.5 mo NS Increased by KPS of 90 or more et al., 2002 (16) 98 mets and immunotherapy

Herfarth et al., LINAC 64 pts 58% single Median 10.6 mo 12 treatment Decreased by extracerebral 2003 (21) 122 mets 47% at 12 mo failures, 81% local tumor manifestation at time 24% at 24 mo control at 12 mo of radiosurgery

Selek et al., 2004 (41) LINAC 103 pts 59% single Median 6.7 mo 49% local control Increased with score index for 153 mets 25.2% at 12 mo at 12 mo, 23.9% radiosurgery (SIR; ref. 50) without new mets at 12 mo

Radbill et al., 2004 (38) GK 51 pts 29% single Median 26 wks 59% local control Decreased by: 188 mets 30% at 1 yr 74% new mets RPA Class II–III Infratentorial lesions Multiple lesions

Koc et al., 2005 (25) GK 26 pts 38% single Median 6 mo NS Decreased with: 72 mets 25% at 12 mo KPS 90 or more Female sex Supratentorial lesions No neurological symptoms

Christopoulou et al., GK 29 pts NS Median 5.7 mo 61% shrink Worse with increased number 2006 (10) 105 mets (including 13.5% of mets and short interval from disappear) primary to brain diagnosis

Present series GK 244 pts 40.2% Median 5.3 mo 86.2% local Decreased with: 754 mets single 42.8% at 6 mo control multiple mets, KPS Յ 80 20.2% at 12 mo 41.7% new volume Ͼ8 cm3 9.3% at 24 mo mets active systemic disease cerebellar mets

a LINAC, linear accelerator; pts, patients; mets, metastases; GK, gamma knife; KPS, Karnofsky performance score; NS, not stated; SIR, Score Index for Radiosurgery; RPA, recursive partitioning analysis.

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radiosurgery for more extensive disease burden (6, 23). In the radiosurgery. Increased total volume was also significantly present study, patients with up to six metastases seemed to associated with distant failure according to Selek et al. (41). benefit from radiosurgery (Fig. 2). Immunotherapy after radiosurgery was another factor found Other significant predictors of survival were systemic dis- to decrease the incidence of new brain metastases in our ease status, KPS, radiosurgery volume, and cerebellar loca- patients. Although it was thought that immunotherapy had a tion. Extracranial disease had the greatest impact on survival. limited effect on cerebral metastases because of its inability to Patients with controlled cancer survived 12.7 months com- penetrate the blood-brain barrier (18, 34), recent studies have pared with 3.9 months if the systemic malignancy was active. reported regression of CNS lesions with immunotherapy (19, Interestingly, RPA class was not a significant predictor of sur- 40). Such therapy may help controlling cerebral micrometas- vival after multivariate analysis. This classification was tases or preventing continuous spread of systemic disease to devised using mostly data from lung cancer patients (13). the CNS. Applicability to melanoma patients has not been consistently demonstrated, although some authors have reported it as a Morbidity and Clinical Outcome survival predictor (7–9, 38). Infratentorial metastases have Gamma knife radiosurgery had a low complication rate in already been reported to portent a worse prognosis (25, 38). In this series. Only 6.6% of the patients experienced symptomatic this study, only cerebellar location caused a worse outcome. adverse radiation effects, 75% of whom recovered completely Having a brainstem lesion did not affect survival, although with corticosteroids. This is similar to the study by Lavine this may be because relatively few patients in this series had et al. (27), who reported that three out of 45 patients experi- metastases in this location. enced transient worsening of symptoms after radiosurgery. Although extracranial disease was the leading cause of death Brown et al. (7) found a higher complication rate, with 5% in our series, brain metastases were responsible for 40.5% of all symptomatic radiation necrosis and an additional 12% symp- deaths. Most neurological deaths were caused by new metasta- tomatic cerebral edema. It has been recognized that radiation- tic spread rather than progression of previous lesions. This pro- induced complications can be reduced by lowering the radia- portion is similar to what has been reported by most authors (7, tion dose for high-volume tumors or tumors located in critical 25, 50). We think increased survival will ultimately depend on areas, such as the brainstem or deep white matter. Dose adjust- improvement of systemic malignancy control. Progress has ments are also required in the case of previous radiation expo- already been made with the use of immunotherapy (4, 47). sure (12). In our study, although no variable was found to be Temozolomide-based chemotherapy is being used in a predictor for complications, total radiosurgery volume melanoma patients in an attempt to translate gains made in the approached statistical significance, reflecting what was previ- care of patients with malignant glial neoplasms (1–3). ously reported in the literature. Melanoma metastases have a strong propensity for causing CNS Disease Control intracerebral hemorrhage. A clinicopathological review of 905 Sustained local control was achieved in 86.2% of tumors and consecutive tumor cases revealed tumor hemorrhage in 50% 69.1% of patients. Actuarial freedom from local progression of melanoma cases (26). In the Duke series of 6953 melanoma was 74.6% at 6 months and 58.9% at 1 year. To our knowledge, patients, 3% of the patients with brain metastases presented 12-month local control rates varying from 47 to 84% have been with a hemorrhage (39). In our series, 22.3% of the patients reported in the literature (9, 36, 41, 42). Radiosurgery volume had intratumoral bleeding, demonstrated on imaging during greater than 8 cm3 and hemorrhagic changes in a metastasis at the follow-up period, leading to clinical deterioration in 58.7% the time of radiosurgery were the only predictors of local fail- of the patients. Most involved an irradiated tumor. The ure after multivariate analysis in our study. Signal changes on median time to tumor hemorrhage was 1.8 months. Radbill MRI scans associated with intratumoral blood render planning et al. (38) noted that clinical deterioration secondary to hem- more difficult, blurring the lesion margins and often increasing orrhage occurred in 19% of their patients after stereotactic its volume, which might explain the higher risk of failure. radiosurgery. Chang et al. (9) reported a 10.5% hemorrhage Increased tumor volume as a local failure prognostic factor has rate after radiosurgery in melanoma patients after a median been confirmed by other investigators (15, 41, 42). Radiation follow-up period of 2.5 months. This short delay raises a ques- dose did not retain prognostic value after multivariate analysis tion regarding the possibility of radiosurgery increasing the in our series. Herfarth et al. (21) reported that margin doses of risk of hemorrhage. This has previously been questioned by 20 Gy or more were associated with improved local control Suzuki et al. (45), who postulated that a high central dose after radiosurgery. could lead to rapid tumor necrosis before tumor vasculature New brain metastases occurred in 41.7% of our patients. obliteration, thereby increasing the bleeding risk. However, Patients presenting with multiple brain lesions were more the rate reported in our series falls well within what is likely to develop new lesions, probably related to more active reported for melanoma brain metastases in the literature. primary disease from the onset. Our data is consistent with Additionally, previous hemorrhage and increased total tumor that reported in other radiosurgery series. Yu et al. (50) iden- volume were associated with a higher risk of a new bleeding tified increased total tumor volume and active systemic dis- episode. This reflects the fact that some tumors probably have ease as significant predictors of new brain metastases after an intrinsic tendency to bleed and that patients with increased

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tumor burden are more at risk of brain hemorrhage. At pres- However, survival in general remains limited, primarily ent, we do not think that radiosurgery increases the risk of because of poor extracranial tumor control. Hopefully, with delayed tumoral hemorrhage, and there is no conclusive evi- future improvements in systemic therapy, the impact of radio- dence in the literature supporting this claim. surgery in allowing long-lasting CNS control will become more Overall, neurological condition remained stable or improved apparent and facilitate significant increases in patient survival. in 71.4% of our patients. More than half (52.4%) were able to discontinue or avoid exogenous corticosteroid use after under- Disclosure going radiosurgery, which is a necessary requirement to con- Douglas Kondziolka, M.D., Ajay Niranjan, M.Ch., and L. Dade Lunsford, tinue with any immunotherapy. Moreover, corticosteroids are a M.D., are consultants for Elekta AB. well-recognized cause of morbidity for brain tumor patients, with a non-negligible impact on quality of life. This suggests REFERENCES that gamma knife radiosurgery can positively impact the clin- 1. Agarwala SS, Kirkwood JM: Temozolomide, a novel alkylating agent with ical condition in a significant majority of patients. activity in the central nervous system, may improve the treatment of advanced metastatic melanoma. Oncologist 5:144–151, 2000. Impact of WBRT 2. Agarwala SS, Kirkwood JM: Temozolomide in combination with interferon The role of WBRT in the management of melanoma brain alpha-2b in patients with metastatic melanoma: A phase I dose-escalation study. Cancer 97:121–127, 2003. metastases has been questioned in the literature. Melanoma 3. 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Gieger M, Wu JK, Ling MN, Wazer D, Tsai JS, Engler MJ: Response of seminated CNS disease (14). intracranial melanoma metastases to stereotactic radiosurgery. Radiat Oncol Investig 5:72–80, 1997. 16. Gonzalez-Martinez J, Hernandez L, Zamorano L, Sloan A, Levin K, Lo S, Li CONCLUSION Q, Diaz F: Gamma knife radiosurgery for intracranial metastatic melanoma: A 6-year experience. J Neurosurg 97 [Suppl 5]:494–498, 2002. Stereotactic radiosurgery is an effective management option 17. Grob JJ, Regis J, Laurans R, Delaunay M, Wolkenstein P, Paul K, Souteyrand for primary and recurrent brain metastases from malignant P, Koeppel MC, Murraciole X, Perragut JC, Bonerandi JJ: Radiosurgery with- melanoma. It improves survival and is associated with a high out whole brain radiotherapy in melanoma brain metastases. Club de local control rate with minimal morbidity. Improved survival Cancerologie Cutanee. Eur J Cancer 34:1187–1192, 1998. 18. 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19. Guirguis LM, Yang JC, White DE, Steinberg SM, Liewehr DJ, Rosenberg SA, 41. Selek U, Chang EL, Hassenbusch SJ 3rd, Shiu AS, Lang FF, Allen P, Weinberg Schwartzentruber DJ: Safety and efficacy of high-dose interleukin-2 therapy J, Sawaya R, Maor MH: Stereotactic radiosurgical treatment in 103 patients in patients with brain metastases. J Immunother 25:82–87, 2002. for 153 cerebral melanoma metastases. Int J Radiat Oncol Biol Phys 20. Hasegawa T, Kondziolka D, Flickinger JC, Germanwala A, Lunsford LD: 59:1097–1106, 2004. Brain metastases treated with radiosurgery alone: An alternative to whole 42. Seung SK, Sneed PK, McDermott MW, Shu HK, Leong SP, Chang S, Petti PL, brain radiotherapy? Neurosurgery 52:1318–1326, 2003. Smith V, Verhey LJ, Wara WM, Phillips TL, Larson DA: Gamma knife radio- 21. Herfarth KK, Izwekowa O, Thilmann C, Pirzkall A, Delorme S, Hofmann U, surgery for malignant melanoma brain metastases. Cancer J Sci Am Schadendorf D, Zierhut D, Wannenmacher M, Debus J: Linac-based radio- 4:103–109, 1998. surgery of cerebral melanoma metastases. Analysis of 122 metastases treated 43. Somaza S, Kondziolka D, Lunsford LD, Kirkwood JM, Flickinger JC: in 64 patients. Strahlenther Onkol 179:366–371, 2003. Stereotactic radiosurgery for cerebral metastatic melanoma. J Neurosurg 22. Isokangas OP, Muhonen T, Kajanti M, Pyrhonen S: Radiation therapy of 79:661–666, 1993. intracranial malignant melanoma. Radiother Oncol 38:139–144, 1996. 44. Stone A, Cooper J, Koenig KL, Golfinos JG, Oratz R: A comparison of survival 23. Jawahar A, Shaya M, Campbell P, Ampil F, Willis BK, Smith D, Nanda A: Role rates for treatment of melanoma metastatic to the brain. Cancer Invest of stereotactic radiosurgery as a primary treatment option in the management 22:492–497, 2004. of newly diagnosed multiple (3–6) intracranial metastases. Surg Neurol 45. Suzuki H, Toyoda S, Muramatsu M, Shimizu T, Kojima T, Taki W: Spon- 64:207–212, 2005. taneous haemorrhage into metastatic brain tumours after stereotactic radio- 24. Jenrette JM: Malignant melanoma: The role of radiation therapy revisited. surgery using a linear accelerator. J Neurol Neurosurg Psychiatry 74: Semin Oncol 23:759–762, 1996. 908–912, 2003. 25. Koc M, McGregor J, Grecula J, Bauer CJ, Gupta N, Gahbauer RA: Gamma 46. Tarhini AA, Agarwala SS: Management of brain metastases in patients with Knife radiosurgery for intracranial metastatic melanoma: An analysis of sur- melanoma. Curr Opin Oncol 16:161–166, 2004. vival and prognostic factors. J Neurooncol 71:307–313, 2005. 47. Tsao H, Atkins MB, Sober AJ: Management of cutaneous melanoma. N Engl 26. Kondziolka D, Bernstein M, Resch L, Tator CH, Fleming JF, Vanderlinden RG, J Med 351:998–1012, 2004. Schutz H: Significance of hemorrhage into brain tumors: Clinicopathological 48. Warnick RE, Darakchiev BJ, Breneman JC: Stereotactic radiosurgery for study. J Neurosurg 67:852–857, 1987. patients with solid brain metastases: Current status. J Neurooncol 69:125–137, 27. Lavine SD, Petrovich Z, Cohen-Gadol AA, Masri LS, Morton DL, O’Day SJ, 2004. Essner R, Zelman V, Yu C, Luxton G, Apuzzo ML: Gamma knife radiosurgery 49. Yu C, Chen JC, Apuzzo ML, O’Day S, Giannotta SL, Weber JS, Petrovich Z: for metastatic melanoma: An analysis of survival, outcome, and complica- Metastatic melanoma to the brain: Prognostic factors after gamma knife tions. Neurosurgery 44:59–66, 1999. radiosurgery. Int J Radiat Oncol Biol Phys 52:1277–1287, 2002. 28. Little JB, Hahn GM, Frindel E, Tubiana M: Repair of potentially lethal radia- tion damage in vitro and in vivo. Radiology 106:689–694, 1973. Acknowledgment 29. Manon R, O’Neill A, Knisely J, Werner-Wasik M, Lazarus HM, Wagner H, Gilbert M, Mehta M; Eastern Cooperative Oncology Group: Phase II trial of This study was awarded the Mahaley Clinical Research Award at the 2006 radiosurgery for one to three newly diagnosed brain metastases from renal Annual Meeting of the Congress of Neurological Surgeons. cell carcinoma, melanoma, and sarcoma: An Eastern Cooperative Oncology Group study (E 6397). J Clin Oncol 23:8870–8876, 2005. 30. McWilliams RR, Brown PD, Buckner JC, Link MJ, Markovic SN: Treatment of COMMENTS brain metastases from melanoma. Mayo Clin Proc 78:1529–1536, 2003. 31. Mehta MP, Tsao MN, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, Mills his is a large, retrospective study of 754 patients who underwent M, Rogers CL, Souhami L: The American Society for Therapeutic Radiology Tgamma knife stereotactic radiosurgery (SRS) for metastatic and Oncology (ASTRO) evidence-based review of the role of radiosurgery for melanoma to the brain. The variables associated with decreased sur- brain metastases. Int J Radiat Oncol Biol Phys 63:37–46, 2005. vival include low Karnofsky Performance Scale scores, multiple metas- 32. Meier S, Baumert BG, Maier T, Wellis G, Burg G, Seifert B, Dummer R: tases, large tumor volumes (Ͼ8 cm3), and cerebellar location. The Survival and prognostic factors in patients with brain metastases from malig- nant melanoma. Onkologie 27:145–149, 2004. authors did not indicate a difference in survival among patients who 33. Mingione V, Oliveira M, Prasad D, Steiner M, Steiner L: Gamma surgery for received SRS as a primary modality versus patients who received SRS melanoma metastases in the brain. J Neurosurg 96:544–551, 2002. after whole-brain radiation therapy (WBRT). 34. Mitchell MS: Relapse in the central nervous system in melanoma patients suc- The median survival rates for patients with multiple and single cessfully treated with biomodulators. J Clin Oncol 7:1701–1709, 1989. metastases were 3.6 and 6.8 months, respectively. The survival rate was 35. Mori Y, Kondziolka D, Flickinger JC, Kirkwood JM, Agarwala S, Lunsford distinctly longer in patients with controlled systemic disease. Thirty LD: Stereotactic radiosurgery for cerebral metastatic melanoma: Factors percent of patients progressed by a mean of 5.5 months after SRS. affecting local disease control and survival. Int J Radiat Oncol Biol Phys Predictors of local failure were large volume and hemorrhagic metas- 42:581–589, 1998. tases. Distant brain failure was common (40%) and seemed to correlate 36. Noel G, Simon JM, Valery CA, Cornu P, Boisserie G, Ledu D, Hasboun D, Tep B, Delattre JY, Marsault C, Baillet F, Mazeron JJ: Linac radiosurgery for brain with multiple metastases and absence of immunotherapy after SRS. metastasis of melanoma. Stereotact Funct Neurosurg 79:245–255, 2002. Overall and with minor variations, this study is compatible with 37. Overgaard J: The role of radiotherapy in recurrent and metastatic malignant the current literature. melanoma: A clinical radiobiological study. Int J Radiat Oncol Biol Phys The main interest lies in its examination of a uniquely large num- 12:867–872, 1986. ber of patients with melanoma metastases. Another interesting fea- 38. Radbill AE, Fiveash JF, Falkenberg ET, Guthrie BL, Young PE, Meleth S, ture pertains to the reported complications. The authors report a Markert JM: Initial treatment of melanoma brain metastases using gamma 6.6% incidence of symptomatic necrosis that is treated primarily knife radiosurgery: An evaluation of efficacy and toxicity. Cancer 101:825–833, with steroids. However, 22% of the patients experienced hemor- 2004. rhage in a metastasis, the majority of which were after SRS. Two- 39. Sampson JH, Carter JH Jr, Friedman AH, Seigler HF: Demographics, progno- thirds of these patients required a craniotomy, and almost 20% died sis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 88:11–20, 1998. as a direct consequence of the hemorrhage. The clustering of hem- 40. Savas B, Arslan G, Gelen T, Karpuzoglu G, Ozkaynak C: Multidrug resistant orrhage over a short period of time after SRS (median, 1.8 mo) raises malignant melanoma with intracranial metastasis responding to immuno- a question concerning the possibility of a causal relationship. In therapy. Anticancer Res 19:4413–4420, 1999. addition, the high morbidity and mortality rates associated with

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hemorrhage constitute a different pattern of what may be expected rain metastasis from melanoma is a grave finding with a low over- from the natural history of melanoma and bleeding risk. In large Ball survival rate despite aggressive multimodality therapy. SRS is an series, only 3% of melanomas present with hemorrhages. It may important tool for the management of melanoma metastases because it have been beneficial to analyze patient characteristics, tumor fea- has higher lesion control rates than WBRT. Despite this data and other tures, and radiation dosages in this subgroup of patients who man- sizeable retrospective studies, we think that controversy remains ifest posttreatment hemorrhages. regarding some important practical issues. The first issue regards the question of how many lesions are too Viviane Tabar many to treat. The literature supports the notion that an increasing Philip H. Gutin number of lesions portends worse prognosis. A higher number of New York, New York metastases to the brain imply a more aggressive disease and a greater likelihood of loss of systemic control. Obtaining local lesion control his is a well prepared report of a large series offering realistic data with higher numbers of lesions then becomes a less relevant factor in regarding the anticipated treatment of malignant melanoma brain T a patient’s overall outcome. Although Mathieu et al. suggest that the metastases with gamma knife radiosurgery. Comparable to most sys- treatment of as many as six lesions may improve survival rates, the temic malignancies, local treatment of limited central nervous system overall additional benefit seems to be very slim. metastases improves control of brain lesions but not survival rates. In the group with four to six tumors, survival was reported as 3.2 When objectively assessing these data, one can argue whether or not months compared with 2.4 months in the group with seven or more the addition of a few weeks survival merits the use of “effective and lesions. On average, patients with seven or more lesions do not seem high rate of durable control.” Regardless, this report sets the standard to fare better than what has historically been reported with WBRT of anticipated results using radiosurgery with or without WBRT. alone. Because only 25% of the patients in this study had four or more Hopefully, improved treatment options will offer a more substantial lesions, it is unclear whether or not the reported difference of roughly rate of survival for future patients. 3 weeks in survival is statistically or clinically meaningful. Joseph M. Piepmeier Therefore, we think patients considered for the treatment of cerebral New Haven, Connecticut polymetastases should be appropriately advised regarding the modest overall benefit of radiosurgery in these circumstances. In our practice, he authors have presented a very large clinical series on the use of we generally exclude patients who have more than four lesions from Tradiosurgery in the management of patients with melanoma brain radiosurgery treatment, regardless of the patient’s performance status. metastases. They found the median survival after radiosurgery to be Another important issue is the role of WBRT in the management of only 5.3 months; the 1-year actuarial survival was 20%. In addition, patients with melanoma. It is likely that overall survival is not substan- more than 40% of the patients were thought to have died from neuro- tially improved with the routine addition of WBRT to radiosurgery. logical progression. This is especially sobering when the aggressive Furthermore, from the present data, it seems that typical doses of care provided after radiosurgery (13% of patients had later cran- WBRT do not prevent the occurrence of new metastases. Based on this iotomies, 20% had additional radiosurgery, and 25% went on to whole and other data, withholding WBRT might be a reasonable option for brain radiation therapy) is taken into consideration. The effect of radio- patients with oligometastases in the setting of melanoma. However, we surgery on the risk of subsequent tumor hemorrhage cannot be continue to believe that patients with polymetastases are probably bet- answered without a control group. However, it is worth noting that ter managed with WBRT alone. Despite these small differences of opin- patients with a hemorrhagic metastasis had worse local tumor control ion, radiosurgery offers tremendous value to patients when compared when compared with non-hemorrhagic tumors. Overall, I agree with with WBRT alone or with open surgical treatment for patients with the authors’ conclusions that aggressive intracranial tumor manage- more than one lesion or lesions that are difficult to access. ment is appropriate for patients whose daily activities are minimally A. Robert Kagan affected by their disease. Neuroradiologist Bruce E. Pollock Joseph C.T. Chen Rochester, Minnesota Los Angeles, California

482 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com CLINICAL STUDIES

EXTRADURAL TRANSCAVERNOUS APPROACH TO CAVERNOUS SINUS HEMANGIOMAS

Ashish Suri, M.Ch. OBJECTIVE: Cavernous sinus hemangiomas (CSHs) are uncommon lesions and com- Department of Neurosurgery, prise fewer than 1% of all parasellar masses. Because of their location, propensity for All India Institute of Medical Sciences, profuse bleeding during surgery, and relationship to complex neurovascular structures, New Delhi, India they are notoriously difficult to excise. Faiz U. Ahmad, M.B.B.S. CLINICAL PRESENTATION: The authors describe their experience with seven cases of Department of Neurosurgery, CSHs. Headache and visual impairment were the most common presenting complaints, All India Institute of Medical Sciences, followed by facial hypesthesia and diplopia. Computed tomographic scans revealed New Delhi, India iso- to hyperdense expansile lesions in the region of the cavernous sinus and middle cra- nial fossa. Magnetic resonance imaging scans revealed hypo- to isointense lesions on Ashok K. Mahapatra, M.Ch. T1-weighted images and markedly hyperintense lesions on T2-weighted images, with Department of Neurosurgery, All India Institute of Medical Sciences, marked homogeneous enhancement after contrast administration. New Delhi, India INTERVENTION: All CSHs were treated by a purely extradural transcavernous approach. This involved reduction of sphenoid ridge, exposure of the superior orbital fissure, Reprint requests: Ashish Suri, M.Ch., drilling of the anterior clinoid process, coagulation and division of the middle meningeal Neurosciences Center, artery, and peeling of the meningeal layer of the lateral wall of the cavernous sinus from All India Institute of Medical Sciences, the inner membranous layer. The cranial nerves in the lateral wall of the cavernous Ansari Nagar, New Delhi 110029, India. sinus were exposed (Cranial Nerves III and IV, as well as V1, V2, and V3). The tumor Email: [email protected] was accessed through its maximum bulge through either the lateral or anterolateral tri- angle. The tumor was removed via rapid decompression, coagulation of the feeder from Received, May 10, 2006. the meningohypophyseal trunk, and dissection along the cranial nerves. All but one Accepted, October 5, 2006. patient had complete tumor excision. Transient ophthalmoparesis (complete resolution in 6–8 wk) was the most common surgical complication. CONCLUSION: To our knowledge, we describe one of the largest series of pure extradural transcavernous approaches to CSHs. CSHs are uncommon but challenging cranial base lesions. The extradural transcavernous approach allows complete excision with mini- mal mortality or long-term morbidity. KEY WORDS: Cavernous sinus, Extradural approach, Hemangioma, Transcavernous, Treatment

Neurosurgery 60:483–489, 2007 DOI: 10.1227/01.NEU.0000255333.95532.13 www.neurosurgery-online.com

avernous sinus hemangiomas (CSHs) are uncommon Although CSHs are histopathologically similar to intracere- lesions and comprise fewer than 1% of all parasellar bral cavernous hemangiomas, their management issues are Cmasses (27). They are benign, well-encapsulated neo- vastly different. Radiation therapy (21) and, more recently, plasms arising within the confines of the cavernous sinus (12, radiosurgery (25) have been shown to decrease tumor size and 20, 28). Because of their location, propensity for profuse bleed- vascularity, but surgical excision remains the treatment of ing during surgery, and relationship to complex neurovascular choice (12, 14). The purpose of this study is to report our expe- structures, they are notoriously difficult to excise (14, 28, 30, 31). rience of complete removal of CSHs through a completely Suzuki et al. (30) reported seven cases of CSHs and reviewed extradural transcavernous approach with acceptable morbidity more than 50 cases in the existing literature. They were able to and blood loss. completely remove only two of the seven CSHs in their series. Although different authors have described their extensive PATIENTS AND METHODS experience with the surgical treatment of cavernous sinus lesions with good clinical results (1–3, 6, 7, 9, 11), these uncom- Between January 1999 and December 2004, more than 100 mon lesions remain a neurosurgical challenge. patients with cavernous sinus tumors underwent operation in

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our department. Seven of these tumors were CSHs, which were presented with visual impairment, two presented with facial operated through a purely extradural approach. The preoper- hypesthesia, and two presented with diplopia. Two patients ative symptoms, clinical findings, operative approach, compli- barely had perception of light in one of the eyes because they cations, and duration of the follow-up period for each patient were referred to us relatively late in the course of the disease. are summarized in Table 1. Interestingly, all seven of our All patients were evaluated preoperatively with contrast- patients were women. The maximum duration of symptoms enhanced CT and MRI scans. Contrast-enhanced CT scans ranged from 6 months to 2 years. All patients were treated revealed iso- to hyperdense expansile lesions in the region of using an extradural transcavernous approach. The precise the cavernous sinus and middle cranial fossa. There were signs access corridor to the tumor in the cavernous sinus depended of variable bony erosion of the anterior clinoid process, sphe- on the exact location of the tumor and the location of the max- noid ridge, or apex of the petrous bone. Calcification or tumor imum tumor bulge in the lateral wall of the cavernous sinus. necrosis was not found in any of the patients. MRI scans Contrast-enhanced computed tomographic (CT) scans and revealed well-demarcated expansile parasellar lesions, which magnetic resonance imaging (MRI) scans were obtained for all were hypo- or isointense on T1-weighted images (WI) and patients. Preoperative radiological diagnosis of CSH was made hyperintense on T2-WI, with marked homogeneous enhance- in all of these patients. Angiography was performed in one ment after intravenous administration of gadolinium diethyl- patient who was referred with a provisional diagnosis of a enetriamine pentaacetic acid contrast in all patients. The parasellar vascular lesion and in whom surgery was first tumors had well-defined borders and extended variably into attempted in a peripheral hospital, but abandoned because the sella and superior orbital fissure (Figs. 1 and 2). One patient biopsy led to profuse blood loss. Postoperative MRI scans to underwent digital subtraction angiography, which revealed a determine the extent of tumor removal were obtained for all late faint parasellar blush fed by cavernous internal carotid patients. The follow-up period ranged from 1 to 4 years. arteries (ICA).

RESULTS Surgical Technique All of the patients were approached through a frontotempo- The clinical features of these patients are summarized in Table ral osteoplastic craniotomy with or without orbitozygomatic 1. Of the seven patients, five presented with headache, four osteotomy. The sphenoid ridge was removed using a high-

TABLE 1. Patient profile of cavernous sinus hemangiomasa

Patient Age Follow-up Side Symptoms Clinical signs Surgical approach Complication no. (yr)/sex (mo) 1 41/F Left H/a: 1 yr; V/a, R: 6/9; Anterolateral triangle Transient 3rd and 4th 19 Poor vision, L eye: 6 mo; L FC: 3ft; (between V1 and V2) nerve paresis L facial hypesthesia: 6 mo L facial 10% sensory loss

2 42/F Left H/a: 1 yr; V/a, R: 6/18; Lateral triangle (be- Transient complete 12 L ptosis: 8 mo; L PLϩ; tween IVth and V1) ophthalmoplegia poor vision, L eye: 2 mo L 3rd nerve palsy

3 50/F Right H/a: 6 mo; V/a, L: 6/36; Lateral triangle (be- None 48 bilateral poor vision: 6 mo R 6th nerve paresis tween IVth and V1) R PL ϩ

4 36/F Right Diplopia, 6 mo V/a: b/l 6/9; Lateral triangle (be- Permanent 6th nerve palsy 30 R 6th paresis tween IVth and V1)

5 38/F Left H/a: 1 yr No deficits Anterolateral triangle Transient complete 14 (between V1 and V2) ophthalmoparesis

6 38/F Right H/a: 2 yr; V/a, R: 6/9; Lateral triangle (be- Transient 3rd nerve paresis 24 R eye poor vision and V/a, L: 6/60; tween IVth and V1) diplopia: 6 mo; R V1 and V2: R facial hypoesthesia: 6 mo 25% sensory loss

7 46/F Left Diplopia: 6 mo R 3rd and 6th paresis Anterolateral triangle Transient 6th nerve paresis 19 (between V1 and V2)

a H/a, headache; L, left; V/a, visual acuity; R, right; FC, finger counting; PL, perception of light; b/l, blood loss.

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speed pneumatic drill (Midas Rex; Medtronics, Minneapolis, The usual feeders from the meningohypophyseal trunk of the MN) and the superior orbital fissure was opened. The tentorial intracavernous ICA were exposed and coagulated early in the duplicature over the base of the anterior clinoid process was course of the surgery (Fig. 3D). The VIth cranial nerve was seen drilled and peeled from the bone. The anterior clinoid process in close proximity to the ICA. The medial extension of the was drilled extradurally, the optic canal was deroofed, and the lesion into the sella was removed. Hemostasis was achieved extracavernous extradural ICA was exposed (Fig. 3A). The tem- using gentle packing with gelatin (Spongstan; Johnson & poral base was drilled, the foramen spinosum was opened, and Johnson Medical Ltd., New Yorkshire, United Kingdom) and the middle meningeal artery was coagulated and cut. The degraded cellulose (Surgicel; Johnson & Johnson Medical Ltd., meningeal layer of the lateral wall of the cavernous sinus was New Yorkshire, United Kingdom), and blood loss was replaced peeled away from the inner membranous layer using sharp using hemato-cell saver (Autotranfusion unit; Didecon, and blunt dissection. The cranial nerves in the lateral wall of Mirandola, Italy). Gross total excision was achieved in all but the cavernous sinus were exposed (Cranial Nerves III and IV, as one patient who underwent partial resection because of profuse well as V1, V2, and V3) (Fig. 3, B and C). The tumor was blood loss. bulging either through the lateral triangle (Parkinson’s triangle, Postoperative morbidity included transient cranial nerve between Cranial Nerve IV and V1) or the anterolateral triangle dysfunction for 2 to 3 months in all but one patient. One patient (Mullan’s triangle, between the V1 and V2 nerves). The vascu- developed permanent VIth nerve palsy (Table 1). Vision lar tumor was removed by rapid decompression using an ultra- improved in all patients with preoperative visual diminution. sonic surgical aspirator and dissected along the cranial nerves. Postoperative MRI scans revealed gross total excision in six out of the seven patients. One patient with residual tumor was advised to undergo a second-stage surgery at a later date, but A B was lost to follow-up. Histopathology revealed the presence of cavernous hemangioma in all patients.

DISCUSSION

Cavernous hemangiomas of the cavernous sinus are rare lesions. The majority of reported cases occur in female patients (11, 30). In our series, all of the patients were female. Suzuki et al. (30) noted that almost half of all reported cases were of Japanese origin.

C D A B

E C D

FIGURE 1. A, contrast-enhanced CT scan showing a right parasellar homogenously enhancing lesion with medial extension into the sella. Sagittal (B), axial (C), and coronal (D) T2-weighted MRI scans showing a homogenously hyperintense tumor in the right parasellar region extend- ing into the sella. E, postoperative MRI scan of the same patient showing FIGURE 2. Axial (A) and coronal (B) contrast-enhanced MRI scans showing complete excision of the lesion. a left sellar and parasellar homogenously enhancing mass encasing the left ICA. Postoperative axial (C) and coronal (D) contrast-enhanced MRI scans showing complete excision of the hemangioma.

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A CSH is the only lesion that is purely intracavernous. Thus, even giant lesions remain within the dural confines of the cav- ernous sinus. The most likely mechanism of growth is consid- ered to be progressive ectasia of the blood vessels or their autonomous development at the edges of the lesion; hemor- rhagic onset is much more rare in CSH than in the intra- parenchymal variety (5, 26). On CT scans, CSHs are isodense or minimally hyperdense, with intense homogenous contrast administration. They may show pressure erosion of the petrous bone (29). On MRI scans, these lesions are well-demarcated and homogenously hypointense to white matter on T1-WI. Characteristically, they are brightly hyperintense on T2-WI, although a few linear septum-like hypointensities are identified (20, 29). They B enhance homogenously and intensely on contrast administra- tion. Unlike their intraparenchymal counterparts, these tumors show no hypointense hemosiderin rim. As the tumors grow in size, they initially displace, and later encase, the ICA. They are often found to extend toward the sella, intercavernous sinus, superior orbital fissure, and Meckel’s cave. On angiography, CSHs are usually described as “occult.” However, after pro- longed selective contrast injection, a mild tumor blush is visi- ble in most patients with CSHs (20, 22, 24). Intracavernous meningiomas and neurilemmomas are the most important lesions to be considered in the differential diag- nosis. As compared with CSH, meningioma is less hyperin- tense on T2-WI, but syncytial meningiomas are very hyperin- tense on T2-WI and are difficult to distinguish (4, 10). C Neurilemmomas are hypointense on T1-WI and hyperintense on T2-WI, but are more heterogeneous in appearance (25). An enlarged foramen ovale favors a diagnosis of trigeminal neurilemmoma; similar lesions from the IIIrd, IVth, or VIth cranial nerves are rare. Linskey and Sekhar (20) reported three cases of CSHs treated with a combined intra- and extradural approach in which total excision was achieved with minimal blood loss and with preservation of cranial nerve function in two cases. In their extensive review of the literature, they found only 25 cases of histopathologically confirmed CSHs. CSHs constituted only 2% of all cavernous sinus lesions operated on at their center. They hypothesized that the tumor arises within the cavernous sinus and, when small, takes its blood supply from the intra- D FIGURE 3. A, intraoperative photograph showing the exploration of the superior orbital fissure (black arrow) after the drilling of the anterior clinoid process, which exposed the tumor (white arrow) and the globe. B, intraop- erative photograph showing the extradural exposure of the cavernous hemangioma after peeling the outer meningeal layer (black arrow) away from the inner membranous layer (white arrow). C, surgeon’s illustration showing the extradural exposure of the cavernous hemangioma after peel- ing the outer meningeal layer away from the inner membranous layer. II, optic nerve; III, oculomotor nerve; IV, trochlear nerve; V1, ophthalmic nerve; V2, maxillary nerve; V3, mandibular nerve; GG, Gasserian gan- glion; GSPN, greater superficial petrosal nerve; LSPN, lesser superficial petrosal nerve; MMA, middle meningeal artery. D, intraoperative photo- graph showing the coagulation of feeders from the intracavernous ICA (black arrow) into the cavernous hemangioma.

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cavernous carotid artery. Because the VIth cranial nerve is the rary or permanent carotid artery occlusion, obtaining early only cranial nerve truly within the cavernous sinus, it will most proximal carotid artery control, carefully developing the plane often run through the substance of the tumor; Cranial Nerves between the dura and the tumor pseudocapsule, early devascu- III, IV, and V (V1, V2, and V3) will always be found stretched larization of the tumor, and avoiding piecemeal tumor resec- over the surface of the tumor in the overlying dura. As the tion (20). However, in very large tumors in which en bloc resec- tumor grows, it can extend medially into the sella turcica or tion is not possible, piecemeal resection is the only option. contralateral cavernous sinus, superiorly into the suprasellar Rapid decompression of the tumor and early control of tumor space, or anteriorly into the orbital apex. As the tumor grows vascularity on its medial side are key to successful removal of laterally, it gradually dissects between the two layers of dura giant tumors (12). Hypothermia, vascular occlusion, and intra- lining the floor of the middle fossa so that it comes underneath operative hypotension have been used by some surgeons dur- Cranial Nerve V2 and, eventually, Cranial Nerve V3. As it ing surgery (13). In our series, temporary carotid occlusion was grows into the middle fossa, it picks up an additional blood not used. If required, proximal carotid control in the postero- supply from the middle meningeal and accessory middle medial (Glasscock’s) triangle could be obtained easily. The CSH meningeal arteries. Because of the presence of the pseudocap- is supplied by the surrounding compressed cavernous sinus sule, there will always be a potential plane between the tumor and a feeder from the meningohypophyseal trunk of the inter- and the overlying dura and cranial nerves. This plane makes it cavernous sinus ICA, which was exposed and coagulated early technically easier to preserve Cranial Nerves III, IV, and V (V1, during the course of surgery. Intraoperative controlled nor- V2, V3) when removing a hemangioma than when removing a motensive anesthesia (mean arterial blood pressure, 70–80 cavernous sinus meningioma that arises from the dura that mmHg) was used using a high plane of anesthesia. invests these nerves. Hypotensive anesthesia is not used in our center because of the In 1997, Goel (11) described his experience with Dolenc’s risk of brain ischemia. technique of complete extradural approach to lesions involv- In our experience, the technical suggestions for the excision ing the cavernous sinus (6, 7, 11, 27). Of five cases described, of CSH lesions are as follows: 1) maximum exposure of the two were CSHs. In 2003, Goel et al. (12) described their expe- cranial base via orbitozygomatic craniotomy; temporal base rience with 13 cases of CSHs, seven of which were operated by drilling; and wide exposure of the optic canal, superior orbital the complete extradural approach. Of these, 12 patients had a fissure, and foramina spinosum, ovale, and rotundum; 2) the complete tumor resection. The cranial nerve outcome in their most painstaking step is the dissection of the meningeal layer series was poor, perhaps because of the large size of the of the cavernous sinus lateral wall from the inner membranous tumors at diagnosis. layers enclosing the IIIrd, IVth, V1, V2, and V3 cranial nerves. Zhou et al. (32) reported 20 surgically treated cases of CSH, This step must involve the maximum usage of sharp dissection. 13 of which were treated using the extradural approach. The intense practice of this step of dissection is emphasized by Complete tumor removal was achieved in 12 cases; at a mean Dolenc’s (7) anatomic dissection of cadavers; 3) minimum han- follow-up period of 3 years, all patients in this group were dling of the IIIrd cranial nerve is important. The triangles for improved without tumor recurrence. entry should be the anterolateral triangle (between Cranial Shi et al. (26) retrospectively analyzed 10 patients with CSHs. Nerves V1 and V2) and the lateral triangle (between Cranial Among the 10 patients, total tumor removal was performed in Nerves IV and V1), staying as far away from the IIIrd cranial four patients, partial removal was performed in two cases, and nerve as possible; and 4) we do not advocate en bloc removal of four patients had tumor biopsies. Both patients who under- a CSH because it results in increased retraction on the nerves in went partial removal developed complete ophthalmoplegia the lateral wall of the cavernous sinus. The key steps are rapid and diminished sensation in the distribution of Cranial Nerve decompression of the tumor via suction and dissection, and V1 after surgery; one patient developed contralateral paralysis. occasionally via an ultrasonic surgical aspirator, avoiding the For the four patients who underwent tumor biopsies, the pro- cranial nerves but aiming for the medially located intercav- cedures were discontinued because of severe intraoperative ernous ICA. In this way, the usual feeder from the meningohy- tumor bleeding. The authors also identified two pathological pophyseal trunk of the intercavernous ICA is exposed and can subtypes, which differed in surgical difficulty, i.e., the soft type be coagulated early in the course of the surgery. This results in with abundant vasculature and the solid type with abundant a marked reduction in tumor vascularity and blood loss. Then, interstitial tissue, for which bleeding control was easier. the lesion is slowly dissected away from of the intercavernous The ideal treatment is total tumor removal with the preserva- ICA and the VIth cranial nerve. Next, from inside out, the tion of neurological function. However, the surgery is difficult lesion is dissected from Cranial Nerves V1, V2, V3, III, and IV because of the complex structures of the cavernous sinus, and its usual extension into the sella. Despite this, one patient encased cranial nerves and ICA, and severe intraoperative developed a permanent VIth cranial nerve palsy, which could bleeding (8, 19, 22, 23, 24, 28). As a result, surgical mortality and have been avoided by gentle dissection of the nerves around morbidity rates as high as 36 to 38% have been reported in the intercavernous ICA. older series (18, 23). Preoperative radiotherapy to decrease tumor size and vascu- Principles for successful and safe excision have been larity (16, 21) and radiosurgery (25) have been useful in some reported as preoperative assessment of the safety of tempo- cases. However, other adjunctive modalities such as preopera-

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tive embolization are not useful (13). Radiosurgery is a useful 30. Suzuki Y, Shibuya M, Baskaya MK, Takakura S, Yamamato M, Saito K, Glazier adjunctive treatment for patients with small residual tumors SS, Sugita K: Extracerebral cavernous angioma of the cavernous sinus in the after surgery (25). middle fossa. Surg Neurol 45:123–132, 1996. 31. Ueki K, Matsutani M, Nakamura O, Nakamura M, Hibi T, Kamata N: Cavernous angioma of the middle fossa: A case report and characteristic MRI REFERENCES findings. Radiat Med 11:31–35, 1993. 32. Zhou LF, Mao Y, Chen L: Diagnosis and surgical treatment of cavernous 1. Al-Mefty O: The cranio-orbital-zygomatic approach for intracranial lesions. sinus hemangiomas: An experience of 20 cases. Surg Neurol 60:31–37, 2003. Contemp Neurosurg 14:1–5, 1992. 2. Al-Mefty O, Ayoubi S, Smith RR: Direct surgery of cavernous sinus: Patient selection. Acta Neurochir Suppl (Wien) 53:117–121, 1991. Acknowledgment 3. Al-Mefty O, Smith RR: Surgery of tumors invading the cavernous sinus. Surg Detailed knowledge of microsurgical anatomy is the key to success in the Neurol 30:370–381, 1988. exposure and dissection of the cavernous sinus. We thank Vinko V. Dolenc, 4. Bradac GB, Riva A, Schorner W, Stura G: Cavernous sinus meningiomas: An M.D., Ph.D., (Slovenia) for his teachings. MRI study. Neuroradiology 29:578–581, 1987. 5. Bristot R, Santoro A, Fantozzi L, Delfini R: Cavernoma of the cavernous sinus: Case report. Surg Neurol 48:160–163, 1997. COMMENTS 6. Dolenc VV: Transcranial epidural approach to pituitary tumors extending Neurosurgery beyond the sella. 41:542–552, 1997. his clinical study reports on a small series of patients with an excep- 7. Dolenc VV: Extradural approach to intracavernous ICA aneurysms. Acta tional and challenging pathology. A highly vascular tumor gener- Neurochir Suppl 72:99–106, 1999. T 8. Dolenc VV: Cavernous angioma of the cavernous sinus: Case report. ally cannot be removed in a single operation. Therefore, the extradural Neurosurgery 27:155, 1990 (comment). exposure, having no control of the nerves and internal carotid artery, 9. Eisenberg MB, Al-Mefty O, DeMonte F, Burson GT: Benign nonmeningeal must be as complete as possible before aggressively pursuing tumor tumors of the cavernous sinus. Neurosurgery 44:949–955, 1999. excision. The authors were able to completely remove the tumors in all 10. Elster AD, Challa VR, Gilbert TH, Richardson DN, Contento JC: Meningi- but one patient and with only one permanent postoperative VIth nerve omas: MR and histopathologic features. Radiology 170:857–862, 1989. palsy. The authors should be commended for their results. My per- 11. Goel A: The extradural approach to lesions involving the cavernous sinus. Br sonal experience includes only three patients with one postoperative J Neurosurg 11:134–138, 1997. VIth nerve palsy. With all vascular lesions, I feel more comfortable 12. Goel A, Muzumdar D, Sharma P: Extradural approach for cavernous heman- gioma of the cavernous sinus: Experience with 13 cases. Neurol Med Chir with preoperative angiography with a balloon occlusion test of the (Tokyo) 43:112–119, 2003. internal carotid artery. 13. Goel A, Nadkarni TD: Cavernous haemangioma in the cavernous sinus. Br J The authors raise the question of a radiosurgical treatment that could Neurosurg 9:77–80, 1995. be considered in the small tumors. However, I am reluctant to use this 14. Gupta S, Goel A: Cavernous haemangioma of cavernous sinus associated treatment because most of the patients are young. In general, I prefer with an internal carotid artery aneurysm. Br J Neurosurg 14:56–59, 2000. to reserve radiosurgery for patients 50 years of age or older. The study 15. Deleted in proof. clearly demonstrates that, with adequate surgical technique, this is a 16. Harada T, Aoyama N, Terada H, Tsujimoto S, Hosogi Y, Iwasaki S: A case of very reasonable option. extracerebral hemangioma of the middle fossa. Prog Comput Tomogr (Tokyo) 4:460–465, 1982. Bernard George 17. Deleted in proof. Paris, France 18. Kudo T, Ueki S, Kobayashi H, Torigoe H, Tadokoro M: Experience with the ultrasonic surgical aspirator in a cavernous hemangioma of the cavernous sinus. Neurosurgery 24:628–631, 1989. ith a series of seven patients, Suri et al. review and describe an 19. Laws ER Jr: Cavernous angioma of the cavernous sinus: Case report. Wextradural transcavernous approach to cavernous hemangiomas. Neurosurgery 27:155, 1990 (comment). The authors describe the excellent results of a purely extradural 20. Linskey ME, Sekhar LN: Cavernous sinus hemangiomas: A series, a review, approach of these difficult cranial base lesions. With the advancement of and an hypothesis. Neurosurgery 30:101–108, 1992. surgical techniques in this area, it is gratifying to see the widespread use 21. Meyer FB, Lombardi D, Scheithauer B, Nichols DA: Extra-axial cavernous of purely extradural approaches for lesions such as these and trigemi- hemangiomas involving the dural sinuses. J Neurosurg 73:187–192, 1990. nal schwannomas. The beauty of resecting a tumor using an extradural 22. Mori K, Handa H, Gi H, Mori K: Cavernomas in the middle fossa. Surg approach is the considerable decline in intracranial morbidity that paves Neurol 14:21–31, 1980. 23. Namba S: Extracerebral cavernous hemangioma of the middle cranial fossa. the way for an excellent result. I personally prefer an extradural Surg Neurol 19:379–388, 1983. approach over resection. I have occasionally been intimidated with 24. Numaguchi Y, Kishikawa T, Fukui M, Sawada K, Kitamura K, Matsuura K, excessive bleeding and have used hypotension and temporary carotid Russell WJ: Prolonged injection angiography for diagnosing intracranial cav- occlusion. It should be stressed that these lesions are rare, and that an ernous hemangiomas. Radiology 131:137–138, 1979. extradural approach is probably the optimal way to proceed. 25. Peker S, Kilic T, Sengoz M, Pamir MN: Radiosurgical treatment of cavernous sinus cavernous haemangiomas. Acta Neurochir (Wien) 146:337–341, 2004. Anil Nanda 26. Shi J, Hang C, Pan Y, Lui C, Zhang Z: Cavernous hemangiomas in the cav- Shreveport, Louisiana ernous sinus. Neurosurgery 45:1308–1318, 1999. 27. Simard JM, Garcia-Bengochea F, Ballinger WE Jr, Mickle JP, Quisling RG: uri et al. share their notable experience managing cavernous sinus Cavernous angioma: A review of 126 collected and 12 new clinical cases. hemangiomas. Although this pathology is rare, it is not extraordi- Neurosurgery 18:162–172, 1986. S 28. Sepehrnia A, Tatagiba M, Brandis A, Samii M, Prawitz RH: Cavernous nary, particularly among Asian women. The authors emphasize the angioma of the cavernous sinus: Case report. Neurosurgery 27:151–155, 1990. importance of using a purely extradural approach to dissect the mass. 29. Sohn CH, Kim SP, Kim IM, Lee JH, Lee HK: Characteristic MR imaging find- They also give emphasis to seeking a very early, preventative hemosta- ings of cavernous hemangiomas in the cavernous sinus. AJNR Am J sis by coagulation and sectioning of the meningohypophysical artery, Neuroradiol 24:1148–1151, 2003. which is the primary feeder of the hemangiomas. This can be accom-

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plished using even piecemeal resection or ultrasonic aspiration point- he authors have described their experience using an extradural tran- ing medially in the direction of the carotid artery. Tscavernous approach in the surgical management of cavernous sinus This is neither the first nor the largest series to propose an extradural hemangiomas. Because these are rare tumors, a series with seven approach; however, the results achieved in this study are remarkable for patients is remarkable for a single department. The authors detail their the radical removal and preservation of postoperative oculomotor nerve technique and recommend rapid decompression of the tumor rather function. The comprehensive discussion of the surgical technique is than en bloc resection to minimize retraction on the cranial nerves in the useful for any surgeon approaching a tumor of the cavernous sinus. I lateral wall of the cavernous sinus. The authors also stress the impor- particularly appreciated the neuroradiological preoperative evaluation tance of early access to the arterial feeders from the meningohy- and the differential diagnosis, which are especially important for a rare pophysial trunk of the intercavernous internal carotid artery because lesion that must be approached via an extradural route. Finally, the early coagulation of the vessels reduces tumor vascularity and blood authors emphasize the importance of training in surgical dissection on loss. The other important points include maximum exposure of the cra- anatomical specimens. This is the only way to develop familiarity with nial base for access to the cavernous sinus, dissection of the meningeal the cavernous sinus region and be confidently prepared to confront layer of the cavernous sinus lateral wall from the inner membranous challenges with the likelihood of obtaining good results. layer, and minimizing the handling of the oculomotor nerve. Alessandro Ducati Andrew H. Kaye Turin, Italy Melbourne, Australia

Illustration showing the process of amyloid protein folding beginning with the unfolded polypep- tide entering a funnel-shaped pathway in which the proteins become more organized as they merge. Courtesy of Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. N Engl J Med 349:583–596, 2003.

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IN VIVO STUDY OF HEAD IMPACTS IN FOOTBALL: A COMPARISON OF NATIONAL COLLEGIATE ATHLETIC ASSOCIATION DIVISION I VERSUS HIGH SCHOOL IMPACTS Brock Schnebel, M.D. Departments of Orthopedics OBJECTIVE: To compare the frequency and magnitude of head impacts between National and Athletics, Collegiate Athletic Association Division I and American high school football players. The University of Oklahoma, Norman, Oklahoma long-term goal is to correlate impact forces with injury patterns, leading to improve- ments in protective headgear. Joseph T. Gwin, B.E. METHODS: The helmets of football players at the University of Oklahoma (n ϭ 40) and Thayer School of Engineering, Casady High School (n ϭ 16) were instrumented with the Head Impact Telemetry System Dartmouth College, Hanover, New Hampshire (Simbex, Lebanon, NH). Data were collected for practices and games for the 2005 foot- ball season and were analyzed by player position and school. Player positions were Scott Anderson, A.T.C. separated into two groups (skill and line) for analysis. Two case studies of athletes who Department of Intercollegiate Athletics, sustained a concussion are also presented. University of Oklahoma, RESULTS: A total of 54,154 impacts were recorded at the University of Oklahoma and Norman, Oklahoma 8326 at Casady High School. College players sustained high-level impacts greater than 98 g more frequently than high school players. The mean linear accelerations for the top Ron Gatlin, A.T.C. Ͻ Department of Athletics, 1, 2, and 5% of all impacts were also higher for college players (P 0.02). Skill posi- Casady High School, tion players received 24.6% of all impacts and sustained an impact greater than 98 g Oklahoma City, Oklahoma once every 70 impacts. In contrast, linemen sustained the highest number of impacts, but most were relatively low-magnitude (20–30 g). Linemen sustained an impact greater Reprint requests: Brock Schnebel, M.D., than 98 g once every 125 impacts. McBride Clinic, CONCLUSION: Differences in the frequency and magnitude of head acceleration after 1110 North Lee Avenue, Oklahoma City, OK 73103. impact exist between a Division I college team and a high school team. Compared with Email: [email protected] linemen, skill position players typically sustain the highest-level impacts. Additional data collection and analysis are required to correlate concussion diagnosis with accel- Received, June 15, 2006. eration magnitude and impact location. Accepted, November 1, 2006. KEY WORDS: Concussion, Football, Head impact biomechanics, Impact tolerance, Mild traumatic brain injury, Sports injury prevention

Neurosurgery 60:490–496, 2007 DOI: 10.1227/01.NEU.0000249286.92255.7F www.neurosurgery-online.com

he Center for Disease Control and Pre- 19, 20), there is little data regarding the fre- vention states that head injury in sport quency, magnitude, and severity of head Tis occurring at an epidemic level (2). impacts in helmeted team sports (2, 8, 15, 18). Decades of impact injury research, primarily The long-term effects of head impacts and in the automotive industry, have led to a better repeated concussions are being studied in a understanding of how the brain responds to variety of sports, but the effects of repeated linear and rotational inputs caused by impact subconcussive blows to the head are not well (1, 17). Although there is an increased aware- understood (8, 11, 21). ness of the physiology of concussions, an Although there has been tremendous effort increased understanding of the short and long- in the research and clinical communities to term effects on the brain neurophysiology, and understand the symptoms and clinical seque- an improved clinical understanding, which lae of concussions and how to manage con- aids return-to-play decisions (5, 6, 9, 10, 12–14, cussions clinically (9, 14), there has been less

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information regarding the mechanisms of concussions (11–13), particularly differences in impact exposure (both incidence and magnitude) and concussion tolerance at different levels of play (e.g., age, experience, size, etc.) (6, 10, 16). An important goal in understanding and correlating head injuries and what causes them is to measure what occurs on the field in vivo. Recently, a system for widespread monitoring of head acceleration during helmeted sports on the playing field has been introduced for use in American football (2, 6, 8, 15). Several concurrent studies are currently in progress at the col- legiate Division I level (2, 8). The purpose of this study is to compare biomechanical measures of head impact magnitude during a single football season between a National Collegiate Athletic Association (NCAA) Division IA football team and a small, mid-level (Division IIA) high school football team.

EXPERIMENTAL METHODS

The football helmets of 40 out of 105 players at the University of Oklahoma (OU) (Norman, OK) and 16 out of 53 players at Casady High School (Oklahoma City, OK) were instrumented with Head Impact Telemetry (HIT) System (Simbex, Lebanon, NH) technology, which is part of the FIGURE 1. Instrumented helmets contain six linear accelerometers. The HIT Sideline Response System (Riddell Inc, Chicago, IL), to meas- System consists of a helmet-mounted player unit, a sideline receiver, and a lap- ure all head impacts from practices and games during the top computer for storing and processing data. 2005 football season. The participating players were selected by the medical staff from the pool of volunteers at each school eter exceeded 10 g. The acceleration data are time-stamped (Ϯ5 to ensure that a wide variety of positions was covered. Start- ms resolution) and wirelessly transmitted to a sideline receiver ers were given preference over second-team players. Players’ interfaced to a laptop computer. These data are immediately concussion histories were not considered in the inclusion or processed using an algorithm that calculates linear head accel- exclusion criteria, but were noted for future research use. eration and impact location (6). Riddell VSR4 (OU, n ϭ 21; Casady, n ϭ 14) and Revolution Data were collected for practices and games during the 2005 (OU, n ϭ 19; Casady, n ϭ 2) helmets were used in this study. football season (OU, 93 practices and 12 games; Casady, 15 Players selected their helmets according to school protocols. practices and nine games). This represents all contact prac- Only players who wore Riddell helmets were eligible to par- tices at OU and a sample of practices at Casady; the training ticipate because the instrumentation was only available for staff at Casady did not use the HIT System during all practice these helmets. Informed consent was obtained for all partici- situations because of time constraints. Data were analyzed by pating athletes in accordance with the OU and St. Anthony player position and school. Player positions were separated Hospital Institutional Review Boards. OU is an NCAA Divi- into two groups (skill and line) for analysis. Linemen were sion IA school with 20 sports and an enrollment of 25,000 stu- defined as players who setup on the line of scrimmage in a dents. Casady High School is an independent, private school three or four-position stance (one or two hands on the ground) in Oklahoma City with an enrollment of 320 students in before each play. Their primary task is to rush the quarter- Grades 9 to 12. back or tackle on defense and to protect the quarterback or The instrumented helmets continuously monitor and record block for the running back on offense. These players sustain an head impact accelerations on the field in real-time (Fig. 1). The impact, often low in magnitude, on almost every play. The system consists of helmet-mounted player units, a sideline remaining players, including quarterbacks, running backs, receiver for communicating with the player units, and a laptop wide receivers, corner backs, and safeties, were defined as skill computer for data storage and processing. Each player unit position players. These players are typically not hit on every consists of sensors (six accelerometers and one temperature play. In addition to all impacts, the top 1, 2, and 5% of all sensor), a wireless transceiver (903–927 MHz), onboard mem- impacts at each school were used to test for differences in ory (up to 100 impacts), and data acquisition capabilities (10 bit; impact distributions between schools and position groups. A 1000 Hz/channel). Helmets instrumented with this technology univariate analysis of variance statistic (SPSS, Chicago, IL) was meet all relevant National Operating Committee on Standards used to compare mean linear acceleration by position group for Athletic Equipment impact attenuation requirements for and school. Significance was set at α ϭ 0.05. In addition, the use on the field. Impact data were collected for 40 milliseconds frequency of impacts greater than an absolute threshold (60 (8 ms pre-trigger and 32 ms post-trigger) when any accelerom- and 98 g) was used to contrast the impact exposures by school

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and position group. For example, linemen impacting each other from a stance 1 m apart will typically sustain a 5- to 15-g head A acceleration during the impact. Open-field impacts with the highest head accelerations can reach accelerations of 200 g or more. Case studies, including biomechanical impact data for the day of the injury, of one OU athlete and one Casady athlete who were diagnosed with concussions by the medical staff are also presented. For the purposes of this study, a concussion has been defined as a traumatically-induced neurological dis- function, manifested primarily by transient alterations in con- sciousness and cognition (3).

RESULTS B A total of 54,154 impacts were recorded at OU and 8326 impacts at Casady. There was no statistical difference in the overall distribution of impact magnitude for all impacts between the two schools (P ϭ 0.340) or by position group (P ϭ 0.601) (Fig. 2). There were statistically significant differences (P Ͻ 0.02) in the mean linear acceleration for the top 1, 2, and 5% of all impacts between schools (Table 1). There were statis- tically significant differences in the mean linear acceleration for position group only for the top 5% of all impacts, inde- pendent of school (P ϭ 0.024). There were no significant inter- actions between school and position group for any of the impact magnitude levels studied. Of all impacts, 79.4% were less than 30 g. College players sus- tained high-level impacts (Ͼ98 g) more frequently than high FIGURE 2. Bar graphs showing the impact distribution as a percentage of school players (Table 2). As a percentage of all impacts, college all impacts by school (A) and by position (B). players also sustained impacts greater than 60 g more fre- quently than high school players. At both the high school and play were diagnosed with concussions. We present two case college levels, skill position players received a higher percent- studies of concussions sustained during play. age of increased level (Ͼ60 g or Ͼ98 g) impacts than linemen. Skill position players accounted for 24% of all impacts (n ϭ Illustrative Cases 15,258) and sustained an impact greater than 98 g approxi- mately once every 70 impacts. In contrast, linemen sustained Patient 1 the highest number of impacts, but most were relatively low- Patient 1 is a high school player who sustained an impact of 109 g to magnitude (20–30 g). Linemen sustained an impact greater than the top of the head during a game. This impact occurred during a 98 g once every 125 impacts (Table 2). defensive play and the injured player was a defensive lineman in the act of tackling. This player had no previous history of concussion but Three instrumented players at OU and three at Casady were did have a history of migraine headaches. The medical staff on the diagnosed with concussions by the medical staff during the sideline took an initial look at this player because the impact, as viewed 2005 football season. The recorded linear accelerations for the from the sideline, seemed to be significant. After showing no concus- associated impacts that are likely to have caused clinical symp- sive symptoms, the player was allowed to return to play. Later in the toms and subsequent medical diagnosis of concussion ranged game, the same player received an impact of 90 g to the front of the in magnitude from 81.9 g (back of the head impact) to 145.7 g head and immediately experienced concussive symptoms. In total, the (top of the head impact). All six concussions occurred during player received 51 impacts to the head during play that day (Fig. 3). games; in each case, the player was not diagnosed with any The earlier impact was one of seven impacts greater than 98 g received other concussions during the season. The linear accelerations by this player during the season, four of which occurred later in the for the concussive impacts were in the top 3% of all impacts season than the concussion event. After the second significant impact that day, this lineman was initially confused and slow to get up. On the recorded for that individual player. The players diagnosed with sidelines, he became very quiet, sat down with his head in his hands, concussions at OU were three defensive players (two lineback- and complained of a severe headache. He was confused and disori- ers and one lineman), all of whom were in the act of tackling at ented to time, place, and situation. He was amnesic for the event, had the time of injury. At Casady, one quarterback who was being poor balance, did not want to stand, could not walk, and wanted to tackled, one defensive lineman in the act of tackling, and one become supine and sleep. He then became progressively more somno- running back who was being blocked during a special teams lent. At that point, transfer to the hospital was initiated. At the emer-

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TABLE 1. Mean linear acceleration for the top 1, 2, and 5% of all impacts for each schoola OU Casady Mean linear Linear Mean linear Linear No. of No. of acceleration, acceleration acceleration, acceleration impacts impacts (g) ؎ 1 SD range(g) (g) ؎ 1 SD range (g) Top 1% 541 127.8 Ϯ 31.8 ≥99.2 83 114.5 Ϯ 26.9 ≥90.6 Top 2% 1083 108.4 Ϯ 29.9 ≥80.6 166 98.7 Ϯ 26.1 ≥75.1 Top 5% 2707 84.2 Ϯ 27.8 ≥58.8 416 77.9 Ϯ 24.3 ≥56.2

a OU, University of Oklahoma; SD, standard deviation.

biomechanics, specifically brain tissue motion during impact, is TABLE 2. Frequency of high-magnitude impacts by position type and directly related to the clinical manifestation of symptoms schoola related to concussion. As data on head impacts from field stud- ies using technologies similar to those used in this study Impacts Impacts > 98 g Impacts > 60 g become available, in-depth analysis of risk factors that lead to > 98 g Skill pos Lineman Skill pos Lineman concussion and correlations between clinical variables associ- OU 563 (1.0%) 210 (1.5%) 353 (0.9%) 870 (6.3%) 1699 (4.2%) ated with concussion and head impact biomechanics are possi- Casady 57 (0.7%) 14 (0.9%) 39 (0.6%) 63 (4.3%) 230 (3.8%) ble. Significant numbers of monitored concussions are required a pos, position; OU, University of Oklahoma. for this type of analysis. This 1-year study of a single NCAA Division I college foot- ball team and a single small high school football team is, to our gency room, a computed tomographic scan was completed and was knowledge, the first to report results comparing head impact negative. His headache persisted and was reported as similar to accelerations between different levels of play and the first to migraines he had experienced in the past. His pain improved with quantify impact distributions at the high school level. The over- Imitrex (GlaxoSmithKline, Research Triangle Park, NC), Tylenol all distribution of linear acceleration after impact for OU play- (McNeil Consumer Healthcare, Guelph, Canada), and rest. He gradu- ally became less somnolent during the next 3 hours and was released ers is consistent with those previously reported (2, 8). This from the emergency room with the diagnosis of concussion with a study revealed that college players tend to have higher impact migraine component. He did not practice for 7 days and then gradually accelerations when compared with high school players in sim- returned to play. He had no further events during the season. ilar positions. Higher accelerations make up a greater percent- Patient 2 age of total impacts in college players compared with high school players. For this study, two absolute thresholds for Patient 2 is a college player who sustained an impact of 145 g to the determining high accelerations were used: impacts greater than front of the helmet above the facemask during a defensive play. The 60 g, approximately the 90th percentile of all impacts, and injured player was a defensive linebacker in the act of tackling; he had no previous history of concussion. The player received 17 impacts to impacts greater than 98 g, the level at which 75% of all impacts the head during the same game before receiving a concussive impact are expected to be concussive according to recent National (Fig. 4). The incident was recorded by multiple video cameras for Football League research (18). The top 1, 2, and 5% of all analysis. This impact was the most severe that the player received dur- impacts were analyzed to facilitate direct comparison of the ing the season and was one of four impacts greater than 98 g. This line- most severe and potentially the most injurious impacts because backer initially seemed dazed and scared but functioned well cogni- the statistically significant differences highlighted by compar- tively. He was able to recall the event, but did complain of an initial ing standard measures across groups, such as medians and unusual sensation in his neck. He was treated and improved while on means, seem clinically irrelevant (Ͻ5 g) in this case. It seems the field. His neck symptoms abated, he had normal pain-free motion, intuitive that the larger, faster players at the Division I college and he denied a headache. He was observed on the sidelines for more level would sustain more and higher-magnitude impacts than than 15 minutes. His neck and neurological examinations were normal and he was allowed to return to play. The following day, he reported high school players. It is impressive, however, that the highest headaches and, in retrospect after reviewing the film and data, it was level impacts at the high school level were both frequent and at our opinion that he had sustained a concussion. His participation was levels greater than 100 g. These findings support epidemiolog- limited until he became asymptomatic. He had no further events dur- ical data showing that concussion rates are significant at both ing the season. the high school and college levels (12, 14, 16, 19, 20, 21). At both OU and Casady, linemen tended to have lower DISCUSSION impact accelerations for most hits, which is also consistent with previously reported data (2, 8). Furthermore, linemen tend to There is very little data in the literature regarding the inci- sustain these low-magnitude impacts on almost every play in dence and severity of head impacts in football. Head impact which they participate. An interesting but anecdotal finding of

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this early data was that the A raw number of impacts per player per game for some Casady high school players was higher than for OU play- ers. We speculate that this may be because some players at the high school level play both offense and defense. It is unknown whether or not this increased exposure increases the likelihood of sustaining a concussion for these players. B There are many unknowns regarding the likelihood of sustaining a concussion on an impact of a given magnitude of linear acceleration. Pell- man et al. (18) found that lin- ear acceleration magnitude correlated well with the likeli- hood of sustaining a concus- sion. On this basis, we report linear head acceleration data FIGURE 3. Case study of a high school player who sustained a concussion. The bar graph (A) shows all impacts sus- here. Other variables, includ- tained on the day of the injury for the injured player. The head form (B) shows the relative magnitude and location ing rotational acceleration, of each of those impacts. impact duration, impact velocity, and whether the injured player was the striking or struck player, are also impor- A tant and relevant variables. The effects of cumulative subcon- cussive impacts and the time history of those impacts are also unknown and will be the subject of subsequent analysis. Furthermore, there is little known regarding the individual risk factors that contribute to concussion incidence and severity. We will explore these variables in subsequent years as the data- base on impacts and concussive events grows. The case studies are presented to demonstrate the types of information available regarding the biomechanical inputs to which the injured athlete is exposed, including the time history of impacts. We combine this information with video analysis of B the injury event when possible and think that this information can be valuable for better understanding the mechanism and severity of the head injury sustained by the athlete. The data from these case studies cannot be extrapolated to other cases at this time. More concussive impacts and associated cumulative head impact and medical histories must be collected before further conclusions can be drawn. Although we had six concus- sive events in this 1-year study, we do not draw conclusions linking the biomechanical data with the clinical history. The second case report does demonstrate some of the difficulties in diagnosis and how real-time impact information, including a player’s impact history, may be used in the future to help clar- FIGURE 4. Case study of a college player who sustained a concussion. The ify for the medical staff the number and magnitude of impacts bar graph (A) shows all impacts sustained on the same day before the received by that player. We think that as a player sustains more injury for the injured player. The head form (B) shows the relative magni- tude and location of each of those impacts. impacts within a given timeframe, he may be at a higher risk for concussion.

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There are several limitations of the current study. First, not all 6. Collins M, Lovell MR, Iverson GL, Ide T, Maroon J: Examining concussion players on both teams were instrumented. Thus, the total expo- rates and return to play in high school football players wearing newer hel- sure to impacts is not captured. The players selected for the met technology: A three-year prospective cohort study. Neurosurgery 58:275–286, 2006. study were a mixture of starters and substitutes from a wide 7. Crisco JJ, Chu JJ, Greenwald RM: An algorithm for estimating acceleration variety of positions. Second, the actual exposure to impacts for magnitude and impact location using multiple nonorthogonal single-axis each player is not quantified. In the future, we propose to nor- accelerometers. J Biomech Eng 126:849–854, 2004. malize the number of impacts by actual exposure in hours and 8. Duma SM, Manoogian SJ, Bussone WR, Brolinson PG, Goforth MW, Donnenwerth JJ, Greenwald RM, Chu JJ, Crisco JJ: Analysis of real-time head to stratify the results by practice and games to quantify differ- accelerations in collegiate football players. Clin J Sport Med 15:3–8, 2005. ences between the two. Anecdotally, the number of head 9. Echemendia RJ, Putukian M, Mackin RS, Julian L, Shoss N: Neuropsycholog- impacts and the magnitude of head linear acceleration is much ical test performance prior to and following sports-related mild traumatic higher in games than in practices, although this may not be the brain injury. Clin J Sport Med 11:23–31, 2001. 10. Field M, Collins MW, Lovell MR, Maroon J: Does age play a role in recovery case at certain times of the year, such as in preseason or spring from sports-related concussion? A comparison of high school and collegiate ball, when players are vying for roster spots and may increase athletes. J Pediatr 142:546–553, 2003. their intensity. These types of analysis merit further research. 11. Guskiewicz KM, McCrea M, Marshall SW, Cantu RC, Randolph C, Barr W, For this study, we do not report other metrics, including rota- Onate JA, Kelly JP: Cumulative effects associated with recurrent concussion in collegiate football players: The NCAA Concussion Study. JAMA 290: tional acceleration or metrics that include impact duration, 2549–2555, 2003. such as the Gadd Severity Index. At the time of data collection, 12. Guskiewicz KM, Weaver NL, Padua DA, Garrett WE Jr: Epidemiology of the technology used for these measurements had not been fully concussion in collegiate and high school football players. Am J Sport Med validated for quantifying rotational accelerations of the head. 28:643–650, 2000. Future reports will include an analysis of these other variables 13. Guskiewicz KM, Cantu RC: The concussion puzzle: Evaluation of sports- related concussion. Am J Med Sports 6:13–21, 2004. as well as correlations to clinical data, including results of cog- 14. Lovell MR, Collins MW, Iverson GL, Johnston KM, Bradley JP: Grade 1 or nitive testing (e.g., the ImPACT test; ImPACT Applications, “ding” concussions in high school athletes. Am J Sport Med 32:47–54, 2004. Inc., Pittsburgh, PA) and clinical data for injured and nonin- 15. Manoogian S, McNeely D, Duma S, Brolinson G, Greenwald R: Head accel- jured athletes (14). Nevertheless, the current data present, for eration is less than 10 percent of helmet acceleration in football impacts. Biomed Sci Instrum 42:383–388, 2006. the first time to our knowledge, a picture of the differences in 16. McCrea M, Hammeke T, Olsen G, Leo P, Guskiewicz K: Unreported concus- head-impact incidence and linear-acceleration magnitude sion in high school football players. Clin J Sport Med 14:13–17, 2004. between college-level players and high school players and as a 17. Nusholtz G, Lux P, Kaiker P, Janicki M: Head impact response–skull deforma- function of player position. tion and angular accelerations, in Backaitis SH (ed): Biomechanics of Impact Injury and Injury Tolerance of the Head-Neck Complex. Troy, Society of Automotive Engineers, 1993, pp 159–192. 18. Pellman EJ, Viano DC, Tucker AM, Casson IR, Waeckerle JF: Concussion in CONCLUSION professional football: Reconstruction of game impacts and injuries. Neurosurgery 53:799–814, 2003. Many questions remain. Are there measurable and reliable 19. Powell JW, Barber-Foss KD: Traumatic brain injury in high school athletes. thresholds for concussion that can be quantified by measurable JAMA 282:958–963, 1999. 20. Powell JW, Barber-Foss KD: Injury Patterns in Selected High School Sports: A parameters? If they exist, are these thresholds a function of Review of the 1995–1997 Seasons. J Athl Train 34:277–284, 1999. age, experience, and impact exposure? Our long-term goals are 21. Scott Delaney JS, Puni V, Rouah F: Mechanisms of injury for concussions in to correlate head acceleration magnitude and impact location university football, ice hockey, and soccer: A pilot study. Clin J Sport Med with clinical diagnosis of concussion and to better understand 16:162–165, 2006. individual risk factors associated with concussion and the potential for further improvements to football headgear to mit- igate the risk of this injury. COMMENTS sing a novel head impact telemetry system, the authors com- Upared the forces of impact in 40 college football players and 16 REFERENCES high school football players. The players’ helmets were instrumented 1. Bandak FA, Eppinger RH: A three dimensional finite element analysis of the to detect linear acceleration and impact frequency. This data was human brain under combined rotational and translational accelerations. accumulated on the field in real-time with telemetry information Presented at the 38th Stapp Car Crash Conference, SAE-279, Warrendale, transmitted to a wireless receiver on the sidelines. Linear head accel- Pennsylvania, 1994. eration and impact location were then recorded. Not surprisingly, the 2. Brolinson PG, Manoogian S, McNeely D, Goforth M, Greenwald R, Duma S: college players sustained higher level impacts than the high school Analysis of linear head accelerations from collegiate football impacts. Curr players, although forces greater than 98 g were not uncommon in Sports Med Rep 5:23–28, 2006. either group. 3. Cantu R (ed): Neurologic Athletic Head and Spine Injuries. Philadelphia, WB Although the authors attempted to correlate the forces with con- Saunders & Co., 2000, p 80. cussions, the numbers were too small and the concussions described 4. Centers for Disease Control and Prevention (CDC): Sports-related recur- rent brain injuries–United States. MMWR Morb Mortal Wkly Rep 46:224– were mild. The authors correctly listed several limitations of the 227, 1997. study, including the lack of uniformity of measurement of all players, 5. Collins MW, Lovell MR, Mckeag DB: Current issues in managing sport- the absence of quantification of the actual exposure to impacts, and related concussion. JAMA 282:2283–2285, 1999. the inability to report other metrics, such as rotational acceleration or

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impact duration. Nevertheless, the study does demonstrate the tech- During the study, six players were diagnosed with concussions, two nology’s potential effectiveness, which may lead to further clinical of whom appear as illustrative cases in this article. Therefore, conclu- correlation in the future. sions are not reached regarding factors such as style of play, threshold force levels, and whether or not subconcussive impacts can be predic- Joseph C. Maroon tive. Although this study may raise more questions than answers, the Pittsburgh, Pennsylvania study is an intriguing inauguration of high technology operation in contact sports for central nervous system injury mitigation. How this chnebel et al. have performed an interesting study using football information is ultimately incorporated into sidelines and subsequent Shelmets mounted with accelerometers to analyze head impacts in medical management and its role in teaching and prevention of repet- college and high school football players. During the 2005 season, more itive concussion are yet to be determined. In addition, factors such as than 54,000 collisions were recorded and various characteristics were costs, practicality, and availability of such instrumentation will eventu- analyzed. The authors found that, although college players and those ally need to be addressed. Emerging research continues to show that holding skilled positions sustained high-impact forces more frequently sports-related, mild traumatic brain injury will continue to be a prob- than high school players and linemen, the latter also had many lem that can have both short and long-term implications, and any effort instances of high-level g forces. Impacts causing concussions ranged to diagnose and prevent these occurrences will be an advantage. The from 81 to 145 g. Previously, we thought that serious head impacts authors should be commended for their efforts to help in bringing for- would occur primarily with high velocity, open-field techniques, such ward this technology. We look forward to receiving future findings as tackling. However, these findings demonstrated that linemen from them and others in this field. undergo the highest number of impacts. Although these are usually of a relatively low magnitude (2–30 g), these players sustained an impact Julian E. Bailes greater than 98 g once in every 125 occurrences. Morgantown, West Virginia

Diagram illustrating the process of a newly synthesized polypeptide chain (beginning in the endoplas- mic reticulum) in an individual who is heterozygous for an amyloidogenic mutation. Illustration shows both normal function (normally metabolized) and mutation (misfolded molecules exhibit high propen- sity to self-aggregate). Courtesy of Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. N Engl J Med 349:583–596, 2003.

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EVALUATION AND TREATMENT OF PATIENTS WITH SUSPECTED NORMAL PRESSURE HYDROCEPHALUS ON C. Rory Goodwin, B.S. LONG-TERM WARFARIN ANTICOAGULATION THERAPY The Johns Hopkins University School of Medicine, Baltimore, Maryland OBJECTIVE: Long-term anticoagulation is often considered a contraindication to shunt surgery for elderly patients with normal pressure hydrocephalus (NPH). However, no Siddharth Kharkar, M.D., M.H.S. studies have investigated this question. Departments of Neurology and Neurosurgery, METHODS: We evaluated 25 patients who were taking warfarin for NPH between 2001 The Johns Hopkins University and 2004 with a protocol of cerebrospinal fluid (CSF) pressure monitoring and con- School of Medicine, and Adult Hydrocephalus Program, trolled CSF drainage via spinal catheter. Warfarin was stopped 5 to 7 days before lum- The Johns Hopkins Hospital, bar puncture or shunt surgery and restarted 3 to 5 days after operation or at the time of Baltimore, Maryland discharge from the hospital. Programmable shunts with antisiphon devices set at the high-pressure range were preferentially used and adjusted in small increments. Paul Wang, M.D. RESULTS: After CSF drainage, 16 patients showed improvement and 15 underwent Department of Neurosurgery, The Johns Hopkins University shunt surgery. Thirteen (87%) out of these 15 patients showed significant improvement School of Medicine, and in at least one symptom during a mean follow-up period of 8.2 months (range, 1–70 mo) Adult Hydrocephalus Program, after shunt surgery. There were two bleeding complications. One patient (6.7%) with cir- The Johns Hopkins Hospital, Baltimore, Maryland rhosis who developed a subdural hematoma 13 days after operation had the shunt removed; another patient who developed an abdominal subcutaneous hematoma 5 days Siddharth Pujari, M.D., M.P.H. after operation required surgical evacuation and shunt revision surgery. Otherwise, 14 Department of International Health, (93.3%) out of the 15 patients had no subdural hematoma during the follow-up period The Johns Hopkins University and there were no thromboembolic complications while the patients were not taking Bloomberg School of Public Health, Baltimore, Maryland warfarin. CONCLUSION: Elderly patients on long-term warfarin anticoagulation can be safely eval- Daniele Rigamonti, M.D. uated and treated for NPH using a protocol of continuous CSF drainage via spinal Department of Neurosurgery, catheter for diagnosis, cautious periprocedural management of anticoagulation, and The Johns Hopkins University use of programmable shunts with antisiphon devices. The risk of subdural hematoma School of Medicine, and Adult Hydrocephalus Program, is not higher than reported series. Long-term anticoagulation with warfarin is not a con- The Johns Hopkins Hospital, traindication per se for shunt surgery in NPH. Baltimore, Maryland KEY WORDS: Anticoagulation, Cerebrospinal fluid shunt, Complications, Diagnosis, Elderly population, Normal pressure hydrocephalus, Warfarin Michael A. Williams, M.D.

Departments of Neurology Neurosurgery 60:497–502, 2007 DOI: 10.1227/01.NEU.0000255349.71700.E1 www.neurosurgery-online.com and Neurosurgery, The Johns Hopkins University School of Medicine, and Adult Hydrocephalus Program, ormal pressure hydrocephalus (NPH) or seventh decade of life (5). Epidemiological The Johns Hopkins Hospital, is a condition characterized by gait data on NPH is limited. Its exact incidence Baltimore, Maryland Nand balance impairment, dementia, and prevalence are unknown but it is esti- Reprint requests: and urinary incontinence in the context of mated that 375,000 people in the United States Michael A. Williams, M.D., ventricular dilation with normal cerebro- with dementia may have NPH (5, 17). The Johns Hopkins University, spinal fluid (CSF) pressure (1). NPH com- Although controversy remains regarding the Adult Hydrocephalus Program, prises two groups: secondary NPH, which best method to identify the subset of patients 600 North Wolfe Street, Phipps 100, Baltimore, MD 21287. has an identifiable precipitating factor such with NPH symptoms who actually have NPH Email: [email protected] as subarachnoid hemorrhage, head trauma, and will benefit from treatment (16), there is a or meningitis, and idiopathic NPH (INPH), consensus that CSF shunt surgery is the best Received, June 14, 2006. which has no identified precipitating factor. treatment for NPH. Successful shunting can Accepted, October 18, 2006. INPH most often affects patients in the sixth result in marked improvement of all symp-

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toms of NPH, including cognition (19, 24). However, CSF before the spinal catheter insertion procedure and shunt sur- shunting carries the risk of immediate and long-term complica- gery. Warfarin administration was restarted 3 to 5 days after tions, including cerebral injury or hemorrhage at the time of operation or at the time of discharge from the hospital. surgery, shunt obstruction, infection, subdural hygroma or Depending on the risk of stopping anticoagulation, some hematoma, and shunt migration (2, 22). patients were admitted to the hospital for intravenous heparin Elderly patients with suspected NPH sometimes have comor- while the warfarin was stopped. The heparin was then stopped bid conditions such as atrial fibrillation, cardiac valvular dis- 6 to 12 hours before the procedure and restarted 24 to 48 hours eases, or deep venous thrombosis that require long-term antico- afterwards. Management of anticoagulation after hospital dis- agulation therapy. Although many would consider long-term charge was at the discretion of each patient’s cardiologist or anticoagulation to be a relative contraindication to shunt sur- primary physician and was managed according to the goals of gery for patients with NPH, no studies have investigated this therapy for the underlying disorder requiring anticoagulation. question (4). There are valid and serious concerns that the ben- efits of shunt surgery may not outweigh the risks of long-term Evaluation and Management Strategy anticoagulation for these patients. At the time of surgery, intrac- We preferentially selected adjustable shunt valves with anti- erebral hemorrhage is considered the primary risk, whereas siphon devices (Medtronic Strata, Minneapolis, MN, or delayed subdural hematoma is the major concern postopera- Codman-Hakim, Raynham, MA) with the SiphonGuard tively (4). We report the results of our experience evaluating (Codman Corp., Raynham, MA) to allow the pressure setting to and treating patients on long-term anticoagulation for NPH. be started high and gradually lowered, with the aim of prevent- ing subdural hygroma or hematoma formation while allowing PATIENTS AND METHODS symptomatic improvement. The valve setting was changed during follow-up examinations as needed until maximum Patient Selection symptomatic improvement was observed without low- pressure side effects. We retrospectively reviewed the records of 448 patients who Follow-up consisted of clinical evaluation at 3 and 6 months were evaluated and treated for NPH between 2001 and 2004 in after surgery and at longer intervals thereafter, if appropriate. the Johns Hopkins Adult Hydrocephalus Program and identi- Head computed tomographic or magnetic resonance imaging fied the records of 25 patients (5.6%) who required long-term scans were obtained as indicated. Using a standardized ques- anticoagulation with warfarin at the time of presentation. To tionnaire, patients and families were asked about change in determine the proportion of patients in the elderly general pop- gait and balance, urinary function, and cognition. Their ulation who receive a prescription for warfarin, we queried the responses were confirmed at the time of the visit, and gait and National Health and Nutrition Examination Survey for 2001 to cognitive function were assessed clinically using the Tinetti 2002 at the National Center for Health Statistics (http:// Assessment Tool and the Mini-Mental State Examination, www.cdc.gov/nchs/nhanes.htm). respectively (23, 25, 26). Improvement in cognitive function Diagnostic Protocol was defined as at least a three-point improvement in the Mini- Mental State Examination score and improvement in the We described our preoperative assessment, diagnostic crite- patient’s cognitive function from either the patient’s or the fam- ria, and treatment algorithm previously (19). Patients with ven- ily’s perspective. Improvement in urinary incontinence was triculomegaly and at least two clinical features of NPH were defined as a decrease in the incidence of urinary frequency, admitted to the hospital. A spinal catheter was inserted percu- urgency, or incontinence that was thought to improve by the taneously into the lumbar subarachnoid space for 2 days of patient or the patient’s family (often characterized by less continuous CSF pressure (Pcsf) monitoring followed by a dependence on an incontinence undergarment or pad). 3-day trial of controlled CSF drainage. Response to drainage Improvement in gait was documented by a change in the was defined as an objective improvement in gait, cognition, or Tinetti Score (23, 26) and on the basis of the patient’s and fam- urinary control. Patients were classified as having INPH and ily’s perspective, including documentation of dependence on were referred for shunt surgery only if they had either clinical assistive devices (e.g., cane, walker, or wheelchair). Symptoms improvement in symptoms during the trial of controlled CSF were classified as improved if they resulted in an improvement drainage, A- or B-waves present on continuous Pcsf monitor- in the patient’s overall quality of life. ing, or both. Treatment response to CSF drainage was defined as improvement in at least one symptom of INPH (gait impair- ment, urinary incontinence, and dementia). RESULTS

Anticoagulation Management Strategy Patient Population and Clinical Presentation With concurrence of each patient’s cardiologist or primary Nine women (36%) and 16 men (64%) with a mean age of physician, warfarin was stopped 5 to 7 days before lumbar 77.6 Ϯ 5 years at the time of presentation were included in the puncture or shunt surgery. Normal international normalized study. The indications for long-term anticoagulation were atrial ratio and activated partial thromboplastin time were confirmed fibrillation (n ϭ 18, 72%), prosthetic valves (n ϭ 5, 20%), deep

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FIGURE 1. Flow chart illustrating patient response to Pcsf monitoring and CSF drainage trial and to shunt surgery. venous thrombosis (n ϭ 1, 4%), and not ascertained (n ϭ 1, 4%). One patient with atrial fibrillation also had an abdominal aortic aneurysm and another had a previous stroke. At the time of presentation, the average daily dose of warfarin was 4.2 Ϯ 1.9 mg, and the average duration of therapy was 5.9 Ϯ 3.2 years. The dose or duration of anticoagulation therapy could FIGURE 2. Pre- and postoperative coagulation profile representing the not be ascertained retrospectively for two and nine patients, data at a single pre- and postoperative point in time for each patient. It is respectively. not meant to represent the long-term control of anticoagulation for the All 25 patients (100%) had gait impairment, 23 (92%) had cohort. INR, international normalized ratio. Dots represent outliers. urinary incontinence or urgency, and 23 (92%) had cognitive impairment. The complete NPH triad was present in 21 intraoperative bleeding complications before, during, or after patients (84%). One patient (4%) had previous shunt surgery. shunt surgery. One patient had a subdural hematoma 13 days The National Health and Nutrition Examination Survey data after shunt surgery. This patient had ascites from hepatitis C reveals that 6.0% (confidence interval, 4.6–7.4%) of the survey liver cirrhosis and was also on intravenous heparin during the ϭ participants older than 60 years (n 1872) and 8.6% (confi- transition to warfarin. The warfarin and heparin were stopped dence interval, 6.7–10.4%) of survey participants older than immediately until the prothrombin time and activated partial ϭ 70 years (n 1132) received a prescription for warfarin during thromboplastin time returned to normal levels; the shunt was the month before the survey in 2001 to 2002. removed on the second day. A second patient had a small Response to CSF Drainage and Shunt Surgery amount of blood in the occipital horn of the right lateral ventri- cle 1 day after shunt surgery, which resolved without inter- The response to CSF drainage and shunt surgery are shown vention. A third patient developed a large abdominal subcuta- in Figure 1. Of the 25 patients, nine (36%) were not referred for neous hematoma 5 days after shunt surgery. Aspiration was shunt surgery and 16 (64%), all of whom demonstrated clinical attempted; however, the hematoma reaccumulated and was, improvement after CSF drainage and eight of whom had B- therefore, surgically evacuated. A bleeding artery was found waves, were referred for shunt surgery. Pcsf monitoring was and coagulated. There were no further complications during not available for three patients. Of the 16 patients referred for the follow-up period. surgery, 15 had the surgery; 13 (87%) out of these 15 patients showed improvement in their symptoms afterwards. B-waves Shunt and Valve Setting Details were seen during Pcsf monitoring in the two patients who did Ventriculoperitoneal shunts with programmable valves were not improve after shunting. The mean duration of follow-up used for all patients except one who had a Level 1.0 Delta valve was 18.1 months (range, 1.1–70.1 mo). (Medtronic PS Medical, Goleta, CA). The median shunt setting Changes in Coagulation Profile at the time of surgery was 80 mm H2O (range, 45–150 mm H2O). Twelve (80%) out of 15 shunts had an antisiphon device. Figure 2 shows the changes in coagulation in shunted and During the course of 103 follow-up visits, there were 48 unshunted patients. The prothrombin time and international shunt setting adjustments and six shunt revision surgeries, normalized ratio were confirmed to be in the normal range one of which was for shunt removal because the patient devel- before spinal catheter insertion or shunt surgery for all patients oped a subdural hematoma and five of which were for shunt and were in the therapeutic range after shunt surgery. revision for valve or tubing obstruction. For two patients, the shunt adjustment was performed to reset the valve after a Complications magnetic resonance imaging scan. The shunt setting was low- No patients experienced thromboembolic episodes, subdural ered for 39 of the 48 patients to improve the patients’ symp- hematoma, or other bleeding complications during the CSF toms. The median decrease in shunt setting was 20 mm H2O drainage trial. There were no thromboembolic episodes or (range, 10–60 mm H2O).

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The shunt setting was increased for seven of the 48 patients, in reduction of ventricular CSF volume and compensatory with a median increase of 30 mm H2O (range, 20–170 mm increase in the subarachnoid CSF volume with widening of H2O). Of these, six increases were performed in response to low the subarachnoid space. Although it is often thought that the pressure symptoms. One patient’s shunt setting was increased presence of SDE is a risk factor for developing subdural to its highest setting, an increase of 170 mm H2O, because the hematomas, this relationship has not been established (4). patient had no clinical improvement despite gradually lower- Nonetheless, it stands to reason that if widening of the sub- ing the shunt setting to 30 mm H2O during 14 months, and it arachnoid space with associated stretching or tearing of the was decided that the risk of a subdural hematoma was greater bridging veins is the cause of chronic subdural hematomas in than the possibility of clinical improvement. the elderly without shunts (7, 15), this same mechanism may be responsible for the development of subdural hematomas in DISCUSSION shunted NPH patients. It is not known whether or not the outcome of chronic subdural hematoma in shunted NPH Our results demonstrate that patients on long-term war- patients differs with or without long-term anticoagulation. A farin anticoagulation therapy can be safely and successfully retrospective study from Nottingham, England suggests that evaluated and treated for NPH. With careful management of there is a relationship between the use of anticoagulation and warfarin anticoagulation therapy and monitoring of the coag- the development of chronic subdural hematomas. However, ulation profile and selection of patients on the basis of the outcome was no worse for patients taking anticoagulants response to a trial of controlled CSF drainage and use of in comparison with those who were not (8). In a retrospective adjustable shunts, the risk of thromboembolic or bleeding series of 1000 patients of all ages with traumatic or atrau- complications is low. When patients were not taking anticoag- matic chronic subdural hematomas in Santiago de ulation therapy, there were neither thromboembolic nor Compostela, Spain, 12.2% were receiving anticoagulation bleeding complications during the CSF drainage trial or at therapy and only 0.6% had a shunt (10). Thus, it is plausible the time of shunt surgery. A single patient had a postoperative that long-term anticoagulation increases the risk of subdural subdural hematoma in the setting of cirrhosis and administra- hematomas in patients with shunts. tion of both warfarin and intravenous heparin; his shunt was Therefore, caution in diagnosing patients who require long- removed and was not reinserted. term anticoagulation with NPH and treating them with shunt The incidence of subdural hematomas after shunting for surgery is well warranted. Ideally, it should be known before INPH is variable, ranging from 2 to 17% (3, 11–14, 20, 21). The shunt surgery that the shunt will benefit the individual patient; 6.7% incidence of subdural hematoma in our series is not sta- therefore, the diagnostic approach is critical. In this series, 13 of tistically different from the 2% rate we reported previously for the 15 patients who improved with CSF drainage also showed a cohort of 132 patients with 179 shunt operations (19) (P ϭ 0.6, improvement after shunt surgery (positive predictive value, χ2 test). The prospective, controlled Dutch NPH study of 96 87%), which compares with our previously published study shunted patients who had a 1-year follow-up period reported (positive predictive value, 75%) (19) and the 90.5% positive subdural effusions (SDE) in 53% of the patients. Of these, 39% predictive value in Marmarou et al.’s (18) recently published resolved spontaneously and 61% were persistent (6). The study series. The reason for the difference in the rates in our two did not report the number of subdural hematomas per se; how- studies is unclear; however, it is reasonable to suggest that our ever, it was described that the majority of SDEs were hypo- clinical decision making was biased to be more conservative for dense, that some contained hyperdense portions, and only a anticoagulated patients in comparison with the overall NPH few were fully hyperdense. Of the 31 patients with persistent population. SDE, eight (25.8%) required surgical therapy, resulting in a In fact, the goal of carefully evaluating these patients is not cohort rate of eight (8.3%) out of 96. only to prevent the burden of complications for patients who We think the strategy of regular clinical evaluation after might be shunted when they should not be, but also to prevent shunt surgery to identify signs of overshunting with the use of the burden of NPH symptoms and impairment for patients adjustable valves to lower the shunt setting gradually in small who should be shunted when they have not been. The success- increments was responsible for the fact that we observed no ful treatment of NPH has tremendous benefits and results in long-term bleeding complications. Zemack and Romner (27) improvement of all symptoms, including cognition (9, 20, 24). found 15 (6.6%) nontraumatic subdural hematomas or SDEs in Patients frequently comment that the treatment has given them a combined INPH and secondary NPH cohort of 228 patients their lives back. treated with adjustable valves. Of these 15 patients, 10 (66.6%) The demonstration of clinical improvement with a trial of were managed conservatively with no treatment other than controlled CSF drainage has the distinct advantage of demon- adjusting the valve setting higher and five (33.3%) required strating not only to the patient, but also to the physician, surgical evacuation (27). It is likely that our management strat- whether or not there is sufficient benefit from CSF drainage to egy was biased to be more conservative because our patients offset the long-term risk of subdural hematoma after shunt sur- were taking anticoagulation therapy. gery (i.e., a favorable risk-to-benefit ratio). Of course, patients The risk factor for development of SDEs after shunt surgery and their families should be counseled carefully regarding is thought to be overdrainage of CSF via the shunt, resulting these risks not only as part of the informed consent process for

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surgery, but also at every follow-up visit because the risk 5. Black PM, Ojemann RG, Tzouras A: CSF shunts for dementia, incontinence, remains present as long as they have a shunt and are not tak- and gait disturbance. Clin Neurosurg 32:632–651, 1985. ing anticoagulants. 6. Boon AJ, Tans JT, Delwel EJ, Egeler-Peerdeman SM, Hanlo PW, Wurzer HA, Avezaat CJ, de Jong DA, Gooskens RH, Hermans J: Dutch Normal-Pressure Without perioperative modification of anticoagulation, the Hydrocephalus Study: Randomized comparison of low- and medium- risk of operative complications in these patients might be pressure shunts. J Neurosurg 88:490–495, 1998. higher than expected (4). In fact, it is easily argued that surgery 7. Cardoso ER, Del Bigio MR, Schroeder G: Age-dependent changes of cerebral could not be performed unless anticoagulation is stopped. ventricular size. Part I: Review of intracranial fluid collections. Acta Neurochir (Wien) 97:40–46, 1989. However, stopping anticoagulation might increase the risk of 8. Diamond T, Gray WJ, Chee CP, Fannin TF: Subdural haematoma associated thromboembolic episodes. It has been suggested that anticoag- with long term oral anticoagulation. Br J Neurosurg 2:351–355, 1988. ulation should not be restarted immediately after surgery (4). 9. Duinkerke A, Williams MA, Rigamonti D, Hillis AE: Cognitive recovery in Our experience suggests that restarting warfarin anticoagula- idiopathic normal pressure hydrocephalus after shunt. Cogn Behav Neurol 17:179–184, 2004. tion therapy by the time of discharge from the hospital is a 10. Gelabert-Gonzalez M, Iglesias-Pais M, Garcia-Allut A, Martinez-Rumbo R: safe management strategy. Chronic subdural haematoma: Surgical treatment and outcome in 1000 cases. There are limitations to our study. It is retrospective and lim- Clin Neurol Neurosurg 107:223–229, 2005. ited to a convenience sample drawn from a tertiary referral cen- 11. Greenberg JO, Shenkin HA, Adam R: Idiopathic normal pressure hydro- J Neurol Neurosurg Psychiatry ter for adult hydrocephalus. Between 2001 and 2004, the num- cephalus—A report of 73 patients. 40: 336–341, 1977. ber of patients with suspected NPH who were taking chronic 12. Hughes CP, Siegel BA, Coxe WS, Gado MH, Grubb RL, Coleman RE, Berg L: warfarin anticoagulation was 25 (5.6%) out of 448, which is sim- Adult idiopathic communicating hydrocephalus with and without shunting. ilar to the percentage of patients in the National Health and J Neurol Neurosurg Psychiatry 41:961–971, 1978. Nutrition Examination Survey survey who received a prescrip- 13. Krauss JK, Droste DW, Vach W, Regel JP, Orszagh M, Borremans JJ, Tietz A, Seeger W: Cerebrospinal fluid shunting in idiopathic normal-pressure hydro- tion for warfarin and were older than 60 (6.0%) or 70 (8.6%) cephalus of the elderly: Effect of periventricular and deep white matter years old. Thus, it seems that this convenience sample approx- lesions. Neurosurgery 39:292–300, 1996. imates the general population in regard to use of long-term 14. Malm J, Kristensen B, Karlsson T, Fagerlund M, Elfverson J, Ekstedt J: The warfarin anticoagulation. In this study, the duration of the predictive value of cerebrospinal fluid dynamic tests in patients with idio- pathic adult hydrocephalus syndrome. Arch Neurol 52:783–789, 1995. follow-up period was not equal in all patients; the minimum 15. Markwalder TM: Chronic subdural hematomas: A review. J Neurosurg follow-up duration in the shunted patients was 1 month after 54:637–645, 1981. the shunt surgery. 16. Marmarou A, Bergsneider M, Klinge P, Relkin N, Black PM: The value of sup- In conclusion, elderly patients receiving long-term warfarin plemental prognostic tests for the preoperative assessment of idiopathic normal-pressure hydrocephalus. Neurosurgery 57 [Suppl 3]:S17–S28, ii–v, anticoagulation can be safely evaluated and treated for NPH 2005. using a protocol of continuous CSF drainage via spinal catheter 17. Marmarou A, Bergsneider M, Relkin N, Klinge P, Black PM: Development of for diagnosis, cautious periprocedural management of antico- guidelines for idiopathic normal-pressure hydrocephalus: Introduction. agulation, and the use of programmable ventriculoperitoneal Neurosurgery 57 [Suppl 3]:S1–S3, ii–v, 2005. 18. Marmarou A, Young HF, Aygok GA, Sawauchi S, Tsuji O, Yamamoto T, shunts with antisiphon devices that are initially set at a high- Dunbar J: Diagnosis and management of idiopathic normal-pressure hydro- pressure setting and gradually lowered in small increments. cephalus: A prospective study in 151 patients. J Neurosurg 102:987–997, 2005. These patients gain the same benefit from accurate diagnosis 19. McGirt MJ, Woodworth G, Coon AL, Thomas G, Williams MA, Rigamonti D: and CSF shunting as other patients with NPH. Long-term anti- Diagnosis, treatment, and analysis of long-term outcomes in idiopathic coagulation with warfarin is not a contraindication for shunt normal-pressure hydrocephalus. Neurosurgery 57:699–705, 2005. 20. Raftopoulos C, Deleval J, Chaskis C, Leonard A, Cantraine F, Desmyttere F, surgery in NPH per se. Clarysse S, Brotchi J: Cognitive recovery in idiopathic normal pressure hydro- cephalus: A prospective study. Neurosurgery 35:397–405, 1994. Disclosures 21. Raftopoulos C, Massager N, Baleriaux D, Deleval J, Clarysse S, Brotchi J: Prospective analysis by computed tomography and long-term outcome of This study was supported by grants from Medtronic Corporation and from 23 adult patients with chronic idiopathic hydrocephalus. Neurosurgery the Schoendorf Foundation. 38:51–59, 1996. 22. Samuelson S, Long DM, Chou SN: Subdural hematoma as a complication of shunting procedures for normal pressure hydrocephalus. J Neurosurg REFERENCES 37:548–551, 1972. 23. Shore WS, deLateur BJ, Kuhlemeier KV, Imteyaz H, Rose G, Williams MA: A 1. Adams RD, Fisher CM, Hakim S, Ojemann RG, Sweet WH: Symptomatic comparison of gait assessment methods: Tinetti and GAITRite electronic occult hdrocepalus with “normal” cerebrospinal-fluid pressure. A treatable walkway. J Am Geriatr Soc 53:2044–2045, 2005. syndrome. N Engl J Med 273:117–126, 1965. 24. Thomas G, McGirt MJ, Woodworth G, Heidler J, Rigamonti D, Hillis AE, 2. Aoki N: Lumboperitoneal shunt: Clinical applications, complications, and Williams MA: Baseline neuropsychological profile and cognitive response to comparison with ventriculoperitoneal shunt. Neurosurgery 26:998–1004, cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus. 1990. Dement Geriatr Cogn Disord 20:163–168, 2005. 3. Benzel EC, Pelletier AL, Levy PG: Communicating hydrocephalus in adults: 25. Tinetti ME: Performance-oriented assessment of mobility problems in elderly Prediction of outcome after ventricular shunting procedures. Neurosurgery patients. J Am Geriatr Soc 34:119–126, 1986. 26:655–660, 1990. 26. Tombaugh TN, McIntyre NJ: The mini-mental state examination: A compre- 4. Bergsneider M, Black PM, Klinge P, Marmarou A, Relkin N: Surgical manage- hensive review. J Am Geriatr Soc 40:922–935, 1992. ment of idiopathic normal-pressure hydrocephalus. Neurosurgery 57 27. Zemack G, Romner B: Adjustable valves in normal-pressure hydrocephalus: [Suppl 3]:ii–v, S29–S39, 2005. A retrospective study of 218 patients. Neurosurgery 51:1392–1402, 2002.

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COMMENTS It should be noted that this study was limited to the anticoagulant warfarin. Similar analyses will be required to determine the safety of his study is an important contribution to the adult hydrocephalus other blood thinning medications, including the antiplatelet agent Tmanagement literature. With our aging population, more patients clopidogrel (Plavix; Bristol-Myers Squibb/Sanofi Pharmaceuticals, requiring chronic anticoagulation will be diagnosed with hydro- New York, NY). Although our experience with patients on warfarin is cephalus and, therefore, require treatment with cerebrospinal fluid similar to those of this study, we have experienced a relatively high shunts. This study demonstrates that if the international normalized complication rate of subdural hematomas with NPH patients placed on ratio is controlled, the subdural hematoma complication rate can be both clopidogrel and aspirin. acceptably low after a cerebrospinal fluid shunt for normal pressure Marvin Bergsneider hydrocephalus (NPH). I think it is important to note that the postoper- Los Angeles, California ative management algorithm used a programmable valve that was ini- tially set at a high pressure setting. Beginning with lower pressure set- already thought that long term anticoagulation was not a contraindi- tings, even with antisiphon devices, would likely have resulted in a I cation for shunt surgery in NPH. When asked if the management of greater number of subdural hematomas. such patients was associated with an increased risk of developing a This study primarily pertains to the risk of spontaneous subdural SDH after a shunting procedure, I answered positively and said that hematoma. My experience is that the risk of traumatic subdural the risk is lower than 10%. Now, based on the precisely reported expe- hematoma, even after very minor injury, is higher with patients on anti- rience of Goodwin et al. with a series of 25 patients, we learn that NPH coagulation therapy. Personally, I advise this group of patients and their patients on warfarin have a 6.7% risk of developing a subdural families that they should have a low threshold for seeking medical atten- hematoma after the implantation of a programmable valve with an tion involving any injury to the head, even after a seemingly minor fall. antisiphon device, having stopped warfarin at least 5 days before the The second key finding the authors report is that anticoagulation can shunt surgery and restarted anticoagulation not less than 3 days post- safely begin as early as 4 days after surgery. The question of when to operatively. This study will serve as a reference for neurosurgeons to reinitiate anticoagulation therapy is often a major issue, especially for assess the risk of this type of complication and inform their patients. patients with prosthetic heart valves. Our institution has traditionally withheld full anticoagulation for at least 7 days after surgery. Based on Christian Raftopoulos this study, we will now change our protocol for selected patients. Brussels, Belgium

Diagram illustrating the kinetics involved with amyloid fibril formation. Conditions in the formation of amyloid fibrils (blue line) initially, do not favor aggregation (lag phase) however, once a critical nucleus is created the environ- ment favors aggregation with increased kinetics. Red line illustrates a similar sit- uation with a shorter lag time due to the addition of preformed fibrils to existing amyloid fibrils. Courtesy of Merlini G, Bellotti V: Molecular mechanisms of amy- loidosis. N Engl J Med 349:583–596, 2003. CLINICAL STUDIES

MINIMALLY INVASIVE LUMBAR SPINAL David S. Rosen, M.D. DECOMPRESSION IN THE ELDERLY: OUTCOMES OF Section of Neurosurgery, Department of Surgery, 50 PATIENTS AGED 75 YEARS AND OLDER University of Chicago Medical Center and Pritzker School of Medicine, Chicago, Illinois OBJECTIVE: Lumbar spinal stenosis and spondylosis are major causes of morbidity among the elderly. Surgical decompression is an effective treatment, but many elderly John E. O’Toole, M.D. patients are not considered as candidates for surgery based on age or comorbidities. Department of Neurosurgery, Rush University Medical Center, Minimally invasive surgical techniques have recently been developed and used suc- Chicago, Illinois cessfully for the treatment of lumbar spinal disease. Our objective was to examine the safety and efficacy of minimally invasive lumbar spinal surgery for elderly patients. Kurt M. Eichholz, M.D. METHODS: We reviewed demographic information, pre- and postoperative Visual Department of Neurosurgery, Analog Scale pain scores, Oswestry Disability Index scores, and Short-Form 36 scores Vanderbilt University Medical Center, Nashville, Tennessee of prospectively accrued patients who underwent minimally invasive decompression of lumbar degenerative disease at two institutions between January 2002 and December Melody Hrubes, B.S. 2005. Data from patients who were at least 75 years old were selected. Statistical analy- Section of Neurosurgery, sis methods included paired t test, multiple linear regression, and linear mixed effects Department of Surgery, modeling. University of Chicago Medical Center and Pritzker School of Medicine, RESULTS: Fifty-seven patients with a mean age of 81 years met the study criteria (median Chicago, Illinois follow-up period, 7 mo; mean follow-up period, 10 mo). No major complications or deaths occurred. Fifty patients had sufficient outcomes data for analysis. Visual Analog Scale Dezheng Huo, M.D., Ph.D. pain scores decreased from 5.7 to 2.2 for back pain and from 5.7 to 2.3 for sympto- Section of Neurosurgery, matic leg pain (P Ͻ 0.05). Oswestry Disability Index scores decreased from 48 to 27; Department of Health Studies, University of Chicago Medical Center Short-Form 36 Body Pain and Physical Function scores also showed statistically signif- and Pritzker School of Medicine, icant improvements after surgery (P Ͻ 0.05). The longitudinal analysis demonstrated Chicago, Illinois durability of the symptom relief.

Faheem A. Sandhu, M.D., CONCLUSION: Minimally invasive lumbar spine decompression is a safe and effica- Ph.D. cious treatment for elderly patients with spinal stenosis and spondylosis. Elderly patients Department of Neurosurgery, should be considered good candidates for lumbar surgical decompression using min- Georgetown University, imally invasive techniques. Washington, D.C. KEY WORDS: Elderly, Lumbar spine, Minimally invasive surgery, Outcomes, Spinal stenosis, Spondylosis

Richard G. Fessler, M.D., Ph.D. Neurosurgery 60:503–510, 2007 DOI: 10.1227/01.NEU.0000255332.87909.58 www.neurosurgery-online.com Section of Neurosurgery, Department of Surgery, University of Chicago Medical Center and Pritzker School of Medicine, egenerative spine disease leading to many elderly patients are not considered can- Chicago, Illinois lumbar stenosis and spondylosis is a didates for surgery because of age, comorbidi- major cause of morbidity among the ties, or, in some cases, subjective impressions Reprint requests: D elderly (24). Although clinical symptoms can of a patient’s fitness for surgery. David S. Rosen, M.D., University of Chicago Hospital, be variable (5), this age-related, progressive Minimally invasive techniques have recently Section of Neurosurgery, disease causes chronic pain and functional been developed for the surgical treatment of 5841 South Maryland Avenue, impairment, resulting in limitations of mobility lumbar spinal disease (1, 17, 19). These tech- MC 3026, and of the ability to perform activities of daily niques differ from commonly used “open” Chicago, IL 60637. Email: [email protected]. living (11). Surgical treatment of spinal stenosis procedures by making smaller skin incisions, uchicago.edu has been used with increasing frequency (6, 16, using a tubular muscle retractor, and sparing 18). Long-term studies have demonstrated the posterior ligamentous and muscle com- Received, June 13, 2006. superior outcomes for surgery compared with plexes. Several reports suggest that minimally Accepted, November 10, 2006. conservative management (2, 4). However, invasive spine surgery techniques are associ-

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ated with less surgical stress, less postoperative pain, shorter hospital stays, and lower complication rates (8, 17, 19). TABLE 1. Characteristics of 57 patients aged 75 years and older The goal of this study was to examine the safety and efficacy undergoing lumbar spine decompressiona of minimally invasive spine surgery for decompression of lum- Demographic bar degenerative disease in elderly patients using validated out- Mean age (range) 80.8 yr (75–97 yr) come measures, including Visual Analog Scale (VAS) pain scores, No. of men 35 (61%) Oswestry Disability Index (ODI), and Short-Form 36 (SF-36). Median length of stay (range) 29 h (range, 5–216 h) Surgical level PATIENTS AND METHODS Single level 40 L2–L3 4 We conducted an analysis of prospectively maintained L3–L4 6 patient databases from two institutions. The databases contain L4–L5 28 patient demographic, surgical, and complication data as well as L5–S1 2 pre- and postoperative outcome scores. The primary study end- Multilevel 17 points were changes in VAS, ODI, and SF-36 scores, length of L2–L4 1 hospitalization, and perioperative complications. The outcome L2–L5 1 instruments were administered in a standard written format L3–L5 12 during clinic visits. The surgical team was not blinded to the L4–S1 3 results of the outcome measures. The databases were searched Side of approach for the above information on patients undergoing spine sur- Right 29 gery between January 2002 and December 2005. Left 27 All operations were performed by one of the senior authors Bilateral 1 (RGF or FAS). Inclusion criteria for this study included age Type of procedure older than 75 years and undergoing minimally invasive decom- MEDS 42 MED 3 pression of lumbar degenerative conditions via the techniques MEF 10 described previously (1, 17, 19). To maintain homogeneity of MED and MEF 1 the data set, patients undergoing decompression for malig- MEDS and resection of a synovial cyst 1 nancy and decompression with instrumented fusion were excluded. Medical records were reviewed to identify complica- a MEDS, microendoscopic decompression of stenosis; MED, microendoscopic tions and the duration of inpatient hospital stay. discectomy; MEF, microendoscopic foraminotomy. Pre- and postoperative VAS pain score, ODI, and SF-36 qual- ity of life indices were compared using paired t tests and con- author (RGF) and 11 patients by another (FAS). The mean patient firmed by nonparametric Wilcoxon signed-rank tests. For age was 80.8 years (range, 75–97 yr); 61% were men. The median patients who had multiple postoperative sets of outcome length of inpatient hospitalization was 29 hours (mean, 53 h; scores, the last set of outcome scores, i.e., the longest duration range, 5–216 h). Neither age nor type of operation was associated of follow-up, was used. Multiple linear regression analysis was with a significant difference in the length of hospitalization. performed to explore factors related to pre- and postoperative Patients undergoing microendoscopic decompression of stenosis changes in outcome scores. Four demographic and clinical fac- had bilateral decompression from a unilateral paramedian tors were examined individually as potential correlates in the approach; those undergoing microendoscopic discectomy or univariate analysis; these included age (continuous or Ն80 yr microendoscopic foraminotomy had a unilateral decompression versus Ͻ80 yr), side of approach, surgical level, and type of from a paramedian approach. Table 1 includes the spinal levels procedure. Variables with P values less than 0.1 in univariate and types of procedures performed. Table 2 contains the preva- analysis were entered in multiple linear regressions with a lence of comorbidities in this cohort of elderly patients. backwards selection procedure. To examine the durability of Pre- and postoperative data was available for outcome analy- postoperative changes in the outcome scores, a longitudinal sis of 50 patients. The median duration of the follow-up period analysis was undertaken with mixed effects linear models, was 7 months (mean, 10 mo; range, 1.3–34 mo). Table 3 indicates which took intrapatient correlation into account. A linear func- the mean outcome scores measured before surgery and at the tion or piecewise linear function with a knot was used at 3 time of the last follow-up visit, as well as the mean changes. months to describe the change in outcome measures with time. P values from paired t tests are presented, all of which were A P value less than 0.05 was considered statistically significant. confirmed by Wilcoxon signed-rank tests. The mean back VAS pain score was 5.7 before surgery and decreased to 2.2 after sur- RESULTS gery (P Ͻ 0.001). Forty patients (80%) decreased, eight patients (16%) increased, and two patients (4%) had no change in back Between 2002 and 2005, 57 patients who were at least 75 years VAS pain scores. Thirty-eight percent of patients were com- of age underwent minimally invasive lumbar spine decompres- pletely free of back pain after surgery. For the analysis of VAS sion surgery. Forty-six patients were operated on by one senior leg pain scores, the leg ipsilateral to the approach was consid-

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analysis. Patients older than 80 years of age showed greater TABLE 2. Prevalence of medical comorbidities in a cohort of eld- improvements in the leg VAS pain score and ODI than younger erly patients undergoing lumbar spine decompression surgery patients. Patients undergoing single-level surgery had greater Condition Percent of patients improvements in the back VAS pain score, ODI, and SF-36 Bodily Pain score. Patients undergoing microendoscopic Heart disease 33% decompression of stenosis had greater improvements than Atrial fibrillation 16% patients undergoing microendoscopic foraminotomy. Hypertension 67% The results of the longitudinal analysis indicate that the postop- Peripheral vascular disease 7% Pulmonary disease 14% erative improvements were long lasting. Figure 1 contains a Gastrointestinal disease 35% graphic representation of the longitudinal analysis. The VAS back Genitourinary disease 16% pain score decreased 0.82 units per month for the first 3 months ϭ Endocrinological disease 26% (P 0.003) and had no statistically significant change after Diabetes 7% 3 months. The symptomatic leg VAS pain score decreased 0.83 ϭ Osteoarthritis 40% units per months for the first 3 months (P 0.005) and the con- History of cancer 21% tralateral leg VAS pain score decreased 0.53 units per month (P ϭ Psychiatric disease 14% 0.03) for the first 3 months. There was no statistically significant History of cerebrovascular event 12% change in the outcome scores after 3 months. The ODI decreased Dementia 5% 5.1 units per months for the first 3 months (P Ͻ 0.001) and had vir- tually no change after 3 months. Both the SF-36 Physical Function score and Bodily Pain score improved during the first 3 months ered the symptomatic leg. The symptomatic leg improved from and did not have a statistically significant change after 3 months. 5.7 before surgery to 2.3 after surgery (P Ͻ 0.001). The con- There was a marginally significant decreasing trend in SF-36 tralateral leg had a lower preoperative VAS pain score of 2.4 General Health score (decrease, 0.61 units/mo; P ϭ 0.05), which and improved to 1.1 after surgery (P ϭ 0.02). The single patient may reflect the aging of the study cohort. who underwent bilateral approaches showed improvement in Table 5 indicates the complications experienced in this series. both legs. Overall, 40% of patients reported that they were free No major complications or perioperative deaths occurred, of pain in their legs after surgery. although one patient died of pneumonia 8 months after sur- Forty-nine patients had pre- and postoperative ODIs. The gery. There were no wound infections. The most common com- mean ODI was 48 before surgery and improved significantly to plications were urinary retention and transient delirium, which 27 after surgery (P Ͻ 0.001). The mean SF-36 Physical Function were typically associated with postoperative narcotic use. score was 26 before surgery and increased to 48 after surgery During the follow-up period, one patient required a second (P Ͻ 0.001). Of the 37 patients with pre- and postoperative SF- lumbar spine operation for additional decompression of steno- 36 Physical Function scores available, 27 scores increased, six sis on the contralateral side and underwent a third operation scores decreased, and four scores did not change. The mean for instrumented fusion at the level of the decompression preoperative SF-36 Bodily Pain score was 28 and increased to 54 5 months after the initial surgery. after surgery (P Ͻ 0.001), with 26 scores increasing, five scores decreasing, and four scores remaining constant. The SF-36 DISCUSSION General Health score was not significantly changed among the 24 patients who had both pre- and postoperative measurement. The results of this study demonstrate that minimally inva- Table 4 contains the results of the multiple linear regression sive lumbar decompressive surgery can be an effective treat-

TABLE 3. Self-reported outcomes for patients aged 75 and older undergoing minimally invasive lumbar spine decompression surgerya Preoperative score Postoperative score Change No. of patients P value mean (SD) Visual Analog Scale pain score Back 50 5.7 (3.4) 2.2 (2.4) –3.5 (4.0) Ͻ0.001 Symptomatic leg 49 5.7 (3.7) 2.3 (2.8) –3.4 (4.5) Ͻ0.001 Contralateral leg 49 2.4 (3.1) 1.4 (2.5) –1.1 (3.1) 0.02 Oswestry Disability Index 49 48 (20) 27 (19) –21 (25) Ͻ0.001 Short-Form 36 Physical function 37 26 (17) 48 (27) 22 (27) Ͻ0.001 Body pain 35 28 (19) 54 (29) 26 (33) Ͻ0.001 General health 24 66 (24) 63 (26) –3 (24) 0.45

a SD, standard deviation.

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TABLE 4. Factors related to self-report outcomes in univariate and multiple linear regression analysis of elderly patients undergoing minimally inva- sive lumbar spine decompression surgerya No. of Preoperative Postoperative Change P Regression P patients (mean ؎ SD) (mean ؎ SD) (95% CI) value coefficientb value VAS back pain score Surgical level Ͻ0.001 Ͻ0.001 Single level 34 6.4 (3.4) 1.6 (1.8) –4.8 (–6.0, –3.6) –4.1 Multilevel 16 4.2 (3.0) 3.6 (3.0) –0.7 (–2.6, 1.2) VAS symptomatic leg pain score Age 0.007 0.007 Ͻ80 yr 25 4.7 (3.8) 3.0 (2.7) –1.8 (–3.7, 0.1) Ն80 yr 24 6.7 (3.5) 1.5 (2.7) –5.2 (–6.8, –3.6) –3.4 Type of procedure 0.03 MEDS 36 5.5 (3.9) 1.7 (2.5) –3.9 (–5.3, –2.5) MEF 8 5.1 (4.0) 5.0 (2.7) –0.1 (–4.7, 4.5) Oswestry Disability Index Age 0.01 Ͻ80 yr 25 42 (19) 29 (19) –13 (–21, –4) Ն80 yr 24 54 (20) 24 (19) –30 (–41, –19) Side of approach 0.002 0.006 Left 22 51 (23) 18 (16) –33 (–44, –22) –18 Right 26 45 (18) 34 (18) –11 (–19, –3) Type of procedure 0.05 MEDS 35 51 (21) 26 (18) –25 (–34, –16) MEF 9 42 (19) 36 (17) –6 (–22, 10) Surgical level 0.001 0.002 Single level 33 50 (20) 21 (16) –29 (–38, –21) –21 Multilevel 16 44 (21) 40 (17) –4 (–14, 5) SF-36: Physical function Side of approach 0.02 0.02 Left 16 22 (13) 56 (27) 34 (19, 49) 22 Right 20 30 (19) 43 (26) 13 (2, 23) SF-36: Body pain Side of approach 0.04 0.15 Left 16 21 (18) 59 (28) 39 (23, 54) 18 Right 18 33 (19) 48 (30) 15 (–2, 32) Surgical level 0.06 0.20 Single level 22 22 (16) 56 (30) 34 (19, 50) 16. Multilevel 13 37 (21) 49 (28) 12 (–4, 28)

a SD, standard deviation; CI, confidence interval; VAS, Visual Analog Scale; MEDS, microendoscopic decompression of stenosis; MEF, microendoscopic foraminotomy; SF-36, Short-Form 36 questionnaire. b Regression coefficients from multiple linear regressions. For models with one clinical factor, the regression coefficient is just the difference in the changing scores. For models with multiple clinical factors, the regression coefficients are the adjusted differences in the changing scores. ment for elderly patients with lumbar spondylosis and spinal correlation between patient age and outcome (3, 7, 9, 10, 12, 16, stenosis. VAS, ODI, and SF-36 Bodily Pain scores demonstrate 20, 21, 23). Arinzon et al. (3) compared 179 patients aged 65 to significant improvements after surgery and the SF-36 Physical 74 years with 104 patients who were 75 years of age or older Function score improved for most patients. To the authors’ and failed to find a correlation between age and outcome. The knowledge, the present study is the first reported large series of multiple linear regression analysis in the present study found elderly patients with lumbar spondylotic disease undergoing that patients older than 80 years of age had greater improve- surgical decompression using minimally invasive techniques. ments in symptoms after surgery than younger patients. The Comparison of these results with previous studies of lumbar reasons for this finding are unclear, but the severity of disease spine surgery in elderly patients is difficult because many and symptoms at the time of surgery may be more important reports group simple decompression and decompression with than age in predicting response to treatment. fusion patients together and use disparate outcome measures, Several investigations have likewise failed to find a correla- lengths of follow-up periods, and age ranges. tion between age and the likelihood of complications (3, 20, Development of lumbar spinal stenosis and aging are related. 22). However, Deyo et al. (7) reviewed 18,122 hospitalizations Not surprisingly, previous investigations have examined the for lumbar spine surgery between 1986 and 1988 and found

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A B

C D

FIGURE 1. Longitudinal modeling analyses of changes in self-reported out- come measures for VAS Back Pain (A), VAS Leg Pain (B), SF-36 Body Pain E (C), SF-36 Physical Function (D), and Oswestry Disability Index (E). that age positively correlated with the complication rate. They reported an overall complication rate of 18% for patients older than 75 years of age. However, their method for identifying complications using a hospital discharge registry may be less sensitive than chart review. Other series have reported compli- cation rates ranging from 20 to 47% (3, 9, 20). Although not demonstrated by our noncontrolled study, we think smaller skin incisions, less anatomic tissue damage, shorter recumbent periods, shorter recovery times, and a more rapid return to nor- mal activities contribute to lower complication rates for mini- mally invasive lumbar spine surgery. The present series did not include any perioperative deaths, but several series have found higher perioperative mortality rates in older patients (6, 7, 14). Jansson et al. (14) reviewed case fatality rates had fallen between the mid 1980s and 2000. 10,494 patients who underwent surgery for spinal stenosis in On the basis of these low case fatality rates, our small sample Sweden between 1987 and 1999 and reported an overall 30-day size does not have the power to identify the impact of mini- case fatality rate of 3.5 per 1000 operations. The case fatality mally invasive spine surgery techniques on the fatality rate. rate increased to 5.6 for patients aged 75 to 79 years and 15.8 for For many patients, spinal stenosis is a progressive disease patients older than 80 years of age. However, they did find that and may require repeat surgery for further decompression. In

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The present study demonstrates that minimally invasive TABLE 5. Complications of lumbar decompression surgery for 57 decompression of lumbar spondylotic disease in elderly patients patients aged 75 years and older may be an efficacious treatment associated with short durations Complication No. of patients of inpatient hospitalization and acceptable complication rates. Patients who were previously not considered eligible for lumbar Urinary retention 6 spinal surgery may be given access to this treatment. Moreover, Transient delirium 5 patients with realistic expectations for surgery are more likely to Unintentional durotomy 3 be satisfied (10). Our results may help surgeons better under- Fever 3 stand and counsel elderly patients about the outcomes of min- Urinary tract infection 2 imally invasive lumbar spine decompressive surgery. Atrial fibrillation 1 Constipation 1 Pneumonia 1 REFERENCES

1. Ahn Y, Lee SH, Park WM, Lee HY: Posterolateral percutaneous endoscopic lumbar foraminotomy for L5-S1 foraminal or lateral exit zone stenosis. addition, surgical decompression of spinal stenosis can cause or Technical note. J Neurosurg 99:320–323, 2003. exacerbate spinal instability, necessitating another operation 2. Amundsen T, Weber H, Nordal HJ, Magnaes B, Abdelnoor M, Lilleas F: for fusion (13). Minimally invasive techniques may reduce the Lumbar spinal stenosis: Conservative or surgical management?: A prospec- tive 10-year study. Spine 25:1424–1436, 2000. likelihood of these phenomena by maintaining the anatomic 3. Arinzon ZH, Fredman B, Zohar E, Shabat S, Feldman JS, Jedeikin R, Gepstein integrity of more of the posterior spinal elements than open RJ: Surgical management of spinal stenosis: A comparison of immediate and surgery. The reoperation rate in our series was 2%. A review of long term outcome in two geriatric patient populations. Arch Gerontol 9664 patients who underwent open spinal stenosis surgery in Geriatr 36:273–279, 2003. 4. Atlas SJ, Keller RB, Wu YA, Deyo RA, Singer DE: Long-term outcomes of sur- Sweden indicated a 2-year reoperation rate of 5% (15). gical and nonsurgical management of lumbar spinal stenosis: 8 to 10 year However, the 10-year reoperation rate was 11%; therefore, a results from the Maine lumbar spine study. Spine 30:936–943, 2005. longer follow-up duration is necessary to determine the over- 5. Benoist M: The natural history of lumbar degenerative spinal stenosis. Joint all likelihood of reoperation for elderly patients undergoing Bone Spine 69:450–457, 2002. minimally invasive spinal decompression. 6. Ciol MA, Deyo RA, Howell E, Kreif S: An assessment of surgery for spinal stenosis: Time trends, geographic variations, complications, and reoperations. The median length of hospitalization in the present series was J Am Geriatr Soc 44:285–290, 1996. 29 hours, which compares favorably with previously reported 7. Deyo RA, Cherkin DC, Loeser JD, Bigos SJ, Ciol MA: Morbidity and mortal- “open” series in which the length of stay varied from 3.9 to 11.6 ity in association with operations on the lumbar spine. The influence of age, days (9, 16, 20, 23). The shorter length of stay may be a result of diagnosis, and procedure. J Bone Joint Surg Am 74:536–543, 1992. 8. Fessler RG, Khoo LT: Minimally invasive cervical microendoscopic foramino- lower levels of postoperative pain with the use of minimally tomy: An initial clinical experience. Neurosurgery 51 [Suppl 5]:S37–S45, 2002. invasive techniques or a lower rate of serious postoperative com- 9. Fredman B, Arinzon Z, Zohar E, Shabat S, Jedeikin R, Fidelman ZG, Gepstein plications. Alternatively, shorter lengths of hospitalization may R: Observations on the safety and efficacy of surgical decompression for lum- lead to lower complication rates by reducing the occurrences of bar spinal stenosis in geriatric patients. Eur Spine J 11:571–574, 2002. nosocomial infections and deep venous thromboses. 10. Gepstein R, Arinzon Z, Adunsky A, Folman Y: Decompression surgery for lumbar spinal stenosis in the elderly: Preoperative expectations and postop- The weaknesses of the present study are related to its design, erative satisfaction. Spinal Cord 44:427–431, 2006. size, and duration of the follow-up period. It is a retrospective 11. Goh KJ, Khalifa W, Anslow P, Cadoux-Hudson T, Donaghy M: The clinical syn- analysis of prospectively collected data from databases drome associated with lumbar spinal stenosis. Eur Neurol 52:242–249, 2004. designed to evaluate the outcomes from many types of mini- 12. Hanakita J, Suwa H, Mizuno M: Surgical treatment of lumbar canal stenosis in the elderly. Neurol Med Chir (Tokyo) 39:519–523, 1999. mally invasive spine surgery, not to specifically measure the 13. Hopp E, Tsou PM: Postdecompression lumbar instability. Clin Orthop Relat endpoints of this study. In addition, the present study lacks a Res 227:143–151, 1988. control group of either conservatively managed or open sur- 14. Jansson KA, Blomqvist P, Granath F, Nemeth G: Spinal stenosis surgery in gery patients. Furthermore, the size of this study is not ade- Sweden 1987–1999. Eur Spine J 12:535–541, 2003. quate to evaluate complications that are encountered less fre- 15. Jansson KA, Nemeth G, Granath F, Blomqvist P: Spinal stenosis re-operation rate in Sweden is 11% at 10 years—A national analysis of 9,664 operations. quently, such as perioperative cardiac events and fatalities. Eur Spine J 14:659–663, 2005. Finally, the duration of the follow-up period varied between 16. Kalbarczyk A, Lukes A, Seiler RW: Surgical treatment of lumbar spinal steno- patients, with a mean of 7 months. The variation in follow-up sis in the elderly. Acta Neurochir (Wien) 140:637–641, 1998. resulted from the study being conducted at two institutions 17. Khoo LT, Fessler RG: Microendoscopic decompressive laminotomy for the treatment of lumbar stenosis. Neurosurgery 51 [Suppl 5]:S146–S154, 2002. with different follow-up schedules, as well as the failure of 18. Nilasena DS, Vaughn RJ, Mori M, Lyon JL: Surgical trends in the treatment of some patients to return for all follow-up appointments. diseases of the lumbar spine in Utah’s Medicare population, 1984 to 1990. Therefore, the long-term efficacy of minimally invasive lumbar Med Care 33:585–597, 1995. stenosis surgery was examined in only a subset of patients with 19. Palmer S, Turner R, Palmer R: Bilateral decompression of lumbar spinal a longer follow-up time. Nevertheless, the longitudinal analy- stenosis involving a unilateral approach with microscope and tubular retrac- tor system. J Neurosurg 97 [Suppl 2]:213–217, 2002. sis used mixed effect linear models to use all available informa- 20. Ragab AA, Fye MA, Bohlman HH: Surgery of the lumbar spine for spinal tion and the results are impressive for the time period studied. stenosis in 118 patients 70 years of age or older. Spine 28:348–353, 2003.

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21. Sanderson PL, Wood PL: Surgery for lumbar spinal stenosis in old people. J with minimally invasive decompression. Their pain scores decreased Bone Joint Surg Br 75:393–397, 1993. significantly, as did their Oswestry Disability Index scores. However, 22. Silvers HR, Lewis PJ, Asch HL: Decompressive lumbar laminectomy for the follow-up duration was less than 1 year. Age alone is not a con- spinal stenosis. J Neurosurg 78:695–701, 1993. traindication for surgery. However, lumbar spinal stenosis may become 23. Vitaz TW, Raque GH, Shields CB, Glassman SD: Surgical treatment of lumbar symptomatic as patients age, and decompressive surgery offers an spinal stenosis in patients older than 75 years of age. J Neurosurg 91 [Suppl excellent treatment option for selected individuals. Additionally, these 2]:181–185, 1999. 24. Yong-Hing K, Kirkaldy-Willis WH: The pathophysiology of degenerative dis- decompressions have been implemented in an open fashion. The ease of the lumbar spine. Orthop Clin North Am 14:491–504, 1983. authors’ work suggests that focused decompressions performed in a minimally invasive fashion may also be safe and efficacious. Vincent C. Traynelis COMMENTS Iowa City, Iowa osen et al. have presented their follow-up study of a large series of Relderly patients who underwent lumbar decompression operations. he authors report the results of minimally invasive spine surgery on Although their results are impressive, they have not addressed the Telderly patients. They correctly point out that a paucity of data mechanism by which they decompress the far lateral recesses and neu- exists on this approach. Likewise, the data available in peer-reviewed roforamina using a minimally invasive approach. Theoretically, recur- journal articles have had small series of patients. Special care must be rent stenosis or failed decompression would be at risk if facet joint taken when interpreting the results of this study because the authors integrity were maintained. In most cases, intact facets would hinder lat- report an extremely short follow-up period for a spine article. Although eral foraminal decompression using a minimally invasive, direct line of this may be acceptable for a study that includes only decompressive sight approach. Their results, however, speak for themselves. The procedures, caution must be exercised when making comparisons with authors should be congratulated for their clinical success and meticu- other studies with follow-up durations of 2 years or more. Does a 2% lous documentation. reoperation rate in this series with a 7-month follow-up period repre- sent an improvement over a 5% rate in historical open procedures with Edward C. Benzel 2 years of follow-up? When studies with short follow-up periods have Cleveland, Ohio appreciable gaps in data (Short Form-36 in 35 out of 57 patients, 60%), there is a concern that the 40% of patients for whom data was not inimally invasive lumbar spine surgery has several advantages obtained may have been less satisfied with their result. Alternatively, Mover conventional approaches, including less soft tissue trauma, equal numbers of satisfied and dissatisfied patients were lost to follow- shorter hospital stays with diminished requirements for narcotic anal- up in 7 months. Nonetheless, it seems that good results were obtained gesics, and fewer hospital-related complications, such as infections, in a relatively large group of elderly patients undergoing decompres- thrombophlebitis, pneumonia, and urinary retention. The authors sive lumbar spine surgery with short-term follow-up periods. achieved excellent results in a group of elderly patients with heteroge- Robert F. Heary neous indications for lumbar decompressive procedures. Because the Newark, New Jersey elderly population is particularly prone to medical complications, a minimally invasive procedure might be particularly advantageous in reducing morbidity in this subset of patients. Two questions that his study evaluates the perioperative morbidity, complications, and remain to be answered are whether or not patients fare better in the Tshort-term (median, 7 mo) outcomes of a cohort of 50 patients over immediate postoperative period and whether or not the long-term the age of 75 years. These patients underwent lumbar nerve root com- results are comparable to open operation. Although I suspect that pression from central, lateral recess, or foraminal stenosis, or herni- patients managed with minimally invasive surgery fare better in the ated disc treated with a minimally invasive approach. Both pre- and early postoperative period in terms of shortened hospital stays, less postoperative outcomes were assessed with validated instruments in pain, and fewer medical complications, there are no controls in this most patients, although comorbidities and complications were appar- study. Similarly, one does not know if the authors’ patients would have ently compiled through a less rigorous retrospective chart review. done any better in terms of long-term outcome, as there is no long-term Based on the data provided in this study, the reader can validly con- outcome in this series. Patients had a median follow-up duration of clude that the minimally invasive approach seems to be relatively safe only 7 months, and at least one patient was followed for less than 2 in this patient population. This study does not, however, support that months. Thirteen of the patients had discectomies or foraminotomies; this minimally invasive approach has any advantage over well-estab- these patients are traditionally managed with small incisions with min- lished and standard open approaches with respect to perioperative imal soft tissue trauma. One might reasonably question whether or morbidity, postoperative complications, clinical outcomes, or delayed not the authors’ approach is any less invasive. instability in this or any other patient population. One could certainly Despite these criticisms, this is an excellent study. In the future, I sus- question the effectiveness of the minimally invasive approach in some pect that the minimally invasive approach will be preferred for patients of the patient subgroups in this study. Based on the data and analysis undergoing lumbar laminectomy for stenosis. These authors will be presented in this study, any suggestion or inference that patients who remembered for their pioneering efforts in the development of these were previously thought to be too medically infirmed to undergo open techniques. surgery could now be considered operative candidates for a minimally invasive approach is not appropriate. Most importantly, there is no Paul R. Cooper control group of patients treated either nonoperatively or with a stan- New York, New York dard open operative approach. Therefore, the efficacy or effectiveness directly attributable to a minimally invasive approach in this popula- he authors performed a retrospective evaluation of 50 patients with tion cannot be validly assessed in an uncontrolled study design. For Tsymptomatic lumbar spinal stenosis. These patients were treated example, there is no way to discern whether or not the relatively mod-

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est average improvement reported in these patients (e.g., average It has yet to be validly established that the minimally invasive visual analog scale leg pain improvement of 3.4 points) was the optimal approach for lumbar decompression is associated with shorter recum- achievable outcome. Indeed, the minimally invasive approach was bent periods, shorter recovery times, and a more rapid return to normal shown to be ineffective (i.e., no significant postoperative improvement) activities, all of which contribute to lower complication rates. Although in patients under the age of 80 years and in multilevel decompression the skin incision may be a few millimeters shorter, the amount of bone, and microendoscopic foraminotomy patients. The reader has no ligament, facet joint, and disc necessary to achieve adequate neural method to critically assess these results. One may question whether or decompression is similar in both contemporary open microdecompres- not there was adequate foraminal or multilevel decompression sion and the minimally invasive approach. Differences in operative achieved and/or maintained, based on postoperative imaging with the time and blood loss between the two procedures are negligible. minimally invasive approach for the many patients who experienced Although there is data to support less pain and reduced analgesic limited or no symptomatic improvement. One may also question intake in the immediate postoperative period in patients treated with whether or not this particular patient population or specific patient a minimally invasive approach, which clearly proves to be more bene- subgroup has, on average, achieved a superior result with standard ficial than the muscle splitting technique, this benefit is only temporary and well established open microsurgical techniques. at best. Any suggestion that a slightly smaller skin incision and muscle Secondly, in the absence of a comparable, contemporary control splitting exposure are less destabilizing and may reduce the likelihood group, the authors relied on a literature review for comparison, which of these phenomena (i.e., spinal instability) by maintaining the is problematic in several aspects. Comparisons to historical cohorts anatomic integrity of more of the posterior spinal elements than open are notoriously prone to bias and nearly always favor the contempo- surgery lacks both validity and clinical, experimental, or empiric sup- rary treatment. Also, the literature analyzed in this study was selec- port. Indeed, the 2% reoperation rate reported in this study at a median tive and not comprehensive. Numerous published studies and follow-up period of 7 months is virtually identical to the 1-year reop- empiric clinical experience attest to the safety and effectiveness of eration rate reported by Jansson et al. (4). It is not clear why the authors standard open microsurgical lumbar decompression in elderly provided the 2-year follow-up data from this study, rather than the patients, particularly predominantly single-level, unilaterally symp- comparable 1-year data. tomatic patients such as those included in this study. I am not aware At some point, the proponents of minimally invasive techniques of any patient who would not be a candidate for open decompression have the responsibility to validly establish their claims of the advan- but who would qualify for a minimally invasive approach. Finally, the tages and superiority of these techniques over current procedures for patient populations, surgical selection criteria, operative perform- which safety and effectiveness have been well established. Innovation ance, and outcome assessment may differ between studies in ways is clearly the driving force for advancement in spinal surgery; however, that may affect the outcome. For example, in this current study, there it must be appropriately and critically evaluated. Fortunately, the were no fusion patients or patients who had undergone previous sur- authors are recognized leaders in these techniques and I am confident gery, both factors that are likely to be associated with greater risk of that the true value of their innovations will ultimately be rigorously complications, perioperative morbidity, length of stay, operative time, assessed for the benefit of all our patients. and blood loss. Furthermore, the patient population in this series was Paul C. McCormick of fairly low complexity because more than 70% of the patients under- New York, New York went only single-level decompression; of these, more than one-third had only unilateral decompression. Most of the patients had predom- inantly or exclusively single-level, unilateral radicular symptoms. In 1. Arinzon ZH, Fredman B, Zohar E, Shabat S, Feldman JS, Jedeikin R, Gepstein contrast, many of the reports used by the authors for comparative RJ: Surgical management of spinal stenosis: A comparison of immediate and analysis included fusion patients and previously operated patients long term outcome in two geriatric patient populations. Arch Gerontol and had a significantly higher percentage of multilevel decompres- Geriatr 36:273–279, 2003. sions than the present study (1–6). Unfortunately, although the 2. Deyo RA, Cherkin DC, Loeser JD, Bigos SJ, Ciol MA: Morbidity and mortal- authors provide a list of medical comorbidities, the reader cannot ity in association with operations on the lumbar spine. The influence of age, comparatively assess their severity or risk through either the diagnosis, and procedure. J Bone Joint Surg Am 74:536–543, 1992. American Society of Anesthesia physical function score or the 3. Jansson KA, Blomqvist P, Granath F, Nemeth G: Spinal stenosis surgery in Cumulative Illness Rating Scale for Geriatrics. Nevertheless, the Sweden 1987–1999. Eur Spine J 12:535–541, 2003. reported complication rate of 20 to 47% noted by the authors from 4. Jansson KA, Nemeth G, Granath F, Blomqvist P: Spinal stenosis re-operation rate in Sweden is 11% at 10 years—A national analysis of 9,664 operations. Eur their limited literature review is similar to their own 38% complica- Spine J 14:659–663, 2005. tion rate (22 out of 57 patients). A rigorous review of these studies 5. Kalbarczyk A, Lukes A, Seiler RW: Surgical treatment of lumbar spinal steno- reveals that the incidence, type, and severity of perioperative compli- sis in the elderly. Acta Neurochir (Wien) 140:637–641, 1998. cations and morbidity are virtually identical in this study compared 6. Ragab AA, Fye MA, Bohlman HH: Surgery of the lumbar spine for spinal with the published studies on standard open lumbar decompression. stenosis in 118 patients 70 years of age or older. Spine 28:348–353, 2003.

510 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com METHODOLOGY IMPROVEMENT

COLOR INTENSITY PROJECTION OF DIGITALLY SUBTRACTED ANGIOGRAPHY FOR THE VISUALIZATION OF BRAIN ARTERIOVENOUS MALFORMATIONS

Keith S. Cover, Ph.D. OBJECTIVE: Reliable and rapid delineation of arteriovenous malformations enables Department of Radiation Oncology, the application of effective treatments such as stereotactic radiosurgery. We describe a VU University Medical Center, new method to improve the speed and reliability of visualizing the flow of contrast Amsterdam, The Netherlands images with digital subtraction angiography. Frank J. Lagerwaard, M.D., Ph.D. METHODS: In line with current practices, digital subtraction angiography was used to Department of Radiation Oncology, produce a sequence of grayscale images. The new method combines the standard VU University Medical Center, grayscale images produced by digital subtraction angiography into a single composite Amsterdam, The Netherlands color image that encodes the contrast arrival time at each point of the brain’s circula- René van den Berg, M.D., Ph.D. tory system. The algorithm is simple, fast, and easy to implement. Department of Radiology RESULTS: The technique allows the flow of contrast from a series of angiography images VU University Medical Center, to be summarized in a single color image. Amsterdam, The Netherlands CONCLUSION: This visualization method promises to improve the speed of manual delin- Dennis R. Buis, M.D. eation of arteriovenous malformations. Further studies are required to evaluate the clin- ical value of the use of color intensity projection images, supplemented by grayscale images Department of Neurosurgery, VU University Medical Center, as necessary, in comparison with contouring on grayscale images only. Amsterdam, The Netherlands KEY WORDS: Angiography, Intracranial arteriovenous malformations, Maximum intensity projections, Radiosurgery, Stereotactic techniques Ben J. Slotman, M.D., Ph.D. Department of Radiation Oncology, Neurosurgery 60:511–515, 2007 DOI: 10.1227/01.NEU.0000255331.49791.B4 www.neurosurgery-online.com VU University Medical Center, Amsterdam, The Netherlands

Reprint requests: tereotactic radiosurgery (SRS) is an estab- to study the various components of the AVM. Keith S. Cover, Ph.D., lished modality for the treatment of brain Usually, a single early phase of DSA is Department of Radiation Oncology, arteriovenous malformations (AVMs). selected for delineation of the nidus in the VU University Medical Center, S Accurate target definition of the AVM nidus is radiosurgery planning system. However, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands. essential to ensure full coverage of the nidus practical considerations limit the reliability of Email: [email protected] by the high-dose region of radiation and, contouring the AVM in a single biplanar DSA equally important, to limit radiation exposure phase because not all shunt areas in the nidus Received, May 22, 2006. to surrounding healthy brain tissue (1, 3–6, 8). exhibit the same pace of flow and, more Accepted, August 31, 2006. Although brain AVMs can be visualized with importantly, because biplanar DSA is a two- three-dimensional imaging techniques such as dimensional imaging modality, overproject- computed tomographic angiography and mag- ing arteries and veins may sometimes obscure netic resonance angiography (MRA), these the actual AVM nidus. This can result in sig- modalities lack the temporal information that nificant intra- and interobserver variations in is essential for discriminating the AVM nidus contouring (1). from feeding arteries and draining veins. In this article, we present a simple but effec- Because stereotactic digital subtraction angiog- tive method for color coding the time that con- raphy (DSA) series provide temporal informa- trast arrives at any location in the brain vascu- tion regarding the filling of the brain vascula- lature in a single composite image. The ture, this technique is still considered the “gold method, arrival-time color intensity projection standard” for contouring brain AVMs for the (CIP), combines the information contained in a purpose of SRS (7). number of sequential DSA images into a single In clinical practice, detailed examination of composite color image. This composite image numerous consecutive DSA images is needed represents the arrival time of contrast at each

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pixel with each pixel’s hue, brightness, and saturation convey- same pattern, all images of the cumulative MinIP sequence can ing the intensity and intensity variation, respectively, of the be easily calculated (Fig. 1). pixel over the DSA component images. The use of color-coded Finally, the arrival-time CIP composite image is derived by images could enhance the discrimination of the AVM nidus applying the percentage-time CIP algorithm to this cumulative from feeding arteries and draining veins, even when these are MinIP sequence. Although the percentage-time CIP algorithm projected over the nidus, which may improve the target defini- has been presented in detail previously (2), it is also presented tion for SRS of AVMs. here for convenience. The first step is to scale the pixel values of the cumulative MinIP sequence to values between 0 and 1. MATERIALS AND METHODS This new image sequence, the normalized cumulative MinIP sequence, is calculated by dividing each pixel in each cumula- The method for summarizing the contrast arrival time in a tive MinIP image by the maximum value of all pixels in all single color image is based on the percentage-time CIP algo- images. The second step is to calculate, on a pixel-by-pixel rithm, which was developed to simplify and speed up the basis, the maximum (MaxIP), mean (MeanIP), and minimum analysis of the mobility of lung tumors (2). In percentage-time (MinIP) of the normalized cumulative MinIP sequence. The CIP, the hue of the color is used to encode the percentage of MaxIP, MeanIP, and MinIP are then combined on a pixel-by- time there is tissue in a particular location. Before applying the pixel basis with the following equations to determine the hue, percentage-time algorithm to a series of DSA images, a new saturation, and brightness of the composite color image: image sequence must be calculated from the original DSA, • Brightness ϭ MaxIP which simulates a continuous flow of contrast after the contrast • Saturation ϭ (MaxIP Ϫ MinIP)/MaxIP injection has started. • Hue ϭ 2/3 ϫ (MeanIP Ϫ MinIP)/(MaxIP Ϫ MinIP) This new image sequence represents a cumulative minimum The hue, saturation, and brightness for each pixel is then con- intensity projection (MinIP) sequence of all DSA images and is verted to the standard red, green, and blue presentation of color simple to calculate. The first image of the cumulative MinIP using widely available subroutines. Applying this method to the sequence is the first image of the original DSA image sequence. cumulative MinIP sequence results in the arrival-time CIP com- The second image of the cumulative MinIP sequence is the posite image. Early phases of the DSA series appear in red, pixel-by-pixel minimum of the first two images of the original intermediate phases appear in yellow, and late phases appear in DSA image sequence. The third image of the cumulative MinIP green and blue (Fig. 2). If desired, the saturation can be multi- sequence is the pixel-by-pixel minimum of the first three plied by a constant larger than unity before conversion to red, images of the original DSA image sequence. Following the green, and blue. This will distinguish the colors more conspic-

A B C D

E F G H

FIGURE 1. Regularly spaced images from the original DSA sequence (A–D) expected, the contrast seen entering in the brain in A does not appear in C or and the cumulative MinIP images at the corresponding times (E–H). As D, but does appear in all of the cumulative MinIP images (E–H).

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A B RESULTS The generation of arrival-time CIP images is illustrated with two patients. Illustrative Cases Patient 1 The first patient is a 46-year-old man who experienced epilepsy as a result of a Spetzler-Martin Grade II AVM feeding from the middle cere- bral artery in the left temporal lobe of the brain. For the purpose of stereotactic irradiation of this AVM, selective angiography of the left internal carotid artery was performed at a frame rate of six images per second. The sequential DSA images and the cumulative MinIP C D sequence of this patient are shown in Figure 1. The corresponding arrival-time CIP image is shown in Figure 3, with the color bar in the upper left corner indicating the ordering of colors; red indicates the ear- liest arrival time, and blue indicates the latest arrival time. For gener- ation of this CIP image, the saturation was multiplied by 1.5 and any resulting saturation values greater than 1 were set to 1. In addition, the hue values were windowed between 0.2 and 0.8, indicating that hue values of 0.2 or less were set to 0, values of 0.8 and above were set to 1, and values between 0.2 and 0.8 were linearly scaled to between 0 and 1. The red color of the AVM and feeding middle cerebral artery (bright red) can be clearly distinguished from the early draining vein of Labbé (yellow) and late draining veins and sinus (green and blue). FIGURE 2. Early (A), intermediate (B), and late (C) single phases of a DSA study. The corresponding composite CIP image (D) illustrates the color differ- Patient 2 entiation of the temporal information. The second patient illustrates the potential impact of the use of arrival-time CIP images for delineating the AVM for the purpose of high-precision SRS. This 52-year-old patient developed focal epilepsy in the right leg as a result of a small Spetzler-Martin Grade I AVM. Before stereotactic treatment, DSA of the left internal carotid artery was performed. Figure 4 shows the arrival-time CIP of the DSA, feed- ing of the AVM by the left pericallosal artery, and drainage into the superior sagittal sinus. The top panel shows the initial contouring of the AVM in the treatment planning system by the treating clinician, which can only be performed on a single grayscale DSA image. The bottom panel shows the subsequent contouring of the AVM on the arrival-time CIP image. When comparing the contour derived from a single grayscale DSA image with the contour from a CIP image, using the full set of grayscale DSA images as the standard of reference, the smaller contour derived from the CIP image seemed more appropri- ate. The color coding of the CIP enabled the differention of the vein from the nidus. Because computed tomographic angiography and MRA lack the temporal resolution of DSA series, this differentiation could not be obtained using these three-dimensional imaging tech- niques. The detail of the AVM shows that the more posterior part of the originally contoured target volume actually consists of looping FIGURE 3. Arrival-time CIP image of the DSA images shown in Figure 1. feeding arteries and draining veins. In this case, the additional infor- The color bar in the upper right corner shows the ordering of the colors, with mation from the CIP image led to a smaller radiosurgery target vol- red indicating the earliest arrival time and blue indicating the latest. The ume and potentially less toxicity of the stereotactic treatment. progress of the contrast from the feeding arteries (red), through the AVM (bright red), on to the early (yellow) and late (green and blue) draining veins is illustrated. DISCUSSION The use of CIP images that summarize all temporal informa- uously on the composite image. In addition, the hue may be tion of a DSA series within a single composite image may have scaled to emphasize early, mid, or late arrival times. The arrival- an advantage over the use of a single early phase image of the time CIP images were calculated on an AMD Duron processor DSA for stereotactic treatment planning. The overprojection of (Advanced Micro Devices, Inc., Sunnyvale, CA) running at feeding arteries and enlarged draining veins can obscure the 1 GHz and took less than 10 seconds to calculate. boundaries of the AVM nidus on conventional biplanar angiog-

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Medical Centre is pursuing a patent on the method described in this study on behalf of two of the authors (KSC and FJL). REFERENCES

1. Buis DR, Lagerwaard FJ, Barkhof F, Dirven CM, Lycklama GJ, Meijer OW, van den Berg R, Langendijk HA, Slotman BJ, Vandertop WP: Stereotactic radio- surgery for brain AVMs: Role of interobserver variation in target definition on digital subtraction angiography. Int J Radiat Oncol Biol Phys 62:246–252, 2005. 2. Cover KS, Lagerwaard FJ, Senan S: Color intensity projections: A rapid approach for evaluating four-dimensional CT scans in treatment planning. Int J Radiat Oncol Biol Phys 64:954–961, 2006. 3. Friedman WA, Bova FJ, Mendenhall WM: Linear accelerator radiosurgery for arteriovenous malformations: The relationship of size to outcome. J Neuro- surg 82:180–189, 1995. 4. Gallina P, Merienne L, Meder JF, Schlienger M, Lefkopoulos D, Merland JJ: Failure in radiosurgery treatment of cerebral arteriovenous malformations. Neurosurgery 42:996–1004, 1998. 5. Kwon Y, Jeon SR, Kim JH, Lee JK, Ra DS, Lee DJ, Kwun BD: Analysis of the causes of treatment failure in gamma knife radiosurgery for intracranial arte- riovenous malformations. J Neurosurg 93 [Suppl 3]:104–106, 2000. 6. Pollock BE, Flickinger JC, Lunsford LD, Maitz A, Kondziolka D: Factors asso- ciated with successful arteriovenous malformation radiosurgery. Neurosurgery 42:1239–1247, 1998. 7. Niranjan A, Maitz A, Kondziolka D, Lunsford L: Radiosurgery: Current tech- niques. Tech Neurosurg 9:119–127, 2003. 8. Schlienger M, Atlan D, Lefkopoulos D, Merienne L, Touboul E, Missir O, Nataf F, Mammar H, Platoni K, Grandjean P, Foulquier JN, Huart J, Oppenheim C, Meder JF, Houdart E, Merland JJ: Linac radiosurgery for cere- bral arteriovenous malformations: Results in 169 patients. Int J Radiat Oncol Biol Phys 46:1135–1142, 2000.

COMMENTS

he authors report an interesting technique that uses digital subtrac- Ttion angiography (DSA) and distinguishes between the arterial, nidal, and venous compartments of cerebral arteriovenous malforma- tions (AVMs). Using an arrival time color intensity protocol, areas that fill with contrast earliest are red, intermediate areas are yellow, and areas that fill late are coded green or blue. Although this technique FIGURE 4. Example of the advantages of contouring an AVM on an arrival- seems to be effective in distinguishing the true nidus from venous time CIP image over DSA images. The arrival-time CIP enables the contour structures and, therefore, has great applicability to radiosurgery, accu- to be drawn smaller with much more confidence compared with the routinely rate nidal measurements will also facilitate a more accurate classifica- used grayscale image. tion of AVMs by size. This protocol could also have enormous applica- bility to intraoperative angiography if data processing is rapid enough. One difficulty with the interpretation of current intraoperative angiog- raphy series. However, these can be better discriminated on raphy is the true definition of shunting and our ability to resolve this CIP images. It remains to be determined whether or not the CIP issue in an intraoperative study. The authors’ report is a useful addition display technique, supplemented by the series of grayscale to the neurosurgical literature. images as necessary, can diminish intra- and interobserver vari- H. Hunt Batjer ations in contouring AVMs, which can be substantial. The lat- Chicago, Illinois ter is the subject of ongoing research at our center. Although the arrival-time CIP algorithm has been demon- over et al. present a novel technique by which standard grayscale strated for imaging the flow of contrast in the brain, it has Cimages produced by DSA can be used to produce a single compos- potential applications in a wide range of fields in which there ite color image that displays contrast arrival time. It is proposed that this novel technique might be useful in the delineation of the nidus of is a need to summarize the changes over a series of grayscale an AVM for treatment purposes during stereotactic radiosurgery. images in a single color image. Some possible fields of applica- At our institution, we feel that we are able to confidently define the tion include other medical imaging modalities, astronomy, nidus of most AVMs for stereotactic radiosurgery planning using DSA engineering, and geophysics. and magnetic resonance imaging studies. The authors are currently undertaking further investigations to elucidate the utility of this tech- Disclosures nique. They state that the technique can be performed in a timely fash- This work was funded by the Department of Radiotherapy at the VU ion to such an extent that would not preclude its use. However, University Medical Center, Amsterdam, The Netherlands. The Vrije University whether or not the addition of the images supplied by the technique

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will lead to decreased intra- and interobserver variations in AVM con- he authors present a new method describing the use of color inten- touring or, more importantly, improved outcomes for patients is yet to Tsity projections of DSA. They describe a visualization technique be determined. that combines the spatial information of a single image and the tempo- Elisa Beres ral information of arterial and venous phases of blood flow into a sin- Robert F. Spetzler gle composite color image. This combined information is immediately Phoenix, Arizona and easily comprehensible. For specific indications, this type of visual- ization simplifies our current grayscale-based image analysis. However, he authors describe a technique that improves the speed and relia- not all visualization techniques that combine different data sets Tbility of visualizing the flow of contrast imaging with DSA. This improve understanding. In most cases, a sequential image-by-image technique combines standard grayscale images into a composite color analysis is required, as details of anatomical structures are easier to image that encodes the contrast arrival time at each point in the brain’s match, especially in complex vascular malformations with intricate circulatory system. The authors report that the composite color image three-dimensional configuration. The color coding of grayscale images may be more accurate in helping to define areas of high-flow, such as integrates additional information, such as the differentiation of venous in the AVM case presented. and arterial phase presented in the report, as well as information on The definition of the limits of an AVM is a subject of great interest. estimates on velocity and perfusion. In addition, color coding might This becomes particularly important in the preparation for surgery or, help to integrate different information from other modalities, such as more likely, in preparation for radiosurgical treatment. The technique magnetic resonance angiography. It will be of great interest for the the authors have defined may certainly improve the accuracy of limit neurosurgical community to obtain additional results and follow-up definition for high-flow lesions, such as AVMs or, potentially, dural data to assess its adaptation to the operative environment. The tech- AVMs. This is a preliminary report and we look forward to studies nique presented may also facilitate an improved understanding of vol- with larger numbers of patients using this technique. The authors are ume-reconstructed images. to be congratulated for their work. Matthias Kirsch Christopher S. Ogilvy Gabriele Schackert Boston, Massachusetts Dresden, Germany

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LITIGATION OF MISSED CERVICAL SPINE INJURIES IN PATIENTS PRESENTING WITH BLUNT TRAUMATIC INJURY

Gregory P. Lekovic, M.D., BACKGROUND: Approximately 800,000 cervical spines are cleared in emergency Ph.D., J.D. departments each year. Errors in diagnosis of cervical spine injury are a potentially huge Division of Neurological Surgery, medicolegal liability, but no established protocol for clearance of the cervical spine is Barrow Neurological Institute, St. Joseph’s Hospital and known to reduce errors or delays in diagnosis. Medical Center, METHODS: The Lexis-Nexis, Westlaw, and Medline databases were queried for cases Phoenix, Arizona, and of missed cervical injury. Errors were categorized according to a novel system of clas- Sandra Day O’Connor School of Law, Arizona State University, sification. Type I errors occurred when inadequate or improper tests were ordered. Type Tempe, Arizona II errors occurred when adequate tests were ordered, but were either misread or not read. Type III errors occurred when adequate tests were ordered and read accurately, Timothy R. Harrington, M.D. but the ordered test was not sensitive enough to detect the injury. Division of Neurological Surgery, Barrow Neurological Institute, RESULTS: Twenty cases of missed or delayed diagnosis of cervical spine injury were St. Joseph’s Hospital and found in 10 jurisdictions. Awards averaged $2.9 million (inflation adjusted to 2002 dol- Medical Center, lars). Eight cases resulted in verdicts in favor of the defendant, but none of these cases Phoenix, Arizona involved an alleged Type II error.

Reprint requests: CONCLUSION: Fear of lawsuits encourages defensive medicine and complicates the Timothy R. Harrington, M.D., process of clearing a patient’s cervical spine. This analysis adds medicolegal support c/o Neuroscience Publications, Barrow Neurological Institute, for the judicious use of imaging studies in current cervical spine clearance protocols. 350 W. Thomas Road, However, exposure to significant liability suggests that a low threshold for computed tomog- Phoenix, AZ 85013. raphy is a reasonable alternative. E-mail: [email protected] KEY WORDS: Medical malpractice, Missed diagnosis, Spinal cord injury, Trauma Received, May 11, 2006. Accepted, November 1, 2006. Neurosurgery 60:516–523, 2007 DOI: 10.1227/01.NEU.0000255337.80285.39 www.neurosurgery-online.com

t has been estimated that 800,000 cervical spines are cleared radiographic screening, only to present later with deficits or in emergency departments and trauma rooms each year, changes on examination that prompt further imaging and Iwith a 2 to 3% incidence of cervical spine injury related to examination. blunt trauma (33). Nevertheless, the correct management algo- The consequences of spinal cord injury are devastating and rithm for the initial evaluation of the cervical spine in patients include the large direct and indirect costs incurred with hospi- presenting with blunt trauma is controversial. Multiple proto- talization, nursing care, and rehabilitation, as well as adverse cols have been developed for cervical spine clearance, and effects on an individual’s productivity (estimated at an average these protocols vary considerably in their recommendations (1, of $13,566 annually per injured person in 1998 dollars) (12). 10, 11, 33, 40). For example, according to the Canadian C-Spine Thus, spinal cord injury imposes a large economic burden, Rule (40), symptomatic patients (i.e., those complaining of neck leading to both high societal costs and substantial settlements pain) may be cleared clinically without the use of x-rays if they and awards for damages in legal actions occurring as a conse- are alert and were not subjected to a high-risk mechanism of quence. This has led some to argue in favor of early computed injury. This heterogeneity of expert opinion and meager evi- tomographic (CT) scanning for clearance of the cervical spine dence led to the recent publication of guidelines for the clear- based on institutional cost, which includes the potential costs of ance of the cervical spine, authored jointly by the Congress of litigation of missed injuries (31). However, there are no data on Neurological Surgeons and the American Association of the actual costs of such litigation. Neurological Surgeons (1). Hence, the standard practice for the The goals of the present study were twofold. First, we have initial evaluation of such patients is to obtain plain x-rays of the attempted to quantify the litigation costs associated with litiga- cervical spine. Therefore, given a 93 to 98% negative predictive tion of missed cervical spine injury. The second goal was to value of plain x-rays (1), an estimated 384 to 1344 spine injuries review legal case reports, jury verdicts, and the medical literature are missed each year. These patients may be cleared after initial to determine whether or not there are any characteristics com-

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mon to missed diagnoses of cervical spine injuries that led to lit- ing plain x-rays of the cervical spine, did not reveal the fractured igation for medical malpractice. What error caused these cases to vertebral body (Type I error). The patient’s cervical fracture was thus go to court? What can be done, if anything, to avoid litigation? missed and she began physical therapy. The judge found that the failure to diagnose the patient’s fractured cervical spine injury METHODS resulted in neurological injury exacerbated by the prescribed physical therapy. A verdict was found in favor of the plaintiff in the amount of Literature Search $525,000 (21). Published reports of jury verdicts and settlements were Pendergrass versus McKenzie and searched on the Lexis-Nexis and Westlaw search engines. Cases Broward General Medical Center included were limited to those with a clear traumatic etiology. Plaintiff Pendergrass, an indigent male involved in a motor vehicle Typically, however, we were unable to determine whether accident, was evaluated in the emergency department at Broward patients were initially evaluated as a “Level I trauma” or sim- General Medical Center. Plain x-rays ordered by the attending emer- ply through the emergency department. Medline was also gency room physician showed a subluxation of C4 on C5. The defen- queried for published reports on missed or delayed diagnoses dant neurosurgeon ordered flexion-extension x-rays and CT scans of of cervical spine injury. Cases reviewed were categorized the cervical spine. The former showed motion at C4–C5; the latter broadly as the following types of error: Type I, inadequate or showed a unilateral jumped facet. However, the defendant maintained improper tests ordered; Type II, adequate tests were ordered that the flexion-extension x-rays were unavailable for his review when but they were misread or not read; and Type III, adequate tests he saw the patient. The CT findings were either erroneously misread as were ordered and read accurately but were not sensitive normal or the defendant failed to act upon the findings. The patient was thus discharged from the emergency department. He returned 3 enough to demonstrate injury. days later (4 d after injury) with progressive weakness and ultimately Limitations of Research Methodology became quadriplegic after surgery. Whether the defendant grossly mis- read the films or whether he reviewed them at all was raised as an The sources for the jury verdicts were commercial trade pub- issue. In either case, however, the defendant missed clearly visible find- lications that publicize cases of interest to the trial attorney bar. ings (locked facet, dynamic instability) on studies that were techni- Thus, no claim of inclusiveness is made. Published jury ver- cally adequate (i.e., Type II error). The jury ruled in favor of the plain- dicts and settlements may be biased in favor of larger settle- tiff for $8.9 million ($250,000 for past lost earnings and medical ments because these are more likely to be reported by the attor- expenses, $1.6 million for future lost earnings and medical expenses, neys involved. Other limitations include a small sample (n ϭ 20) and $7.1 million for noneconomic damages [i.e., pain, suffering, and loss of capacity for enjoyment of life]) (27, 38). and a variable amount of pertinent clinical information. Finally, error was imputed according to the information available from Coe versus Henry Mayo Newhall Medical Center jury verdicts and settlement reports that rely on the findings of In May 1992, a 37-year-old woman, plaintiff Violeta Coe, was fact by the court; a primary review of court transcripts, evi- involved in a rollover motor vehicle accident. She was transported to dence, or both was not possible. Henry Mayo Newhall Memorial Hospital and evaluated through the hospital’s Level II trauma service. The patient’s initial evaluation con- RESULTS sisted of plain x-rays of the cervical spine that were interpreted as negative by both the trauma surgeon and the defendant radiologist. Between 1987 and 2002, 20 cases meeting the inclusion crite- The trauma surgeon also documented that the patient’s cervical spine ria were identified from 10 different states: Arizona, California, was not tender. Thus her cervical spine was cleared. The patient was Florida, Georgia, Illinois, Kentucky, Louisiana, New Jersey, Pennsylvania, and Texas (2, 4–9, 15–23, 25–28, 38). Twelve of these cases resulted in awards averaging $2.9 million (inflation adjusted to 2002 dollars). The awards ranged from $153,000 to $8,900,000 (Table 1) (2, 4, 7, 15, 17, 18, 21, 23, 25–28, 38). Eight of the cases resulted in verdicts in favor of the defendant (Table 2) (5, 6, 8, 9, 16, 19, 20, 22). With respect to category of error, only Type II errors were never successfully defended (Fig. 1). Of the 20 cases, eight resulted in findings for the defense and 11 resulted in favor of the plaintiff. In one case, no category of error could be imputed based on the available information. ILLUSTRATIVE CASES FIGURE 1. Bar graph showing the outcome of litigation according to the category of error. There were no verdicts in favor of defendants who com- Gay versus Piggly-Wiggly mitted Type II errors. Only 19 out of the 20 cases discussed are included because the type of error could not be determined in one case based on the Annie Ruth Gay was involved in a motor vehicle accident and sus- available information. tained a fracture of the fifth cervical vertebra. Imaging studies, includ-

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TABLE 1. Summary of litigation cases resulting in awardsa

Plaintiff Type of Verdict (US Case (ref. no.) State age (yr)/ Mechanism Injury Delay Complication Reason for error error dollars) sex Gay versus Piggly- GA 60/F MVA C5 fracture Unk Quad and Incomplete cervical spine I 525,000 Wiggly, 1987 (21) death x-rays (failed to visualize C5)

Lee and Lee versus FL 57/M MVA C1–C2 1 mo Unk X-rays including F/E missed III 153,000 Amisub, 1990 (26) subluxation C1–C2 subluxation

Kaberline versus Martha IL 22/M Fall from C4/C5 1 d C6 quad Emergency room doctor II 7.9 million Washington Hospital, porch subluxation misread plain x-rays 1990 (23) showing subluxation Johnson versus SAS FL 39/M Fall during Unk Unk Unk Unk Unk 2.85 million Ambulance, 1991 (25) Masonic initiation ritual Pendergrass versus FL 42/M MVA C4/C5 6 d Quad Films ordered but not II 8.9 million McKenzie, 1993 unilateral followed up (27, 38) locked facet and subluxation

Walsworth versus LA 70/F GLF Unk 5 hr Quad Misdiagnosed as stroke I 525,000 Lousiana Medical Mutual, 1995 (15) Rodenbaugh versus PA 60/F Fall down C6–C7 2 d C6 quad AP and oblique x-rays II 300,000 Suburban General stairs subluxation and death misread Hospital, 1996 (18) Coe versus Mayo, CA 37/F MVA C6–C7 1 d Quad Plain x-rays adequate and III 2.75 million 1996 (28) rollover subluxation negative (“a subtle finding”) (settlement, verdict for defending radiologist)

Hammer versus CA 72/M MVA C5–C6 1 d Quad “Slight” subluxation of II 300,000 Kaiser, 1998 (7) instability C5 on C6 on initial radiographs, no CT scan or F/E ordered Pennington versus CA 50/M MVA C5–C6 1 d C4–C5 quad CT scan showed C5–C6 II 2.0 million Regents of University of fracture after cleared fracture misread California, 2000 (17) in OR for aorta repair Plazola versus CA 52/F Thrown C2 fracture 36 mo Failure to Plain x-rays of odontoid III 316,000 Casey, 2000 (2) from horse fuse with and CT scan of C3–C5 (66,000 halo brace, failed to show C2 fracture economic, 3 years of 250,000 pain neck pain and suffering)

Anonymous, 2001 (4) MA 80/Unk — C5–C6 3 d Quad and Fracture not seen on plain III 2.25 million fracture, death x-rays, neurological dislocation decline prompted CT scan

a MVA, moving vehicle accident; Unk, unknown; Quad, quadriplegia; F/E, flexion and extension; GLF, ground level fall; AP, anteroposterior; CT, computed tomographic; OR, operating room.

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TABLE 2. Summary of litigation resulting in verdicts in favor of the defendanta

Plaintiff Juris- Type of Case (ref. no.) age Mechanism Verdict Injury Delay Complication Explanation diction error (yr)/sex Samurin versus AZ 44/M MVA Defendant C5/C6 18 mo Arachnoiditis HNP not diagnosed III Oei et al., 1990 (20) HNP after until CT myelography MVA performed; no neurological examination performed Boyer versus CA 49/M Body Defendant C6 burst 10 d– Permanent III Clark et al., 1991 (22) surfing fracture 1 mo motor deficit Ringgenberg versus CA 24/M MVA Defendant C7–T1 Unk Residual C-spine films obtained I Regents of the fracture weakness but were inadequate University of California, 1993 (16) Roberson versus van CA 51/M MVA Defendant C6/C7 7 d Neurological Films negative, MRI III Dyke, 1998 (6) HNP deficit positive for HNP Lee versus Levine, CA 80/Unk GLF Defendant C7–T1 Unk Quadriplegia, C7 poorly visualized on I 1998 (5) EDH death plain films, MRI positive Mynear versus KY 14/M Unk Defendant Unk 1 d Quadriparesis, No films obtained, patient I Wright, 1999 (19) incontinence cleared from fall from trampoline on physical examination Galik versus Clara NJ 80/F GLF Defendantb C5–C6 16 d Death C-spine plain films (2 I Maas, 2000 (9) subluxation views only), injury discov- ered with MRI scan after complaining of neck pain Matson versus TX 43/M MVA Defendant C2 fracture 40 d Delayed Poor quality/ incomplete I Gbalazeh, and C4/ fusion, failed plain films, no 2002 (8) C5 facet halo bracing flexion/extension fracture

a MVA, moving vehicle accident; HNP, herniated nucleus pulposus; CT, computed tomographic; Unk, unknown; MRI, magnetic resonance imaging; GLF, ground level fall; EDH, epidural hematoma. b Verdict was reversed and remanded on appeal.

admitted to the intensive care unit for management of unrelated Missed Injuries and Types of Error injuries and began to complain of neck pain. She was examined by the trauma surgeon the next morning and was found to have com- Missed Cervical Fractures plete C7 quadriparesis. CT scans showed anterior subluxation of C6 Although the sensitivity of CT scanning for fractures has on C7. The trauma surgeon and other defendants settled out of court. The defendant radiologist was successful in defending the missed been reported to be 100% (11), autopsy reports have docu- diagnosis because the court found that the plain x-rays were ade- mented cases of cervical spine injuries, including fractures, that quate (i.e., included the entire cervical spine including C7–T1) and were missed on CT scans (41). Nevertheless, the use of CT scan- negative and that subluxation detected in retrospect constituted a ning would have detected three of the four cervical fractures “subtle finding” that could not give rise to liability (28). missed on plain films. In one patient, plain films were inade- quate owing to body habitus (Type I error). In two other DISCUSSION patients, plain films were not sensitive enough to detect the In general, injuries to the spine are either to the bony or lig- injury (Type III error). In these cases, the injuries were discov- amentous elements of the spine. Both may contribute to cervi- ered on CT scans only after the patients experienced neurolog- cal instability and cause neurological deficits. Of the cases suc- ical decline. In the other case (Pennington versus Regents of cessfully litigated, we found four cases of missed fractures, six California), a CT scan was ordered and misread (Type II error). cases of missed subluxations, and two cases in which the exact Thus, the use of CT scanning would have eliminated errors of missed diagnosis could not be determined. inadequate visualization of the cervical spine as well as errors

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attributable to the relative insensitivity of plain x-rays (Type I missed injuries, plain x-rays were inadequate in 23 cases. In 15 and III errors, respectively). of the same 34 patients, the error was identified and attributed to inadequate or incomplete films in 15 cases (Type I error), Missed Cervical Instability whereas the initial radiographic studies showed no apparent Cervical instability may be evident on flexion-extension stud- injury (Type III) in 16 cases. ies in the presence of normal bony anatomy on CT scans (1). In Gerrelts et al. (30) reviewed 1331 blunt trauma patients a recent study evaluating the use of magnetic resonance imag- evaluated by plain x-rays, 75 of whom were found to have ing (MRI) in the setting of Level 1 trauma, even MRI sequences cervical injuries. Of these 75 patients, 61 were diagnosed with sensitive to soft tissue injury, such as short tau inversion recov- a fracture, subluxation, or both, and five were missed on ini- ery (STIR) sequences, were found to be inadequate in predict- tial evaluation. The indications for further evaluation were ing cervical instability (34). Dynamic studies of the cervical pain in two patients and neurological symptoms in three. spine are required to detect such radiographically occult These five patients were initially evaluated with plain x-rays. injuries (i.e., purely ligamentous injury to the cervical spine In all cases, the delay in their diagnosis was attributed to without bony abnormality) (14, 39). Thus, flexion-extension inadequate visualization of the cervical spine (Type I error). x-rays of the cervical spine remain the “gold standard” for lig- One study was also misread (Type II error). Together, these amentous instability in patients with cervical pain without findings indicate that the patterns of error in the evaluation of radiographic evidence of fracture (1). the cervical spine, as designated in our study, accurately Estimates of the incidence of such pure ligamentous injuries reflected the errors that most often delay the diagnosis of vary (36, 39). Of the successfully litigated cases described in this traumatic cervical spine injuries. article, six cases involved missed subluxations (in two cases, the diagnosis could not be determined). The clinical data available Costs of Litigation for review are limited. In five of these cases of cervical instabil- In addition to the direct and indirect medical, social, and eco- ity, however, the facts seem consistent with a ligamentous cause nomic costs associated with medical errors is the threat of litiga- of instability (in one case, jumped facets were also missed on tion, particularly in the United States. However, recent studies plain films). Presumably, flexion-extension x-rays would have on medical errors in the United Kingdom and Europe indicate enabled the diagnosis in these cases. In the case of Lee and Lee that the threat of litigation is an increasingly common concern versus Amisub (26), however, flexion-extension x-rays were in these regions as well (32, 35). Litigation, or the fear of litiga- ordered but failed to demonstrate C1–C2 instability. tion, tends to add to costs by encouraging medically unneces- sary tests and by imposing an additional cost of potential litiga- Misread Films tion for missed diagnoses. In terms of clearance of the cervical spine, another consider- We agree with Grogan et al. (31) that the costs of litigation for ation for emergency department physicians or trauma surgeons potentially missed injuries should be included in the evaluation may be the ease of interpretation of radiographic studies (i.e., of a given overall treatment paradigm. In a recent decision-tree Type II errors). The sensitivity of plain x-rays for cervical frac- analysis of the cost-benefit ratio of using helical CT scans versus tures has been estimated at 93 to 98% to trained interpreters (1). plain x-rays to clear the cervical spine, these authors estimated However, in a study of errors in the interpretation of trauma the cost of a helical CT scan of the cervical spine at $328.93 com- x-rays, only 29% of house staff and 74% of attending physicians pared with $120.05 for plain x-rays alone. These authors esti- in emergency departments correctly identified cervical sublux- mated the cost of litigation at $500,000. Taking these relative ation on plain x-rays (37). Initial radiographic studies obtained costs into account in their decision-tree analysis, they concluded in trauma rooms and emergency departments are often that obtaining a CT scan to clear the cervical spine is justified on reviewed by emergency department staff or trauma surgeons. a cost-benefit basis. These studies may be technically adequate, especially to the Our findings lend further support to this conclusion. trained eye. Arguably, however, the findings are more difficult Specifically, we found that the mean cost of litigation (i.e., irre- to interpret than CT scans with reconstructed images. spective of outcome) is actually $2.9 million. However, certain Consequently, the evidence presented here can be interpreted problems are associated with establishing the cost of litiga- as supporting the use of diagnostic modalities, such as CT or tion. When a patient is evaluated for cervical injury, the injury MRI scanning, that are easy to interpret rather than basing jus- is missed, and litigation ensues, there may be multiple defen- tifications for the use of these modalities on their increased dants, which may or may not include the institution per se sensitivity per se. (i.e., hospital). Furthermore, each party may settle or litigate The incidence of radiographically occult injury as opposed to their culpability independently. We lacked comprehensive radiographic misinterpretation has been evaluated in two ret- data to address the litigation costs associated with all defen- rospective reviews on the origins of missed cervical spine dants in the individual cases analyzed. Rather, the present injuries. Davis et al. (24) reviewed the records of 32,117 patients data were limited to the cost to the provider evaluating the seen in San Diego County emergency departments and trauma patient at the time the injury was missed (i.e., the emergency centers. Of these, 740 had a cervical spine injury, of which 34 room physician, trauma surgeon, or neurosurgeon). Thus, this diagnoses were delayed or missed by 1 to 30 days. Of the 34 institutional cost may reasonably be expected to underesti-

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mate the entire “litigation cost” obtained by including all par- We think the patterns of error we have described are useful ties (e.g., hospital, radiologist, surgeon). in analyzing how the errors or delays in diagnosis described here could have been avoided. We have found that almost all of Causes of Litigation the Type I and III errors could have been easily avoided by Since the Institute of Medicine’s report To Err is Human was obtaining CT scans and flexion-extension x-rays (only one published in 1999, data have been reported on the incidence of injury was not evident on CT scans). Therefore, the number of iatrogenic injury related to medical error and on the percentage errors in the diagnosis of cervical spine injuries might be of error attributable to negligence (36). However, there is a reduced simply by the judicious use of imaging studies. A sub- paucity of data to suggest what kind of adverse events, negli- stantial number of Type II errors may have also been avoided gent or not, result in actions for medical malpractice. In fact, by the relatively greater ease of interpretation of CT scans. Type although Brennan et al. (13) determined that 28% of adverse II errors in which the physician fails to follow-up on ordered events were attributable to negligence, there was no correlation studies or fails to interpret a study correctly are the only errors between negligent adverse events and litigation. Nor is litiga- that the use of CT scanning would not have prevented. tion necessarily even correlated with actual injury, regardless of Importantly, these are cases in which the physician, by not fol- whether the result of an alleged adverse event is attributable to lowing up on an ordered study or by failing to diagnose a negligence or is the result of some other cause of action. clearly evident finding, failed to provide the standard of care Indeed, the connection between litigation and actual injury required for patients. Unsurprisingly, these are also the cases in may be tenuous. In a review of one neurosurgeon’s experience which no defense has been successful. as an expert in 866 litigated cases followed over 8 years, only No radiographic protocol will capture 100% of cervical 20% of the cases were found to have “authentic and support- spine injuries. Nevertheless, a combination of CT scanning able” injuries (29). Yet, 681 cases (76%) settled and an addi- and flexion-extension imaging studies would have likely tional 26 cases (3%) resulted in a verdict in favor of the plain- detected the injuries involved in all of the successfully liti- tiff. Thus, a causal, or even correlative, relationship between gated cases described in this study. In our opinion, that signif- errors in diagnosis or treatment, damage resulting from such icant morbidity could have been avoided by the use of addi- errors, and litigation being brought to bear as a result of this tional imaging studies such as CT scans and flexion-extension damage has never been demonstrated in the literature. films supports the early use of these studies in the clearance One goal of this study was to better define the factors con- of the cervical spine. Finally, because of the high documented tributing to errors in the diagnosis of traumatic cervical spine costs associated with litigation, the routine use of such stud- injury that lead to successful legal action. To our knowledge, no previous study has attempted to correlate specific diagnostic ies may also be justifiable from an institutional perspective of errors with the outcomes of litigation. We hope that our results cost effectiveness. will aid clinicians in the judicious use of appropriate imaging for clearance of the cervical spine. Specifically, the outcomes of REFERENCES litigation do not support the contention that more imaging is 1. Anonomyous: Radiographic assessment of the cervical spine in symptomatic necessarily a defense against litigation. Rather, the judicious trauma patients. Neurosurgery 50 [Suppl 3]:S36–S43, 2002. use of imaging studies is supported as long as the studies are 2. Anonymous: Vicki Plazola v. Danny L. Casey, MD and Ashok Madahar, MD, interpreted correctly and technically adequate. Clearing the No.YC 033 218. California Jury Verdicts Weekly, 2000. cervical spine based on clinical indications and on findings of 3. Deleted in proof. plain x-rays, even if an injury is later discovered on CT or MRI 4. Anonymous: Case name withheld. Nat J V Review & Anal 17:C2, 2001. scans, will not necessarily result in a finding of malpractice. The 5. Anonymous: Lee v. Levine. California Jury Verdicts Weekly, 2002. 6. Anonymous: Roberson v. Van Dyke. California Jury Verdicts Weekly, 2002. only “indefensible” error is to obtain studies that demonstrate 7. Anonymous: Hammer v. Kaiser Foundation Health Plan, Inc. Nat J V Review an injury and either fail to recognize the finding or fail to fol- & Anal 13:10, 2003. low up on the study. 8. Anonymous: Matson v. Gbalazeh. 2002 WL 454441 (ALM Tex Jury), 2003. 9. Anonymous: Simone Galik v. Clara Maass Medical Center et al.-167 N.J 341. CONCLUSION Supreme Court of New Jersey, 2005. 10. April RS, Lanfranchi R: Clinical criteria to rule out cervical-spine injury. Defensive medical practices such as the overutilization of N Engl J Med 343:1339, 2000. 11. Barba CA, Taggert J, Morgan AS, Guerra J, Bernstein B, Lorenzo M, Gershon diagnostic tests increases medical costs in ways that are diffi- A, Epstein N: A new cervical spine clearance protocol using computed cult to analyze. Ideally, medical decision making should not be tomography. J Trauma 51:652–657, 2001. influenced by socioeconomic concerns such as the perceived 12. Berkowitz M, O’Leary PK, Kruse DL, Harvey C: Spinal Cord Injury: An Analysis risk of litigation. Unfortunately, such defensive medicine is per- of Medical and Societal Costs. New York, Demos Medical Publishing, Inc., 1998. vasive in today’s medicolegal climate. This study is an attempt 13. Brennan TA, Leape LL, Laird NM, Hebert L, Localio AR, Lawthers AG, to introduce quantitative data on the extent of litigation in cases Newhouse JP, Weiler PC, Hiatt HH: Incidence of adverse events and negli- gence in hospitalized patients. Results of the Harvard Medical Practice Study of missed cervical injuries, with the goal of helping clinicians to I. N Engl J Med 324:370–376, 1991. make a rational cost-benefit analysis of their choice of imaging, 14. Bresler MJ, Rich GH: Occult cervical spine fracture in an ambulatory patients. rather than one motivated by fear. Ann Emerg Med 11:440–442, 1982.

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15. Case No 94–998-E: Walsworth v. Louisiana Medical Mutual Ins. Co. Verdicts, COMMENTS Settlements & Tactics, 1995. 16. Case No.64–61–36: Ringgenberg v. Regents of the University of California. his article by Lekovic and Harrington provides an interesting snap- Jury Verdict Weekly (California), 1993. Tshot of part of a clinical practice that we are all aware of but, in real- 17. Case No.791594: Willie Pennington and Renate Pennington. Nat J V Review ity, know very little about. I applaud the authors in their efforts to & Anal, 2000. bring objectivity to this important part of our lives. I think the authors 18. Case No.91–02308: Rodenbaugh v. Suburban General Hospital. Nat J V have recognized the limitations of their study and have taken the time Review & Anal, 1996. to spell them out for the reader. 19. Case No.97 C10131: Mynear v. Wright. Kentucky Trial Court Review, 2000. 20. Case No.CV-87–32632: Samurin v. Oei et al. National Jury Verdict Review The results were what one would reasonably expect. It is difficult to Analysis, 1990. defend oneself against misinterpretation of an investigation (Type II 21. Case No.D-32691: Annie Ruth Gay, Individually and as Executrix of the Estate error) when an adverse outcome is the result for the patient. Certainly, of Eula P. Denmark et al vs Piggly Wiggly Southern, Inc. Nat J V Review & the size of the awards (averaging 2.9 million per case) are cause for con- Anal, 1987. cern and exemplify the difficulties faced by American neurosurgeons 22. Case No.WEC 106966: Boyer v. Clark et al. Jury Verdict Weekly (California), with respect to malpractice insurance. 1991. It is difficult for me to accept that a defendant could be found neg- 23. Case number Unknown: Kaberline vs. Martha Washington Hospital, et al. ligent in a case in which proper tests were ordered and interpreted cor- Nat J V Review & Anal, December, 1990. rectly (Type III errors). Although it is not possible to dissect the reason- 24. Davis JW, Phreaner DL, Hoyt DB, Mackersie RC: The etiology of missed cer- vical spine injuries. J Trauma 34:342–346, 1993. ing from the data provided by Lekovic and Harrington, one can only 25. Docket No.85–4752 and FJVR Reference No.91:11–84: Vernon Johnson vs SAS conclude that, just as there is room for improvement in our practices, Ambulance Service, Inc., Emiliana E. Garcia, MD, St. Anthony’s Hospital, there is also room for improvement in the justice system. et al. Florida Jury Verdict Reporter, 1991. Perhaps this is the most important message of the entire article. 26. Docket no.88–43120 CA 11 and FJVR Reference No.90:8–31: William Lee & Those of us who have had our principles and practices examined Carolyn Lee, his wife vs AMISUB of Florida, Inc., d/b/a Southeastern through litigation are painfully aware of both the emotional and time- Medical Center, et al. Florida Jury Verdict Reporter, 1990. related costs involved in defending ourselves against such claims. 27. Docket number 89–008135: Pendergrass vs. McKenzie et al. Nat J V Review Regardless of how careful we think we are, the outcome of litigation is & Anal, 1993. largely dependent on how well, or how poorly, the judge or jury has 28. Docket Number PC009526(II): Coe vs Henry Mayo Newhall Memorial Hospital. Trials Digest Publishing, Inc., 2003. been educated by lawyers and expert witnesses. They are given the 29. Fager CA: Injury, pseudoinjury, and litigation. Surg Neurol 60:478–482, 2003. task of learning enough information in just a few weeks to be capable 30. Gerrelts BD, Petersen EU, Mabry J, Petersen SR: Delayed diagnosis of cervi- of passing judgment on skills that have taken decades to acquire. cal spine injuries. J Trauma 31:1622–1626, 1991. Decisions handed down in the court system can, therefore, be equally 31. Grogan EL, Morris JA Jr, Dittus RS, Moore DE, Poulose BK, Diaz JJ, Speroff or more faulty than the practices being scrutinized. T: Cervical spine evaluation in urban trauma centers: Lowering institutional Herein also lies the biggest limitation of this article. It is very impor- costs and complications through helical CT scan. J Am Coll Surg 200:160–165, tant that surgeons do not alter their practices with anticipation of the 2005. cases presented here. Without doubt, several of these legal decisions are 32. Guly HR: Diagnostic errors in an accident and emergency department. Emerg flawed and, therefore, provide a poor infrastructure on which to base Med J 18:263–269, 2001. 33. Hoffman JR, Mower WR, Wolfson AB, Todd KH, Zucker MI: Validity of a set our practice of medicine. This is especially pertinent in light of the hun- of clinical criteria to rule out injury to the cervical spine in patients with dreds of thousands of cases that are appropriately managed each year blunt trauma. National Emergency X-Radiography Utilization Study Group. through the same practices being examined in court. It is incumbent on N Engl J Med 343:94–99, 2000. us to practice medicine based on sound principles established by Class 34. Horn EM, Lekovic GP, Feiz-Erfan I, Sonntag VK, Theodore N: Cervical mag- I, II, and III evidence. Only then can our actions be properly defended netic resonance imaging abnormalities not predictive of cervical spine insta- in a court of law, even though the outcome cannot be guaranteed. bility in traumatically injured patients. Invited submission from the Joint I must disagree with the authors’ concluding statement that, because Section Meeting on Disorders of the Spine and Peripheral Nerves, March of the high documented costs associated with litigation, the routine use 2004. J Neurosurg Spine 1:39–42, 2004. of such studies may be justifiable from an institutional perspective of 35. Kirch W, Schafii C: Misdiagnosis at a university hospital in 4 medical eras. Medicine (Baltimore) 75:29–40, 1996. cost effectiveness. In best practice and in the best defensible practice, 36. Mace SE: The unstable occult cervical spine fracture: A review. Am J Emerg the ordering of routine medical tests must not be based on cost, litiga- Med 10:136–142, 1992. tion, or the needs of the physician or institution, but rather on the 37. McLauchlan CA, Jones K, Guly HR: Interpretation of trauma radiographs by needs of the patient. junior doctors in accident and emergency departments: A cause for concern? It would be a medical tragedy, a huge misuse of resources, and J Accid Emerg Med 14:295–298, 1997. harmful to our patients if C0–T1 spiral computed tomographic (CT) 38. Pendergrass, B. Pendergrass vs McKenzie and North Broward Hospital scans were to become a routine investigation for all types of cervical District, d/b/a Broward General Medical Center. Florida Jury Verdict spine trauma because of concerns over litigation. I refuse to believe this Reporter, March, 1993. is the type of outcome Lekovic and Harrington are advocating. Instead, 39. Robert KQ 3rd, Ricciardi EJ, Harris BM: Occult ligamentous injury of the cervical spine. South Med J 93:974–976, 2000. as they indicate, there are several excellent peer-reviewed algorithms 40. Stiell IG, Wells GA, Vandemheen KL, Clement CM, Lesiuk H, De Maio VJ, that continue to evolve and help us in our daily activities of clearing the Laupacis A, Schull M, McKnight RD, Verbeek R, Brison R, Cass D, Dreyer J, cervical spine (1–3). The reader should rely on these types of publica- Eisenhauer MA, Greenberg GH, MacPhail I, Morrison L, Reardon M, tions to aid in shaping their practice. Malpractice litigation may be an Worthington J: The Canadian C-spine rule for radiography in alert and stable unpleasant occurrence, but it should never be misconstrued as a prac- trauma patients. JAMA 286:1841–1848, 2001. tice guideline. 41. Sweeney JF, Rosemurgy AS, Gill S, Albrink MH: Is the cervical spine clear? Undetected cervical fractures diagnosed only at autopsy. Ann Emerg Med R. John Hurlbert 21:1288–1290, 1992. Calgary, Canada

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Eisenhauer MA, Greenberg GH, MacPhail I, Morrison L, Reardon M, 1. Anonymous: Radiographic assessment of the cervical spine in asymptomatic Worthington J: The Canadian C-spine rule for radiography in alert and stable trauma patients. Neurosurgery 50 [Suppl 3]:S30–S35, 2002. trauma patients. JAMA 286:1841–1848, 2001. 2. Hoffman JR, Mower WR, Wolfson AB, Todd KH, Zucker MI: Validity of a set of clinical criteria to rule our injury to the cervical spine in patients with blunt ailure to diagnose cervical spine fractures, subluxations, and insta- trauma. National Emergency X-Radiography Utilization Study Group. N Engl bility may potentially produce or exacerbate spinal cord injury and J Med 343:94–99, 2000. F 3. Widder S, Doig C, Burrowes P, Larsen G, Hurlbert RJ, Kortbeek JB: Prospective could result in legal liability for caretakers and hospitals. Although, as evaluation of computed tomographic scanning for the spinal clearance of the authors indicate, their survey has probably missed several cases of obtunded trauma patients: Preliminary results. J Trauma 56:1179–1184, 2004. failure to diagnose and their numbers are too small for statistical analy- sis, their data and classification of three error types are most informa- tive and instructive. They confirm that caretakers are vulnerable when ekovic and Harrington used two legal search engines and Medline adequate tests are ordered and either not read or misread (Type II Lin an effort to identify patients who pursued litigation after a error). It is interesting that defendants were more likely to win lawsuits missed or delayed diagnosis of a cervical spine injury. Twenty cases when they made a Type I error (inadequate or improper tests ordered). were identified and reviewed. The authors categorized the errors It seems that cervical injury is unlikely to be missed if CT scans are associated with a missed or delayed diagnosis into three groups. obtained after flexion-extension films. I agree that there should be a low Type II errors occurred when adequate tests were ordered and either threshold for obtaining CT scans. However, it is unclear which patients not read or misread. It is not surprising that all defendants obtained should have these studies. Although the authors focus on financial lia- unfavorable verdicts when a Type II error was alleged. The authors bility and a cost-benefit analysis of financial payout versus the cost of suggest that helical CT scans be used to clear the cervical spine as imaging studies, it is at least equally important to be aware of the opposed to plain x-rays. avoidable personal tragedies that may transpire as a result of missing A number of individuals have thoughtfully reviewed the literature a bony or ligamentous injury that renders the cervical spine unstable. and developed guidelines for the clearance of cervical spine injuries. Two of these works have been referenced by the authors (1, 2). The data Paul R. Cooper presented in this article is anecdotal. Routine use of helical CT scans to New York, New York clear the cervical spine in all trauma patients is probably not cost-effec- tive. Furthermore, it would not eliminate Type II errors. lthough Lekovic and Harrington have provided an interesting arti- Acle, the methodology of their analysis is admittedly flawed. Vincent C. Traynelis Nevertheless, the information and derived message presented seem to Iowa City, Iowa be useful. In spite of the varied opinions regarding the diagnosis and management of acute cervical spine trauma, the definition of a medicolegal impetus for algorithm modification seems justified. For the 1. Anonymous: Radiographic assessment of the cervical spine in asymptomatic provision of this insight, the authors are to be congratulated. trauma patients. Neurosurgery 50 [Suppl 3]:S30–S35, 2002. 2. Stiell IG, Wells GA, Vandemheen KL, Clement CM, Lesuik H, De Maio VJ, Edward C. Benzel Laupacis A, Schull M, McKnight RD, Verbeek R, Brison R, Cass D, Dreyer J, Cleveland, Ohio

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QUANTUM DOTS ARE PHAGOCYTIZED BY MACROPHAGES AND COLOCALIZE WITH EXPERIMENTAL GLIOMAS Heather Jackson, B.S. Brain Tumor Institute, OBJECTIVE: The identification of neoplastic tissue within normal brain during biopsy The Cleveland Clinic Foundation, Cleveland, Ohio and tumor resection remains a problem in the operative management of gliomas. A variety of nanoparticles are phagocytized by macrophages in vivo. This feature may Osman Muhammad, B.S. allow optical nanoparticles, such as quantum dots, to colocalize with brain tumors and Brain Tumor Institute, serve as an optical aid in the surgical resection or biopsy of brain tumors. The Cleveland Clinic Foundation, METHODS: Male Fisher rats (Charles River Labs, Wilmington, MA) were implanted Cleveland, Ohio intracranially with C6 gliosarcoma cell lines to establish tumors. Two weeks after the Hamid Daneshvar, M.S. implantation of tumors, 705-nm emission Qdot ITK Amino(PEG) Quantum Dots (Quantum Brain Tumor Institute, Dot Corp., Hayward, CA) were injected via the tail vein at doses of 3 to 17 nmol. The The Cleveland Clinic Foundation, animals were sacrificed 24 hours after the injection of quantum dots and their tissues Cleveland, Ohio were examined.

Jennifer Nelms, Ph.D. RESULTS: Quantum dots are avidly phagocytized by macrophages and are taken up by the liver, spleen, and lymph nodes. A dose-response relationship was noted. At low Brain Tumor Institute, The Cleveland Clinic Foundation, doses, the majority of the quantum dots are sequestered in the liver, spleen, and lymph Cleveland, Ohio nodes. At higher doses, increasing quantities of quantum dots are noted within the experimental brain tumors. Macrophages and microglia colocalize with glioma cells, Alexandra Popescu, M.D. carrying the quantum dot and thereby optically outlining the tumor. Excitation with Brain Tumor Institute, blue or ultraviolet wavelengths stimulates the quantum dots, which give off a deep red The Cleveland Clinic Foundation, Cleveland, Ohio fluorescence detectable with charge-coupled device cameras, optical spectroscopy units, and in dark-field fluorescence microscopy. Michael A. Vogelbaum, CONCLUSION: Quantum dots are optical nanoparticles that, when delivered in nanomole M.D., Ph.D. doses, are phagocytized by the macrophages and microglia that infiltrate experimen- Brain Tumor Institute, tal gliomas. The optical signal may be detected, allowing for improved identification The Cleveland Clinic Foundation, Cleveland, Ohio and visualization of tumors, potentially augmenting brain tumor biopsy and resection. KEY WORDS: Brain tumor, Fluorophore, Nanoparticle, Optical nanocrystal Marcel Bruchez, Ph.D. Quantum Dot Corporation, Neurosurgery 60:524–530, 2007 DOI: 10.1227/01.NEU.0000255334.95532.DD www.neurosurgery-online.com Hayward, California

Steven A. Toms, M.D., he distinction of tumor from normal brain approaches, including optical spectroscopy and M.P.H. is crucial to limit patient morbidity and the preoperative injection of fluorescent dyes, Brain Tumor Institute, improve the completeness of resection in have also been investigated to aid in surgical The Cleveland Clinic Foundation, T glioma surgery. Patient prognosis may be resection (13, 19, 26). Unfortunately, these tech- Cleveland, Ohio improved with aggressive surgical resection of niques are limited in their applicability because Reprint requests: high-grade gliomas (16), but it is often difficult of difficulties with tissue discrimination, speci- Steven A. Toms, M.D., M.P.H., or impossible to distinguish functional neural ficity of tumor uptake, and the photobleaching Brain Tumor Institute, Desk R20, tissue from glioma using existing methods. of fluorescent dyes (13, 19, 26). The Cleveland Clinic Foundation, Techniques such as intraoperative ultrasound One class of nanoparticles, the ultrasmall 9500 Euclid Avenue, Cleveland, OH 44195. and magnetic resonance imaging (MRI) scan- paramagnetic iron oxide particle (USPIO), has Email: [email protected] ning have shown promise in improving surgi- previously been shown to localize with experi- cal biopsy and resection of brain tumors. mental and human gliomas (9, 12, 15, 30). Received, May 23, 2006. However, these systems are not widely used Delivered intravenously, USPIOs are avidly Accepted, November 2, 2006. during surgical procedures (2, 3, 18). Optical phagocytized by elements of the reticuloen-

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dothelial system (RES), including the liver, spleen, and lymph male Fisher rats were used (Charles River Labs, Wilmington, nodes (6, 8, 27, 30). At high iron-loading doses, USPIOs are MA). Rats were anesthetized with 200 µl of ketamine (Fort taken up by peripheral tissue macrophages and may be Dodge Laboratories, Fort Dodge, IA) for tail-vein injections detected by MRI scans, effectively outlining inflammatory and and tumor implantation. neoplastic lesions (9, 12, 13, 15, 22, 26). Although USPIOs may be used with intraoperative MRI scanning to outline human Brain Tumor Models gliomas (12), intraoperative MRI scans are required to visualize Rats were injected using a rat stereotactic frame (David Kopf the nanoparticles, adding to the surgical time and expense. As Instruments, Tujunga, CA) using landmarks of 2.5 mm lateral a result, it is not anticipated that these techniques will be widely to the bregma and 1 mm anterior to the bregma with the ipsi- adopted outside of academic neurosurgical practices. Optically lateral basal ganglia as the target. After a twist drill cran- tagged USPIOs have been designed for multimodality imaging iotomy, 5 ϫ 105 C6 rat glioma cells (ATCC, Manassas, VA) via combining USPIOs and organic fluorophores, such as Cy5.5 were injected using a 27-gauge needle. Rats were housed in (15). Unfortunately, toxicity issues and rapid photobleaching of negative pressure isolation cages and tumors were grown for the organic dyes may limit the development of such nanoparti- 14 days before treatment. cles for clinical use. Quantum dots (QDs) are optical semiconductor nanocrys- MRI Scans tals that exhibit stable, bright fluorescence through narrow, Rats were anesthetized with 200 µl of ketamine and taken for size-tunable emission bands. The use of fluorescent semicon- MRI scanning. The animals were injected with 200 µl of ductor nanocrystals (QDs) for biological applications has been gadolinium (Berlex Laboratories, Wayne, NJ) via tail-vein injec- rapidly evolving (1, 4, 5, 11, 14, 17, 20). QDs are nanoparticles tion. After allowing 5 minutes of circulation time, T1-weighted constructed of an optical core surrounded by a protective shell. images were obtained on a 3-T MRI unit (Siemens AG, The shell may be modified to promote water solubility, to allow Erlangen, Germany) after positioning the animals within a conjugation to proteins and nucleic acids, and to improve cir- human wrist coil. Animals in which tumor growth was con- culation half-life (1, 4, 5, 11, 14, 17, 20). Previous studies have firmed were selected for QD injection. shown that the circulation half-life of QDs might be prolonged by increasing the length of polyethylene glycol (PEG) poly- QDs mers attached to the QD shell (1). QDot ITK Amino/PEG 705-nm emission QDs (Quantum Dot The size-tunable optical properties of QDs allow multiplex- Corp., Hayward, CA) were injected via a rat tail-vein method. ing with multiple emission wavelengths from a single excita- For 2 minutes, 3 to 17 nmol of the QDs were slowly injected. tion source (4, 5, 11, 20). QDs may be linked to antibodies, pep- tides, and nucleic acids for use as fluorescence probes in vitro Histopathology and in vivo (11, 20). QDs have been used in animal studies for mapping cell fate during development (7, 23), optical angiogra- After MRI scanning 24 to 48 hours after QD injection, the ani- phy (17), sentinel lymph node mapping (14, 25), monitoring the mals were sacrificed by CO2 and potassium chloride intracar- extravasation of tumor cells into the pulmonary vasculature diac injection. The animals’ brains, livers, spleens, and lymph (28), and conjugated to antibodies for visualizing tumor cells in nodes were fixed in a sucrose solution before formalin fixation. µ vitro and in vivo (10, 29). Formalin-fixed tissues were sectioned at 8 m using a cryostat A major difficulty limiting the in vivo use of nanoparticles (Leica Microsystems AG, Wetzlar, Germany). Tissue sections such as QDs is the phagocytosis of circulating nanoparticles by were stained with hematoxylin and eosin. Sections for QD visu- components of the RES. RES sequestration limits circulation alization were left unstained for ultraviolet (UV) microscopy half-life, thus impeding the delivery of circulating nanoparti- (Nikon, Melville, NY). cles to target tissues (21, 30). Tissue macrophages and microglia Immunohistochemistry was performed with primary anti- are phagocytic cells that infiltrate gliomas and accurately out- bodies to glial fibrillary acidic protein (GFAP) (Sigma-Aldrich, line glioma tumor borders (9, 12, 15). We hypothesized that Cambridge, MA), CD11b (Serotec, Raleigh, NC), and secondary QDs might be delivered in concentrations to saturate RES antibodies of fluorescein isothiocyanate (Sigma-Aldrich) and uptake, permitting phagocytosis by glioma tumor-infiltrating 525-nm-emitting QD secondary antibodies (Quantum Dot tissue macrophages and optically outlining solid, non- Corp.). infiltrative experimental glioma. Fluorescence Imaging QDs were visualized in whole organs using a fluorescence- MATERIALS AND METHODS imaging chamber (filter set no. 3, IVIS system; Xenogen, Alameda, CA). Stereoscopic images of thick tissue slices Animals were imaged with a stereoscope (Leica Microsystems AG) Animal care was in accordance with approved institutional using a filter set optimized for 705-nm QDs (400 nm Ϯ 50 nm protocols from the Lerner Research Institute of the Cleveland excitation; 705 nm Ϯ 20 nm emission) (Chroma Technology Clinic Foundation, Cleveland, OH. For these studies, 350-g Corp., Rockingham, VT). UV photomicroscopy was per-

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A B TABLE 1. Quantum dot concentration increase in brain only after quantum dot saturation of liver uptakea QD concen- Mean QD SD P value tration (nmol) counts/HPF Brain 3.4 0.3 0.7 0.001b 8.5 8.0 5.4 0.000045c 17 114.4 45.3 Liver 3.4 126.8 19.0 0.028d 8.5 178.4 16.7 0.50e 17 167.8 28.5 C a QD, quantum dots; HPF, high-power fields; SD, standard deviation. D b Comparison of injection of 3.4 nmol versus 8.5 nmol QDs. c Comparison of injection of 8.5 nmol versus 17 nmol QDs. d Comparison of injection of 3.4 nmol versus 8.5 nmol QDs. e Comparison of injection of 8.5 nmol versus 17 nmol QDs.

Further increases in the injected dose of QDs to 17 nmol had no apparent acute toxicity on the animals during the course of the experiments. There was no evidence of injury or inflamma- tion in any of the brain, liver, spleen, or lymph node tissues studied microscopically. Microscopic examination of RES tis- FIGURE 1. Low-magnification opti- sues showed a small increase in the QD concentration in these cal imaging (original magnification, tissues between the 3.4- and 8.5-nmol injection levels. However, ϫ8–25) of the liver (A), spleen (B), there was no significant difference in the concentration of QDs and lymph nodes (C) of rats injected with 3.4 nmol of QDs. At this dose, high- in the RES between 8.5 and 17 nmol. This suggests that maxi- power microscopy detected few QDs in experimental rat gliomas. D, at injec- mal RES phagocytosis of QDs was reached between the 3.4- tions of 8.5-nmol, QDs were more frequently detectable with high-power and 8.5-nmol doses. RES saturation limiting further QD phago- ϫ microscopy (original magnification, 200) but remained undetectable on low- cytosis occurred before the large increases in the number of power or whole-organ imaging. QDs visualized in brain tumors themselves at 17-nmol QD injection (Table 1). formed on a microscope at a magnification of ϫ200 (Nikon) At 17 nmol, the highest dose studied, optical imaging tech- and images were collected using a camera system (Polaroid, niques identified QD-specific fluorescence within the experi- Waltham, MA) before digital storage (Dell Computers, mental gliomas at the whole-brain and tissue-slice levels Round Rock, TX). (Fig. 2, A–E). In some animals, fluorescence imaging identified satellite tumors distant from the implant site (Fig. 2C). Hema- Statistics toxylin and eosin stains and UV microscopy were used to con- QD counts per high-power field were recorded from the liv- firm that the region of fluorescence contained tumor cells and ers and brains of two animals at each dose. Data was entered in QDs in both the primary tumor implants and the satellite Sigma Plot 2001 (Systat Software, Inc., Point Richmond, CA). lesions. This example demonstrates the ability of QD-based Means, standard deviations, and paired t tests were used to optical imaging techniques to outline even small, submillime- analyze the data. ter metastatic lesions. QDs identified within the brains of experimental animals RESULTS seemed to home specifically to the gliomas. Control, nontumor-bearing animals administered QDs had no evi- A dose-response relationship was observed between the dence of QDs in brain tissues. Similarly, the “normal” con- amount of QDs injected and the concentration of QDs in exper- tralateral hemispheres of animals with gliomas had no QDs imental glioma. With 3.4-nmol injections of QDs, the liver, present. Even the normal white matter immediately adjacent spleen, and lymph nodes had large concentrations of QDs to tumor borders was without QDs (Fig. 3A). Confocal (Fig. 1, A–C), but few QDs were identified in the rat brain microscopy using immunoreactivity to GFAP, an intermedi- tumors. With injections of 8.5 nmol, QDs were more frequently ate filament found in the cytoplasm and dendritic processes visible in experimental gliomas by high-power UV microscopy of normal astrocytes, demonstrated that QDs were absent (Fig. 1D). However, the number of QDs remained below the from GFAP-positive astrocytes (Fig. 3B). Instead, the QDs detection threshold of optical imaging techniques in thick, low- were specifically localized to CD11b-positive cells, the macro- power tissue slices or at the whole-brain level. phages and microglia (Fig. 3C).

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ACB DISCUSSION In the treatment of human gliomas, patient survival corre- lates with the extent of resection (16). Image-guided surgery, nearly universally used in the surgery of gliomas, relies on pre- operative images, such as MRI scans, to guide the neurosur- geon during tumor biopsy and resection (24). Unfortunately, the spatial resolution of the preoperative data degrades during a procedure because of registration inaccuracies and brain tis- sue shifts during brain tumor resection (24). Optical techniques, such as optical labeling of tumors with QDs, could provide the surgeon with critical data regarding the location of the tumor D during tumor resections and biopsies in real-time. Additional modifications to QDs, such as coating the QD shell with gadolinium, a paramagnetic MRI scan contrast agent, seem capable of preserving QD optical properties and adding the ability to detect QDs with MRI scanning (11). A QD conjugated to gadolinium might, therefore, function as a mul- timodal imaging particle detectable preoperatively by MRI scanning for surgical navigational studies and intraoperatively using optical techniques. Such a multimodal imaging particle could provide the surgeon with feedback regarding the location of tumor and completeness of resection during glioma surgery, improving on the inherent inaccuracies of current systems of image-guided surgery that rely solely on preoperative imaging. The technique described in this study, the optical labeling of tumors with nanoparticles colocalizing with macrophages within tumor boundaries, has the potential to work for a vari- E ety of inflammatory and neoplastic lesions that attract macrophages. Although it is possible that circulating macro- phages phagocytize QDs and are drawn to the tumor by cyto- kines, we hypothesize that the dual CD11b/QD-positive cells within tumor borders are the resident tumor-infiltrating macrophages and microglia. We think polyethylene glycol- coated QDs are able to saturate the RES when delivered intra- venously at doses of nanomoles of QDs per kilogram of body weight. This dose of QDs enhances the exposure of circulating QDs to tissue macrophages and microglia in or near the brain tumors, effectively tagging them optically. Optical imaging and optical spectroscopic systems are avail- able to identify QDs that emit in the red or near-infrared spec- tra (19, 25). Optical detection systems are relatively inexpensive compared with intraoperative techniques such as MRI scan- ning. Existing optical systems may be easily adapted to open surgical resections of tumors in an attempt to improve surgical resections and patient survival. Prototype systems that use fiberoptic channels to deliver and collect light have been designed to fit inside human brain biopsy needles. Preliminary FIGURE 2. Fluorescence imaging of control brain (A) and two experimental testing in animal models suggests that nanoparticle-assisted, gliomas (B and C). Note that there are both primary (red arrow) and satel- optical spectroscopically guided brain biopsy is feasible lite (green arrow) lesions on the surface of the brain in C. D, hematoxylin and (unpublished data). If these preliminary tests are confirmed, eosin staining of the frontal tumor shown in C, showing the blue hypercellu- larity of this tumor on the cortical surface of the brain. E, fluorescence imag- these techniques may permit less invasive, more accurate, opti- ing of brain surface of the tumor shown in C and D at an original magnifica- cally guided surgical procedures in the brain and elsewhere in tion of ϫ20 showing vivid fluorescence emanating from the QDs localized the body. within the superficial tumor (arrows) versus the black background of the nor- The emission wavelength of the QDs used would depend mal brain. on the application. QDs that fluoresce in wavelengths from

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A At this time, QDs are in the preclinical evaluation stage and are not available for human clinical trials. The federal govern- ment has developed a new mechanism, the Nanotechnology Characterization Laboratory (NCL) of the National Cancer Institute, to evaluate the safety of QDs and a growing number of newly developed nanoparticles. At the present time, animal studies have not shown evidence of significant toxicity from QDs despite their semiconductor, heavy metal composition of cadmium, lead, or arsenic cores. It seems that the zinc-sulfide capping shell used to make water-soluble QDs functional pre- vents the ionization of the heavy metal cores (1). Nonetheless, the potential for significant toxicity exists and will be analyzed by the NCL before the issuance of an investigation device exemption necessary for clinical trials. It is anticipated that the preclinical toxicological evaluation of the first generation of fluorescent nanoparticles such as QDs will emerge from the B NCL and be available for human clinical trial development within 3 years (personal communication, Scott E. McNeil, Ph.D., Director, NCL, October 2005). We have demonstrated that the intravenous delivery of QDs in nanomolar concentrations can saturate the phagocytic capa- bility of the RES. This allows phagocytic cells in other regions of the body, such as tumor-infiltrating macrophages, to engulf QDs, optically outlining the solid portion of the tumor mass. Optical imaging and spectroscopic techniques exist to use this information to guide the completeness of surgical resection of tumors or to aid in the identification of tumors during needle biopsy, potentially improving patient outcomes in brain tumor surgery.

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10. Gao X, Cui Y, Levenson RM, Chung LW, Nie S: In vivo cancer targeting and Acknowledgments Nat Biotechnol imaging with semiconductor quantum dots. 8:969–976, 2004. Quantum dot materials were developed with partial support from the 11. Gao X, Yang L, Petros JA, Marshall FF, Simons JW, Nie S: In vivo molecular National Institutes of Health/National Institute of Biomedical Imaging and Curr Opin Biotechnol and cellular imaging with quantum dots. 16:63–72, Bioengineering Research Partnership Program R01 EB 000364 and the National 2005. Institute of Standards and Technology Advanced Technology Program 70 NAN 12. Hunt MA, Bago AG, Neuwelt EA: Single-dose contrast agent for intraopera- BOH 3000. tive MR imaging of intrinsic brain tumors by using ferumoxtran-10. AJNR Am J Neuroradiol 26:1084–1088, 2005. 13. 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his study demonstrates that macrophage-rich pathologies, such as The authors are to be congratulated on this innovative work. We Thigh-grade gliomas, can be labeled with quantum dots; therefore, look forward to their continuing studies, which will hopefully bring they can be identified as targets when viewed under ultraviolet light. this to clinical completion. This has practical applications. Viewing these dots in the operating Mitchel S. Berger room enables the surgeon to determine that the biopsy is a sample of San Francisco, California the target and facilitates efficient pathological evaluation. What this technique cannot do is provide specificity because other macrophage- uantum dots are optical nanoparticles that are readily phagocy- infiltrated pathologies, such as stroke and multiple sclerosis, will also tized by macrophages. The authors set up an animal model using take up the quantum dots. These non-tumor pathologies can resemble Q the C6 rat glioma cell line implanted into rat brains to observe whether tumors on anatomic imaging, and this technique will not help to differ- or not peripherally injected quantum dots would be taken up by retic- entiate between them. Regardless, I can foresee that using quantum uloendothelial cells, some of which would then travel to localize within dots will help ensure that the surgeon is sending target tissue to the the growing brain tumor. Fluorescence imaging was then be used to pathologist. Whether or not this strategy achieves clinical use remains visualize the quantum dot cells and provide indirect imaging of the to be determined. implanted tumor. Joseph M. Piepmeier At high doses of quantum dot injections, the authors were able to New Haven, Connecticut successfully outline the tumor using optical imaging. Immuno- histochemical analysis provided data colocalizing the quantum dots with CD11b-positive cells, which was interpreted to represent specific he authors describe very interesting and innovative experimental uptake by tumor-infiltrating macrophages and microglia. The authors data on the use of a quantum dot nanoparticle that could be used as T suggest that the intraoperative determination of tumor margins during an optical imaging agent for tumor cells. The mechanism in which quan- resection could be optimized using this technique. tum dots are incorporated into tumors is probably related to the phago- The utility of such technology for intraoperative imaging during cytosis of the quantum dots by macrophages in microglia that infiltrate glioma resection would be significant in the clinical setting. Whether or tumors. Thus, this is not a direct incorporation of the quantum dot by the not such a system could be used for humans remains to be seen. The tumor cell. Therefore, the imaging may be only as good as the degree of choice of the noninvasive C6 rat glioma model is unfortunate because macrophage infiltration into the tumor cells. This leads to the intriguing there are few histological and anatomical parallels between C6-derived question of whether or not the infiltrating tumor cell itself could be tumors and the much more invasive human correlate. Because the pro- detected in the brain adjacent to the tumor with any likelihood of using posed goal for the development of quantum dot imaging is to improve this as an intraoperative detection methodology. This would also require the ability to identify the limits of tumor invasion during surgical resec- some form of intraoperative optical imaging. The other potential prob- tion, the use of an animal model that demonstrates invasive tumor lem with this technology is that quantum dots are toxic and cannot be growth is desirable as an additional step toward evaluating the feasi- given to patients. This is a very interesting technology and could be bility of clinical application. used in the future to image the true extent of the lesion in a way that MRI is not capable of doing; it could also be used as a method of intraopera- Allen Waziri tive detection of infiltrating tumor cells. This would be a very welcome Jeffrey N. Bruce addition to current intraoperative detection methods. New York, New York

Renal biopsy specimen of Glu526Val variant of fibrinogen A ␣-Chain amyloidosis. Immunohistochemical staining shows presence of fibrinogen within the deposits (left, x100), middle image displays enlarged glomeruli and normal tissue architecture virtually obliterated by amyloid deposits (viewed under cross-polarized light, x100), right panel shows same section (Congo red stain, x100). Courtesy of Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, Pepys MB, Hawkins PN: Misdiagnosis of hereditary amyloido- sis as AL (Primary) amyloidosis. N Engl J Med 346:1786–1791, 2002. EXPERIMENTAL STUDIES

P53 MAY PLAY AN ORCHESTRATING ROLE IN APOPTOTIC CELL DEATH AFTER EXPERIMENTAL SUBARACHNOID HEMORRHAGE

Julian Cahill, M.B. OBJECTIVE: Secondary brain injury after subarachnoid hemorrhage (SAH) is poorly Department of Physiology, understood. As a result, there are few treatment options. Consequently, SAH is associ- Loma Linda University ated with a high rate of morbidity and mortality. In an effort to combat these problems, Medical School, Loma Linda, California the role of apoptosis was examined in the whole brain after SAH. In particular, the role of p53 and the three major apoptotic cascades were studied, the caspase-dependent John W. Calvert, Ph.D. and caspase-independent cascades and the mitochondrial pathway. Department of Physiology, METHODS: In this study, 195 Sprague-Dawley rats were divided into three groups, includ- Loma Linda University α Medical School, ing sham, nontreatment, and treatment (Pifithrin- ; BIOMOL, Inc., Plymouth Meeting, Loma Linda, California PA) groups. The monofilament puncture model was used to induce SAH and the animals were subsequently sacrificed at 24 and 72 hours. Western blot analysis, histology, phys- Suzzanne Marcantonio, B.S. iological parameters, terminal deoxynucleotidyl transferase-mediated deoxyuridine Department of Physiology, triphosphate nick end-labeling, and immunohistological techniques were used to demon- Loma Linda University strate the role of p53 and the apoptotic cascades in the rat brain after SAH. In addition, Medical School, Loma Linda, California outcome was determined based on mortality rates and neurological outcome scores. RESULTS: We found that p53 and associated apoptotic proteins were up-regulated after John H. Zhang, M.D., Ph.D. SAH and that downstream mediators of apoptosis were negatively influenced by the Department of Physiology, inhibition of p53 by Pifithrin-α. Furthermore, we found that apoptotic inhibition resulted Loma Linda University Medical School, in less cell death and an overall favorable outcome in the treated animals. Loma Linda, California CONCLUSION: These results suggest that apoptosis may be an important cause of cell death in the brain after SAH and that p53 may play an orchestrating role regarding Reprint requests: John H. Zhang, M.D., Ph.D., apoptosis in SAH. Division of Neurosurgery, KEY WORDS: Apoptosis, Early brain injury, p53, Subarachnoid hemorrhage Loma Linda University Medical Center, Neurosurgery 60:531–545, 2007 DOI: 10.1227/01.NEU.0000249287.99878.9B www.neurosurgery-online.com 11234 Anderson Street, Room 2562B, Loma Linda, CA 92354. Email: [email protected] espite intensive research efforts in the ment of the secondary brain injuries associated field of subarachnoid hemorrhage with SAH (5, 17, 19, 23, 36). Early brain injury Received, May 8, 2006. D(SAH), little progress has been made to has recently been used to describe some of the Accepted, October 5, 2006. attenuate the often crippling secondary brain more immediate pathological processes occur- injuries associated with SAH (38). SAH re- ring before the onset of vasospasm and has mains an important cause of premature death now been recognized as a primary cause of and disability, accounting for 5% of all strokes mortality in SAH patients (2, 6). As a result, worldwide. Approximately 6% of the popula- early brain injury should be considered a pri- tion harbor an intracranial aneurysm and 10 mary target for research to combat these out of 100,000 people experience SAH every injuries (8). year (25). SAH is associated with a mortality The role of apoptosis has been previously rate of 12% before hospital admission and an described in detail with regard to stroke and additional 40% within 1 month of admission other ischemic pathologies (3, 4, 15, 16, 24, 51). (37). With a morbidity rate of 30% for sur- However, the role of apoptosis in relation to vivors, it is easy to see why SAH is such a dev- SAH has not been described in detail. The astating disease (14, 18, 40, 42). tumor suppressor p53 is a transcription factor To date, research efforts have focused largely that may play a central role in the organization on vasospasm in relation to SAH, to the detri- and orchestration of apoptosis (21, 27, 28, 33,

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35, 41). It was previously shown that p53 plays an important bars (Kent Scientific, Torrington, CT) and a microcraniectomy role in the development of vasospasm after SAH (7, 49). It is was performed on the side contralateral to the puncture, as thought that p53 is stabilized in the cytoplasm as a result of the previously described (30). Blood flow was measured using a physiological changes that occur as a direct result of SAH, laser Doppler monitor (Periflux System 5000; Perimed, Järfälla, which has been well described previously (26). It has been Sweden), which generated a laser beam at a wavelength of 740 shown that p53 is stabilized through a pathway involving the nm, which is capable of penetrating the brain tissue to a depth death receptors, particularly tumor necrosis factor-α and pos- of 1 mm. Once the probe was securely in place, the animal was sibly Fas (48, 49). secured in a supine position and a rectal thermometer was In light of these facts, the objective of this study was to deter- inserted. The animal’s temperature was maintained at mine the short- and long-term roles of the apoptotic machinery 37.0 Ϯ 0.5ЊC with the use of a heating pad. in SAH in brain tissue. The role p53 plays in the orchestration The carotid tree was dissected as previously described (20, of these cascades was also examined. Three recognized apop- 30, 32), and a 4–0 sharpened monofilament suture was placed totic pathways were examined, the caspase-dependent and in the external carotid artery stump and threaded up to the caspase-independent pathways and the mitochondrial path- junction of the middle cerebral artery and the anterior cerebral way. Cytochrome C was chosen to represent the mitochondrial artery via the internal carotid artery. The suture was then pathway, apoptosis-inducing factor (AIF) was chosen to repre- pushed through the middle cerebral artery and anterior cere- sent the caspase-independent pathway, and caspases 3 and 8 bral artery junction to a depth of approximately 1 mm to create were chosen to represent the caspase-dependent pathway. By SAH. A similar procedure was performed for the sham group, examining these five proteins, we hoped to provide an except that a blunt 4–0 suture was used and was removed once overview of the apoptotic pathways in this model. resistance was felt at the middle cerebral artery and anterior cerebral artery junction. In all cases, the suture was removed immediately and the vessel clamps were released to allow nor- MATERIALS AND METHODS mal blood flow to resume. The animals were maintained on the All experiments were performed according to the rules of the ventilator until they were capable of normal respiration, at which time they were returned to the vivarium. Animal Experimentation and Guide for the care and use of ϩ Laboratory Animals of Loma Linda University, Loma Linda, CA. Three hours after the procedure, both the SAH DMSO group and the SAH ϩ PFT-α group received an intraperitoneal α Experimental Groups injection of either DMSO or PFT- , which was administered blindly. PFT-α is a small lipophilic compound capable of cross- One hundred and ninety-five Sprague-Dawley male rats ing the BBB. PFT-α inhibits p53 deoxyribonucleic acid binding weighing between 280 and 350 g were randomly assigned to activity and the activation of the p53 responsive gene (bax) ϩ one of three groups: sham, SAH dimethyl sulfoxide (DMSO) without affecting the production of p53 (49). ϩ α (nontreatment), or SAH Pifithrin (PFT)- (BIOMOL, Inc., PFT-α was administered at a dose of 2 mg/kg and then diluted Plymouth Meeting, PA) (treatment). Tissue samples were taken in DMSO to a final volume of 2 ml. This dose was decided from at 24 and 72 hours for analysis. A total of 42 animals were used careful titration experiments performed by Culmsee et al. (10, 11), for each group, 21 animals per time point. Six animals were who concluded that smaller doses were ineffective and higher required for Western blot analysis, brain weights, and blood- doses were associated with cell death. The nontreatment group brain barrier (BBB) breakdown and three animals were simply received DMSO at the same volume. required for histology, immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphos- Mortality and Neurological Scores phate nick end-labeling (TUNEL). The neurological scores were recorded in a blinded fashion Experimental SAH Rat Model at 6, 24, 48, and 72 hours. The neurological examination was performed using the modified (30, 32) scoring system of Garcia In this experiment, the rat SAH monofilament puncture model et al. (13). The maximum score using this system is 27 and the was used as previously described by this laboratory (30, 32) and minimum score is 9. Three aspects were examined: motor score, originally described by Bederson et al. (2) in 1995. Briefly, each sensory score, and reflexes. Mortality was calculated at the same animal underwent an anesthetic induction using 4% isoflurane time points, as well as the immediate intraoperative mortality. with 60% medical air and 40% oxygen and was maintained with a mixture of 2% isoflurane. Each animal was intubated and mechanically ventilated using a small animal ventilator (Harvard Brain Water Content Apparatus model 683; Harvard Apparatus, Holliston, MA) Brain water content was calculated using the formula (wet throughout the entire procedure. Each animal had a femoral line weight Ϫ dry weight) Ϭ wet weight ϫ 100% and was recorded inserted for analysis of blood pressure, heart rate, and ease of at 24 and 72 hours. After sacrifice, each animal’s brain was blood sample collection for blood gas and glucose analysis. removed and weighed immediately to obtain the wet weight, To measure the cerebral blood flow (CBF), each animal was then dried at 105ЊC for 48 hours to obtain the dry weight, as placed in a Benchmark stereotactic frame with 45-degree ear previously described by others (31, 46).

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BBB Permeability ingen (BD Biosciences, San Jose, CA). In addition, phosphory- The BBB permeability was also measured at 24 and 72 hours, lated p53 (p-p53) antibody (Ser 15) was purchased from Cell according to the procedure described by Uyama et al. (44) and Signaling Technology (Danvers, MA). previously performed by us (31). Briefly, Evan’s blue dye was Immunoblots were processed with secondary antibodies administered through a femoral line at a dose of 5 ml/kg (2%) for 1 hour at room temperature and were then probed with an and allowed to circulate for 1 hour while the animal was anes- ECL Plus chemiluminescence reagent kit (Amersham, Newark, NJ) to visualize the signal before exposure to x-ray thetized. After this, phosphate-buffered saline (PBS) was β infused through the femoral line until a clear effluent was film. As an internal control, -actin (C-11) (Santa Cruz observed emerging from the left ventricle. The animal was then Biotechnology, Inc.) was blotted on the same membranes after sacrificed and the brain was removed. The brain was divided stripping (28). The x-ray films were scanned and the optical into the right and left hemispheres, brainstem, and cerebellum. density was determined using Image J (National Institutes of The amount of Evan’s blue dye was determined by spectroflu- Health, Bethesda, MD). orophotometry. Measurements were performed at an excita- tion wavelength of 620 nm, an emission wavelength of 680 nm, Histology, Immunohistochemistry Staining, and TUNEL and a bandwidth of 10 nm. At the 72-hour time point, the animals were sacrificed in a fashion similar to that described above. On this occasion, how- Western Blot ever, the animals were perfused with 60 ml of 0.1 mol/L PBS (pH 7.4) and 60 ml of 4% formalin in 0.1 mol/L PBS (pH 7.4). Western blot analysis was performed as described previ- After perfusion, the brains were removed, postfixed in forma- ously (9, 43, 47, 49). Briefly, animals under anesthetic were lin, and stored at 4ЊC until use. Paraffin-embedded brains were infused with 200 ml of ice-cold 0.1 mmol PBS through the left then sectioned (9) and stained with Nissl stain, as previously ventricle. Brains were then removed and snap frozen using described (30). liquid nitrogen and stored at Ϫ80ЊC until analysis. The frozen Immunohistochemistry was performed at 24 hours, as previ- brain samples were homogenized in extract buffer (50 mmol/L ously described (50). Briefly, sections were rehydrated and Tris-HCl, 150 mmol/L NaCl, 1% Triton X-100, 10% glycerol, treated with 3% hydrogen peroxide (H O ) for 10 minutes to 1 mmol/L ethylenediamine tetra-acetic acid, 1 mmol/L ethyl- 2 2 prevent reaction with endogenous peroxidases, followed by ene glycol tetra-acetic acid, 1 mmol/L NaF, 20 mmol/L treatment with a blocking serum for 1 hour at room tempera- Na P OP , 2 mmol/L Na VO , 0.1% sodium dodecyl sulfate, 4 2 2 3 4 ture. Incubation with the primary antibodies was performed 0.5% deoxycholate, 1 mmol/L phenylmethylsulfonyl fluoride, overnight at 4ЊC. The same antibodies for p-p53 and caspase 3 10 nmol/L leupeptin, and 10 nmol/L pepstatin A, pH 7.4) and used for Western blotting were also used for immunohisto- centrifuged (Marathon 21000R centrifuge; Fisher Scientific, chemistry. After washing in PBS, the sections were treated with Pittsburgh, PA) at 1300 ϫ g for 2 minutes at 4ЊC to remove the a goat or rabbit ABC kit (Santa Cruz Biotechnology, Inc.) for cellular debris. p-p53 and caspase 3, respectively. The sections were then incu- The resultant supernatant samples were further centrifuged bated in the biotinylated secondary antibody for 30 minutes at 16,000 ϫ g for 30 minutes at 4ЊC. The supernatant (postmito- and treated with the AB enzyme according to the manufac- chondrial fraction) was removed so the pellet (mitochondrial turer’s instructions. The subsequent peroxidase activity was fraction) could be resuspended in the extract buffer. Aliquots of revealed by staining the sections in a combination of 3-3؅ each fraction were then used to determine the protein concen- diaminobenzidine and H O at room temperature for 5 min- tration of each sample using a DC protein assay (BioRad, 2 2 utes. Sections were dried and coverslips were applied. To pro- Hercules, CA). Protein samples (50 µg) for p53 and AIF were vide a negative control, the control serum was applied to some then placed in a sample buffer (125 mmol/L Tris, 4% sodium slides instead of the primary antibody. dodecyl sulfate, 20% glycerol, 10% β-mercaptoethanol, and TUNEL staining was performed at 24 hours, as previously 0.025% bromophenol blue, pH 6.8), denatured at 95ЊC for described, using a TUNEL staining kit (Roche Inc., Basel, 5 minutes, and electrophoresed in a 7% dodecyl sulfate- Switzerland). The TUNEL-positive cells were expressed by flu- polyacrylamide gel at 125 V (Mini Protean 3; BioRad). The pro- orescein deoxyuridine triphosphate with deoxyribonucleoside tein samples (50 µg) for caspase 3 and 8 and cytochrome C -triphosphate or horse-radish peroxidase with 3-3؅ diaminoben were electrophoresed in Tris-Tricine gradient gels (BioRad). The zidine, according to the manufacturer’s instructions (49). proteins were then transferred to a nitrocellulose membrane at 80 V for 75 minutes. Membranes were then blocked with 5% nonfat milk in Tris-buffered saline for 2 hours. Data Analysis The membranes were incubated overnight at 4ЊC with the Data is expressed as the standard error of the mean (SEM). primary antibodies. The following primary antibodies were Statistical significance was assured by one-way analysis of vari- purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, ance (ANOVA) followed by the Tukey test for multiple compar- CA): goat polyclonal anti-cytochrome C (C20); goat polyclonal isons. The clinical behavior scores were compared by Kruskal- anti-AIF (D-20); and goat polyclonal anti-caspase 8 (T16). Rab- Wallis one-way ANOVA on ranks; if these were significant, bit polyclonal anti-caspase 3 was purchased from BD Pharm- t tests were performed. A P value of less than 0.05 was consid-

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ered statistically significant. Mortality was analyzed using the Gehan-Breslow survival curve. A

RESULTS

Physiological Variables An acute drop in blood pressure was noted immediately after the puncture, but returned to normal or slightly above normal during the course of the following 2 hours (data not shown). We associated an acute increase in blood pressure in this experimental model with death. Depending on the model and the individual studies, blood pressure has been shown to decrease, increase, or remain at baseline levels (2, 30, 39). There was no significant difference noted between the treatment and nontreatment groups (data not shown). The blood pressure for B the sham group remained at baseline. The blood gas analysis revealed no statistical difference between the groups and the pO2 remained within normal lim- its. Therefore, hypoxia was not a factor. All variables were measured at the start of the experiment to determine the base- line and before and after the puncture to eliminate bias regard- ing the surgical procedure, anesthetic, ventilation, etc. (data not shown). A modest increase in the glucose levels in the pre- puncture measurements and a significant increase in the post- puncture group were noted. We think this is in response to the SAH as a stress event; thus, this is a normal pathophysiologi- cal response in this model. As expected, the CBF measurements showed an acute drop in blood flow in the SAH groups and there was no statistical differ- FIGURE 1. Line graphs demonstrating outcome and neurological ence between the SAH groups (data not shown). The SAH groups scores. A, Gehan-Breslow survival graph. The total mortality rate for experienced a decrease in CBF to approximately 30% of normal; the experiment was 35.4%. No animals in the sham group died. At the 48- and 72-hour time points, a significant difference (P Ͻ 0.05) was the CBF rose to 60% of baseline during the following 2 hours. This observed between the treated and nontreated groups. B, neurological data is in keeping with previous studies (2, 30). The sham group scores in different groups. There was a statistically significant difference did not deviate from baseline throughout the procedure. between the sham groups and the SAH groups at all time points. A small but significant difference in the treated and nontreated groups was Mortality noted at 48 and 72 hours but not at the 6- or 24-hour time points. Ͻ The overall mortality rate for this experiment was 35.4%, Asterisk, P 0.05 compared with the sham group; double asterisk, Ͻ which is consistent with previous studies (30, 32). No animal in P 0.05 compared with the nontreatment and sham groups (ANOVA the sham group died. In the first 3 hours, the overall mortality with Tukey test). was 40.6% between the groups. Because the treatment was not administered until 3 hours after the insult, this time point does seems to suggest this as well, certainly with regard to mortal- not divide the animals into treatment or nontreatment groups. ity. The mortality data was analyzed using a Gehan-Breslow At the 6-hour time point, a small but noteworthy difference test, which found a significant difference between the survival was observed; 17.4% of the nontreatment and 13.0% of the curves. These data are represented in Figure 1A. treated groups died. However, at 24 hours, a significant differ- ence between the two groups was observed and the nontreat- Neurological Scores ment group had a mortality rate of 23.2%, whereas the treat- Neurological examinations were performed as early as 6 ment group had a mortality rate of 5.7%. Therefore, the overall hours (Fig. 1B). A decreased score was found in all groups, mortality rates for the nontreatment (after 3 h) and treatment including the sham group, at the 6-hour time point, which we groups were 40 and 23.6%, respectively. think was a result of the anesthetic because these animals were Interestingly, after 24 hours, the mortality rate was zero also ventilated for 2 hours. However, after this point, some ani- across the board. Most studies using this model have not pro- mals in the sham group did not receive a full score. This was ceeded to the 72-hour time point; therefore, it is difficult to largely because of the scoring system itself, e.g., an animal may make comparisons. However, it is known that the zenith of the not be moving at the time of the examination or not approach injuries occurs in the first 24 hours. The experimental data all sides of the cage and would, therefore, receive a reduced

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score. A small but significant difference in the treated and ingly, a higher than expected value for the brainstem and cere- untreated groups was noted at 48 and 72 hours but not at the bellum was found, with 9.4 Ϯ 0.3 µg/g of tissue found in the 6- or 24-hour time points. Both of the SAH groups were signif- nontreated brainstem and 4.8 Ϯ 0.3 µg/g of tissue in the treated icantly worse than the sham group. group. There was a significant difference found in all brain regions between the groups at the 24-hour time point. Again, BBB Permeability this difference subsided significantly at the 72-hour time point, At 24 hours, the BBB permeability results showed that the at which no difference between the time points was noticed. amount of Evan’s blue detected in the left hemisphere was However, the trend remained. 6.9 Ϯ 0.4 µg/g of tissue in the DMSO group compared with Brain Water Content 1.9 Ϯ 0.2 µg/g of tissue in the sham group (Fig. 2A). This was reduced significantly to 2.6 Ϯ 0.3 µg/g of tissue in the treated The overall brain water content in the sham animals was Ϯ Ϯ group. Similar findings were observed in the contralateral found to be 75.5 0.1% compared with 78.8 0.8% in the hemisphere, although the damage was not as severe. Interest- nontreated group at 24 hours, which was significantly in- creased (Fig. 2B). In comparison, the treated group had a water content of 77.6 Ϯ 0.1%, which was reduced from the nontreated A group. However, at the 72-hour time point, the results were 76.1 Ϯ 0.4% and 75.9 Ϯ 0.8% for the nontreated and treated groups, respectively, which were not significantly different. Western Blot The Western blot analysis revealed increased p-p53 expres- sion (Fig. 3) after SAH in all areas of the brain examined, including the cortex, striatum, hippocampus, and brainstem. The greatest increase was observed at the 24-hour time point in the cortex and striatum, which was approximately twice that observed in the hippocampus and brainstem. PFT-α signifi- cantly reduced the expression of p-p53 in all of the brain regions. However, at the 72-hour time point, the findings, although similar, were not as dramatic. Cytochrome C (Fig. 4) was also up-regulated after SAH, par- B ticularly in the cortex (by a factor of six) and the hippocampus (by a factor of three). This expression was reduced in the PFT-α group. In fact, throughout the brain, the reduction in the treat- ment groups is similar to the baseline. However, the changes observed were not as significant at the 72-hour time point. AIF expression (Fig. 5) was also reduced by PFT-α administration, which was most obvious in the cortex and hippocampus, in which it was reduced by a factor of four. Substantial attenuation was still observed at 72 hours in most cases. The caspases revealed similar changes, although the expres- sion of caspase 8 (Fig. 6) was strongest in the hippocampus. Furthermore, the attenuation by PFT-α was not as prominent as that observed for the other proteins. Caspase 3 expression (Fig. 7) was dominant in the cortex and striatum and signifi- cantly reduced in the treatment groups. FIGURE 2. Bar graphs demonstrating BBB and brain water content Finally, we examined the mitochondrial fraction of analysis. A, BBB breakdown over time. The BBB analysis revealed a sig- cytochrome C and AIF to clearly demonstrate the transloca- nificant difference between the groups at 24 hours but not at the 72-hour time point, suggesting that BBB breakdown was complete at this point. B, tion of these proteins from the mitochondria to the cytoplasm water content. Results similar to those of the BBB examination were found in response to SAH. The translocation of these proteins is inhib- in the analysis of the water content in the brain, which was found to be ited in the treatment groups (data not shown). 78.8 Ϯ 0.8% in the nontreated group (n ϭ 6), compared with 77.6 Ϯ 0.1% in the treated group (n ϭ 6) (P Ͻ 0.05). Again, no difference was observed Histology at the 72-hour time point. Values are expressed as mean Ϯ SEM. Asterisk, Nissl staining showed a loss of hippocampal neuronal cells in P Ͻ 0.05 compared with sham; double asterisk, P Ͻ 0.05 compared with the CA1 region of the hippocampus (Fig. 8, A–F) compared with Ͻ nontreatment and sham; pound symbol, P 0.05 compared with non- the sham group, with a modest preservation of cell bodies in the treatment but not sham (ANOVAwith Tukey test). treatment group. In the nontreatment group, the cell bodies of

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A

B

FIGURE 3. Western blot analysis of p-p53 in the rat brain. A, representative immunoblots of p-p53 at the 24- and 72- hour time points in the cortex, striatum, hippocampus, and brainstem. B, bar graphs representing p-p53 expression meas- ured using densitometry analysis. Values are expressed as mean Ϯ SEM, with six animals per group in three independ- ent experiments normalized to actin and expressed as a percentage of the mean value of the sham group. Asterisk, P Ͻ 0.05 compared with sham; double dagger, P Ͻ 0.05 compared with nontreatment and sham; pound symbol, P Ͻ 0.05 compared with nontreatment but not sham (ANOVAwith Tukey test); R, right; L, left. the hippocampus were shrunken, with small pyknotic nuclei almost unrecognizable cortical neurons were observed (Fig. 8K). and twisted axonal processes (Fig. 8E). These changes were PFT-α prevented this widespread cell death as can be observed largely prevented in the treatment group, in which only a few in Figure 8L, in which many cells appear normal. The histologi- distorted cell bodies were observed (Fig. 8F). The cortex showed cal results reflect the Western blot findings in that the hippocam- areas of widespread cell loss (Fig. 8H); at higher magnification, pus and the cortex showed the most damage.

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A

B

FIGURE 4. Western blot analysis of cytochrome C in the rat brain. A, representative immunoblots of cytochrome C at the 24- and 72-hour time points in the cortex, striatum, hippocampus, and brainstem. B, bar graphs representing cytochrome C expression measured using densitometry analysis. Values are expressed as mean Ϯ SEM with six ani- mals per group in three independent experiments normalized to actin and expressed as a percentage of the mean value of the sham group. Asterisk, P Ͻ 0.05 compared with sham; double dagger, P Ͻ 0.05 compared with nontreatment and sham; pound symbol, P Ͻ 0.05 compared with nontreatment but not sham (ANOVAwith Tukey test).

Immunohistochemistry and TUNEL and J). Strong immunostaining was noted for p-p53 (Fig. 9, B The immunohistochemistry of p-p53 and caspase 3 for both and E) and even more so for caspase 3 in the nontreated group the cortex and the hippocampus are shown in Figure 9. The (Fig. 9, H and K), which was much attenuated in the treated control slides for both p-p53 and caspase 3 showed very weak group in both the cortex and the hippocampus (Fig. 9, C, F, I, staining in both the cortex and the hippocampus (Fig. 9 A, D, G, and L).

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A

B

FIGURE 5. Western blot analysis of AIF in the rat brain. A, representative immunoblots of AIF at the 24- and 72-hour time points in the cortex, striatum, hippocampus, and brainstem. B, bar graphs representing AIF expres- sion measured using densitometry analysis. Values are expressed as mean Ϯ SEM with six animals per group in three independent experiments normalized to actin and expressed as a percentage of the mean value of the sham group. Asterisk, P Ͻ 0.05 compared with sham; double dagger, P Ͻ 0.05 compared with nontreatment and sham; pound symbol, P Ͻ 0.05 compared with nontreatment but not sham (ANOVAwith Tukey test).

Fluoroscopy revealed strongly TUNEL-stained cells in the cor- DISCUSSION tex of the untreated group (Fig. 10A). This was considerably attenuated by treatment with PFT-α (Fig. 10B). A similar picture Secondary brain injury as a result of SAH has been recog- was observed in the hippocampus, although the staining is more nized as a leading cause of death and disability in patients (2). To diffuse with more viable cells in evidence (Fig. 10C). Again, as date, the etiology of secondary brain injury has not been well expected, the treated group showed less staining (Fig. 10D). described. It has been hypothesized that apoptosis is a major

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A

B

FIGURE 6. Western blot analysis of caspase 8 in the rat brain. A, representative immunoblots of caspase 8 at the 24- and 72-hour time points in the cortex, striatum, hippocampus, and brainstem. B, bar graphs representing cas- pase 8 expression measured using densitometry analysis. Values are expressed as mean Ϯ SEM with six animals per group in three independent experiments normalized to actin and expressed as a percentage of the mean value of the sham group. Asterisk, P Ͻ 0.05 compared with sham; double dagger, P Ͻ 0.05 compared with nontreat- ment and sham; pound symbol, P Ͻ 0.05 compared with nontreatment but not sham (ANOVAwith Tukey test).

etiological factor in secondary brain injury and that p53 may down-regulation of apoptosis combined with an intact BBB and play an orchestrating role, resulting in cell death. In this study, it reduced brain edema resulted in less cell death, particularly in has been demonstrated that, once stabilized, p53 is found in the the hippocampus and the cortex (Fig. 8). This allowed for an cytosol after SAH and that its inhibition resulted in a down- improvement in the neurological scores combined with less mor- regulation of the apoptotic proteins examined. The overall tality in the treated animals. These benefits were found to be

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A

B

FIGURE 7. Western blot analysis of caspase 3 in the rat brain. A, representative immunoblots of caspase 3 at the 24- and 72-hour time points in the cortex, striatum, hippocampus, and brainstem. B, bar graphs representing cas- pase 3 expression measured using densitometry analysis. Values are expressed as mean Ϯ SEM with six animals per group in three independent experiments normalized to actin and expressed as a percentage of the mean value of the sham group. Asterisk, P Ͻ 0.05 compared with sham; double dagger, P Ͻ 0.05 compared with nontreatment and sham; pound symbol, P Ͻ 0.05 compared with nontreatment but not sham (ANOVAwith Tukey test). significant overall in the acute phase and, although less dra- in relation to stroke, Alzheimer’s disease, Parkinson’s disease, matic, the trend remained at 72 hours. and, more recently, SAH (12, 22, 24). p53 is usually found in the p53 is a nuclear transcription factor, perhaps best known for nucleus, where it is translocated by murine double minute 2 to its role in neoplastic disease. Of late, it has enjoyed a certain the cytosol, where it is rapidly degraded (29). In certain situa- notoriety as an important component of the apoptotic cascades tions, such as SAH, the phosphorylation of p53, perhaps by

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A B C

D E F

G H I

J K L

FIGURE 8. Nissl staining on brain sections in the cortex and hippocampus at loss. In comparison, the treatment group (F) shows some attenuation, with the 72 hours. A–C, sections of the hippocampus in the sham, nontreatment, and survival of some normal-appearing neurons. A number of abnormal cells can treatment groups, respectively. The CA1 region of the hippocampus is indicated be seen (arrows). G–I, representative sections of the parietal association cortex by the arrowheads. Note the obvious loss of neurons in the CA1 (arrow- of the left cortex. The normal appearance can be seen in G, whereas the non- heads) region of the hippocampus in the nontreatment group, which was pre- treated group had wide areas of neuronal loss, as indicated by the asterisks in vented by treatment with PFT-α (C). These findings are shown at higher mag- H. The treated group (I) did not show any evidence of widespread loss. nification in D–E. The normal appearance of the hippocampal neuronal cells can However, under higher magnification, abnormal cells are again evident in the be seen in D. In the nontreatment group (E), the neurons are clearly distorted, nontreated group (K), which is attenuated by treatment, as can be seen in L, in with pyknotic nuclei, loss of the normal nuclear-to-cytoplasmic ratio, and a which a number of normal-appearing cells can be seen (arrows). Scale bars at much thinner layer of cells in comparison with the treatment group, indicating the high and low magnifications represent 200 and 20 µm, respectively.

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FIGURE 9. Immunohistochemical staining of rat cortex and hippocampus (C and F). Caspase 3 immunoreactivity in both brain regions was even at 24 hours. Representative photomicrographs of p53 immunohistochem- more evident (arrows) in the untreated group (H and K), which was istry in the cortex (A–C) and the hippocampus (D–F), as well as caspase reduced by the administration of PFT-α (I and L). For comparison, the 3 immunohistochemistry in the cortex (G–I) and the hippocampus (J–L). staining in the sham group is represented in A and G for the cortex and A significant number of immunoreactive cells (arrows) for p53 can be seen D and J for the hippocampus. Scale bars represent 20 µm. in both brain regions (B and E) which is attenuated in the treatment group

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by the inhibition of p-p53, A B leading to cell survival. This, in turn, prevented BBB destruction and subsequent brain edema, which was ade- quately reflected in the sur- vival curves and neurological outcome scores (Fig. 1). However, it must be pointed out that the outcome was sig- nificant only in the first 24 hours. At the 72-hour time C D point, the differences were not as obvious, even though the trend remained. Further- more, the degree of apoptosis, brain edema, and BBB break- down were all less at the 72- hour time point, reflecting the time span of apoptosis. This study shows that many of the apoptotic changes are at a maximum at FIGURE 10. TUNEL fluoroscopy of rat cortex and hippocampus at 24 hours. Sections are indicative of the TUNEL stain- the 24-hour time point. ing in the cortex (A and B) and the hippocampus (C and D). A, TUNEL-positive cells (arrows) in the untreated group Although this time point are reduced in the treated group (B). In addition, a similar pattern (arrowheads, TUNEL-positive cells) was seen in the coincides with vasospasm, hippocampus for the untreated (C) and the treated groups (D). Scale bars represent 200 µm. the appearance of apoptosis in areas not supplied by the tumor necrosis factor-α, allows for its stabilization (48, 49). p- vessel in spasm suggests an alternative etiology. The etiology of p53 was found to be present in the cytosol after SAH and its the apoptotic cascades may be the result of the initial global presence coincided with an up-regulation of the apoptotic ischemic injury that occurs at the time of the SAH as a result of machinery. Apoptosis was associated with a disruption in the the decrease in CBF and increase in intracranial pressure. There BBB and brain edema, the combination of which resulted in cell are currently no treatment options available to combat these death in the hippocampus and the cortex. pathological processes and, in fact, these injuries are often However, the inhibition of p-p53 resulted not only in a blamed, perhaps incorrectly, on vasospasm. We often see down-regulation of p-p53, but also of the apoptotic proteins patients who do not have any clinical or radiographic evidence and an overall improved outcome. p53, once stabilized in the of vasospasm yet do not do as well as expected. There is also a cytosol, which has been shown to occur after SAH, results in large number of patients who experience long-term psycho- the release of both cytochrome C and AIF, probably through logical and memory problems yet had a relatively benign SAH its interaction with the Bcl-2 family of proteins, which seem to and recovery (34, 45). These problems may be caused by the act as messengers between p-p53 and the mitochondria (30). apoptotic cascades resulting in cell death in the hippocampus Although the Bcl-2 family of proteins were not specifically and cortex, as shown in this study. examined in this study, it was hypothesized that the inhibition In summary, we think apoptosis is as important as, or per- of p-p53 allowed for the balance of pro- to anti-apoptotic haps more important than, vasospasm as a major contributor to members of the Bcl-2 family to tip in favor of survival, thereby morbidity and mortality in SAH patients. We would contend preventing mitochondrial pore formation and, ultimately, the that p53 plays a major role in the organization of the caspase- release of cytochrome C and AIF (1). dependent and -independent pathways as well as the mito- In addition, p-p53 resulted in an up-regulation of caspase 8 chondrial cascades. Many previous studies have used caspase and 3, suggesting that the caspase-dependent pathways are and pancaspase inhibitors in an attempt to attenuate the dev- also affected not only by the down-regulation of the apopto- astating effects of apoptosis with some success. Similarly, we some, but also the cytosolic cascades. The overall picture for attempted inhibition of apoptosis through p53. However, as this experimental model suggests that p53 may play a signifi- more information becomes available regarding apoptosis it cant role in the orchestration of the apoptotic cascades in SAH. seems clear that blocking any one protein will simply be The three main pathways, caspase dependent and independent bypassed and apoptosis will occur despite our best efforts. and the mitochondrial pathway, were examined in this study. It Despite this, as we obtain a fuller picture of the mechanisms was shown that these pathways could be significantly altered involved, the role of multiple inhibitors at many different lev-

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els in the apoptotic machinery becomes more appealing as a 22. Leker RR, Aharonowiz M, Greig NH, Ovadia H: The role of p53-induced powerful therapeutic option. There is little argument that the apoptosis in cerebral ischemia: Effects of the p53 inhibitor pifithrin alpha. Exp prevention of apoptosis in SAH is a worthwhile venture on Neurol 187:478–486, 2004. 23. Macdonald RL, Weir B, Zhang J, Marton LS, Sajdak M, Johns LM: Adenosine which to embark. triphosphate and hemoglobin in vasospastic monkeys. Neurosurg Focus 3:e3, 1997. REFERENCES 24. Mattson MP: Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1:120–129, 2000. 1. Antonsson B, Martinou JC: The Bcl-2 protein family. Exp Cell Res 256:50–57, 25. McCormick WF, Nofzinger JD: Saccular intracranial aneurysms: An autopsy 2000. study. J Neurosurg 22:155–159, 1965. 2. Bederson JB, Germano IM, Guarino L: Cortical blood flow and cerebral per- 26. 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Schievink WI, Riedinger M, Jhutty TK, Simon P: Racial disparities in sub- MP: A synthetic inhibitor of p53 protects neurons against death induced by arachnoid hemorrhage mortality: Los Angeles County, California, 1985–1998. ischemic and excitotoxic insults, and amyloid beta-peptide. J Neurochem Neuroepidemiology 23:299–305, 2004. 77:220–228, 2001. 39. Schwartz AY, Masago A, Sehba FA, Bederson JB: Experimental models of 12. Daily D, Barzilai A, Offen D, Kamsler A, Melamed E, Ziv I: The involvement subarachnoid hemorrhage in the rat: A refinement of the endovascular fila- of p53 in dopamine-induced apoptosis of cerebellar granule neurons and ment model. J Neurosci Methods 96:161–167, 2000. leukemic cells overexpressing p53. Cell Mol Neurobiol 19:261–276, 1999. 40. Sekhar LN, Wechsler LR, Yonas H, Luyckx K, Obrist W: Value of transcranial 13. Garcia JH, Wagner S, Liu KF, Hu XJ: Neurological deficit and extent of neu- Doppler examination in the diagnosis of cerebral vasospasm after subarach- ronal necrosis attributable to middle cerebral artery occlusion in rats. noid hemorrhage. Neurosurgery 22:813–821, 1988. Statistical validation. Stroke 26:627–635, 1995. 41. Sheikh MS, Fornace AJ Jr: Death and decoy receptors and p53-mediated 14. Grosset DG, Straiton J, du Trevou M, Bullock R: Prediction of symptomatic apoptosis. Leukemia 14:1509–1513, 2000. vasospasm after subarachnoid hemorrhage by rapidly increasing transcranial 42. Sobey CG, Faraci FM: Subarachnoid haemorrhage: What happens to the cere- Doppler velocity and cerebral blood flow changes. Stroke 23:674–679, 1992. bral arteries? Clin Exp Pharmacol Physiol 25:867–876, 1998. 15. Gules I, Satoh M, Nanda A, Zhang JH: Apoptosis, blood-brain barrier, and 43. Sun Y, Zhou C, Polk P, Nanda A, Zhang JH: Mechanisms of erythropoietin- subarachnoid hemorrhage. Acta Neurochir Suppl 86:483–487, 2003. induced brain protection in neonatal hypoxia-ischemia rat model. J Cereb 16. Hammond EM, Giaccia AJ: The role of p53 in hypoxia-induced apoptosis. Blood Flow Metab 24:259–270, 2004. Biochem Biophys Res Commun 331:718–725, 2005. 44. Uyama O, Okamura N, Yanase M, Narita M, Kawabata K, Sugita M: 17. Hansen-Schwartz J, Hoel NL, Xu CB, Svendgaard NA, Edvinsson L: Quantitative evaluation of vascular permeability in the gerbil brain after Subarachnoid hemorrhage-induced upregulation of the 5-HT1B receptor in transient ischemia using Evans blue fluorescence. J Cereb Blood Flow Metab cerebral arteries in rats. J Neurosurg 99:115–120, 2003. 8:282–284, 1988. 18. Kaptain GJ, Lanzino G, Kassell NF: Subarachnoid haemorrhage: Epidem- 45. Will BE, Philipp A: Quality of life after SAH and clipping of cerebral iology, risk factors, and treatment options. Drugs Aging 17:183–199, 2000. aneurysm. Neurol Neurochir Pol 34 [Suppl 6]:61–63, 2000. 19. Kessler IM, Pacheco YG, Lozzi SP, de Araujo AS Jr, Onishi FJ, de Mello PA: 46. Xi G, Hua Y, Keep RF, Younger JG, Hoff JT: Brain edema after intracerebral Endothelin-1 levels in plasma and cerebrospinal fluid of patients with cere- hemorrhage: The effects of systemic complement depletion. Acta Neurochir bral vasospasm after aneurysmal subarachnoid hemorrhage. Surg Neurol Suppl 81:253–256, 2002. 64 [Suppl 1]:S1–S5, 2005. 47. Yamaguchi M, Zhou C, Nanda A, Zhang JH: Ras protein contributes to cerebral 20. Kusaka G, Ishikawa M, Nanda A, Granger DN, Zhang JH: Signaling path- vasospasm in a canine double-hemorrhage model. Stroke 35:1750–1755, 2004. ways for early brain injury after subarachnoid hemorrhage. J Cereb Blood 48. Yeung MC, Lau AS: Tumor suppressor p53 as a component of the tumor Flow Metab 24:916–925, 2004. necrosis factor-induced, protein kinase PKR-mediated apoptotic pathway in 21. Lane DP: Cancer. p53, guardian of the genome. 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49. Zhou C, Yamaguchi M, Colohan AR, Zhang JH: Role of p53 and apoptosis in internal carotid artery bifurcation, and several components of the apop- cerebral vasospasm after experimental subarachnoid hemorrhage. J Cereb totic cascade were examined using Western blotting and immunohisto- Blood Flow Metab 25:572–582, 2005. chemistry 24 and 72 hours after SAH. In addition, neuronal cell loss 50. Zhou C, Yamaguchi M, Kusaka G, Schonholz C, Nanda A, Zhang JH: Caspase was assessed with histology at 72 hours; functional outcome, as inhibitors prevent endothelial apoptosis and cerebral vasospasm in dog assessed by mortality rate and neurological score, was evaluated model of experimental subarachnoid hemorrhage. J Cereb Blood Flow between 3 and 72 hours. Finally, the effect of PFT-·, a selective inhibitor Metab 24:419–431, 2004. 51. Zubkov AY, Ogihara K, Bernanke DH, Parent AD, Zhang J: Apoptosis of of p53 transcriptional activity, was examined. endothelial cells in vessels affected by cerebral vasospasm. Surg Neurol The authors found that all apoptotic compounds examined, includ- 53:260–266, 2000. ing phosphorylated p53, cytochrome C, apoptosis-inducing factor, cas- pase 3, and caspase 8 were elevated after SAH, and that PFT-· admin- Acknowledgments istration significantly attenuated this response. Moreover, neuronal cell This study was partially supported by grants from the American Heart loss in the hippocampus and cortex after SAH was reduced by PFT-·. Association, the Educational Foundation, and the National Institutes of Health Finally, the mortality rate and neurological score after SAH were grants RO1 HD43120 and RO1 NS43338 (JHZ). improved in rats treated with PFT-· when compared with the control animals. Overall, these results suggest that neuronal cell death via COMMENTS apoptosis is likely to be a significant contributor to brain injury after SAH and that p53 may be a key mediator in this process. Importantly, sing the monofilament puncture model of subarachnoid hemor- the beneficial effects of PFT-· were noted in animals treated 3 hours Urhage (SAH), Cahill et al. have demonstrated a neuroprotective after SAH, which provided evidence that a substantial therapeutic win- effect for the p53-inhibitor, pifithrin-· (PFT-·). This is a sophisticated set dow may exist for antiapoptotic treatment. of experiments that explore the role of p53 and certain other apoptotic This study is a valuable addition to the nascent literature and one of the cascade molecules in the pathophysiology of secondary neuronal injury first reports to address a potential mechanism. Further experiments will after SAH in the rat brain. The authors administered PFT-· intraperi- be required to help confirm p53 as a key mediator to this process. The use toneally 3 hours after SAH induction and sacrificed a subset of the of additional pharmacological inhibitors of p53 activity and/or p53-defi- animals at 24 and 72 hours. The expression levels of p53, cytochrome cient mice in similar experiments would provide critical additional sup- C, apoptosis-inducing factor, caspase 8, and caspase 3 were then port to the hypothesis of SAH-induced p53-mediated neuronal apoptosis. assessed in the harvested brains using Western blot analysis and In addition, a more rigorous assessment of neuronal cell loss (e.g., quan- immunohistochemistry. The results demonstrated a significantly titative assessment of apoptotic cell death) and functional outcome (e.g., reduced expression of all the apoptosis-related molecules in the PFT-· behavioral measures of cognitive function) at later time points (Ͼ72 hr) -treated animals compared with the dimethyl-sulfoxide-treated or are expected before advancing these strategies to the clinic. sham control animals. In addition, cerebral tissue from treated animals had less neuronal loss and greater neuronal survival. Looking at histo- Gregory J. Zipfel logical data, the authors clearly demonstrated neuronal protection in Ralph G. Dacey, Jr. the PFT-· -treated animals compared with the control animals. St. Louis, Missouri This study seems to have been carefully conducted by an experi- enced group of investigators. The findings of this study and others ahill et al. present a large study that examines the possible role of suggest that secondary brain injury after SAH may be preventable with Capoptosis after SAH in a rat model. They perform a detailed char- early intervention using antiapoptosis agents. Of course, additional acterization of physiological parameters, overall mortality, gross neu- research on this topic will need to be achieved before clinical applica- rological examination, cellular changes, and apoptosis-related protein tion. Nevertheless, understanding the time course and consequences of level changes in the rat model during and after experimentally-induced the molecular cascades after SAH will provide opportunities for neu- SAH. In addition, improved outcome is revealed in rats treated with a roprotection, which may have a direct impact on our efforts to treat p53 deoxyribonucleic acid-binding inhibitor, PFT-·. Overall, this study patients with SAH. presents a large body of interesting research highlighting p53-mediated apoptosis as an important facet of post-SAH brain injury. An intriguing Linda M. Liau and challenging opportunity has been opened to the possibility of Los Angeles, California developing appropriate antiapoptosis therapeutic strategies for improving clinical outcome in SAH patients. n this report, Cahill et al. have examined the role of the proapoptotic Itranscription factor, p53, in apoptotic cell death after experimental John S. Kuo SAH. SAH was induced in rats through monofilament puncture of the Madison, Wisconsin EXPERIMENTAL STUDIES

TREATMENT OF TRAUMATIC BRAIN INJURY WITH A COMBINATION THERAPY OF MARROW STROMAL CELLS AND ATORVASTATIN IN RATS

Asim Mahmood, M.D. OBJECTIVE: This study investigated the effects of a combination therapy of marrow Department of Neurosurgery, stromal cells (MSCs) and statins (atorvastatin) after traumatic brain injury in rats. Henry Ford Health System, Detroit, Michigan METHODS: Thirty-two female Wistar rats were injured by controlled cortical impact and divided into four groups. Group I was injected with MSCs (1 ϫ 106) intravenously Dunyue Lu, Ph.D. 24 hrs after traumatic brain injury. Group II was administered atorvastatin (0.5 mg/kg) Department of Neurosurgery, orally for 14 days starting 24 hours after traumatic brain injury. Group III received MSCs Henry Ford Health System, (1 ϫ 106) combined with atorvastatin (0.5 mg/kg). Group IV (control) was injected with Detroit, Michigan saline. MSCs were harvested from the bone marrow of male rats to identify male donor Changsheng Qu, M.D. cells within female recipient animals by localization of Y chromosomes. Functional analysis was performed using modified neurological severity scores and the Morris Department of Neurosurgery, Henry Ford Health System, water maze test. Animals were sacrificed 35 days after injury and brain sections stained Detroit, Michigan with immunohistochemistry. RESULTS: No functional improvement was seen in animals treated with MSCs or ator- Anton Goussev, M.D. vastatin alone (Groups I and II). However, functional improvement was seen with both Department of Neurosurgery, Henry Ford Health System, testing modalities (modified neurological severity scores and Morris water maze) in Detroit, Michigan animals receiving combination therapy (Group III). Microscopic analysis showed that significantly more MSCs were present in animals receiving combination therapy than Michael Chopp, Ph.D. in those receiving MSCs alone. Also, significantly more endogenous cellular prolifer- Department of Neurology, ation was seen in the hippocampus and injury boundary zone of the combination ther- Henry Ford Health System, apy group than in the monotherapy or control groups. Detroit, Michigan CONCLUSION: When administered in combination with MSCs, atorvastatin increases Reprint requests: MSC access and/or survival within the injured brain and enhances functional recovery Asim Mahmood, M.D., compared with monotherapy. Department of Neurosurgery, Henry Ford Health System, KEY WORDS: Atorvastatin, Marrow stromal cells, Traumatic brain injury 2799 W. Grand Boulevard, Detroit, MI 48202. Neurosurgery 60:546–554, 2007 DOI: 10.1227/01.NEU.0000255346.25959.99 www.neurosurgery-online.com Email: [email protected]

Received, May 31, 2006. Accepted, October 5, 2006. raumatic brain injury (TBI) is a major TBI in rats. Our results have shown that MSCs, health problem in the United States. The when administered intravenously, migrate to Tannual incidence of patients with closed the injured area in the brain, promote neuroge- head injuries admitted to hospitals is 200 per nesis, and enhance functional recovery (21, 22, 100,000 (25). Currently, there is no effective 24). We have also found that statins, when clinical treatment to promote recovery after administered orally after TBI, improve func- TBI; however, new interventions are being tional outcome and enhance neuroplasticity explored in experimental studies. These neu- (13, 16, 17). After showing benefits with rorestorative treatments for TBI and neural monotherapies using MSCs and statins, we injury have taken essentially two paths, cellu- designed this novel study to use a combina- lar (1, 3, 14, 15, 18, 21, 22, 24, 28, 33) and phar- tion therapy of MSCs and a statin (i.e., atorvas- macological. We have used both of these tatin). The rationale for using this combination approaches with marrow stromal cells (MSCs) was that these treatments are complementary (i.e., cell therapy) (18, 22, 24) and pharmacolog- and likely additive. Statins, for example, ical agents such as statins (13, 16, 17) to treat enhance angiogenesis and improve cerebral

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perfusion after TBI (16, 17) and thus increase the access of Brain Sample Preparation MSCs into the injured tissues. Also, once the MSCs have Brain tissues from each group were processed for prepara- reached target tissue they may act synergistically with statins tion of paraffin sections, which were used for histological because both treatments enhance neurogenesis (13, 17, 20) and analysis and immunohistochemical staining. induce production of growth factors (4, 19). Based on our pre- ϫ vious studies, we selected subtherapeutic doses of MSCs (1 In Situ Hybridization 106) (21, 24) and atorvastatin (0.5 mg/kg) (13, 17) and admin- istered them alone and in combination. This experimental Female rat brains were removed and stored in 10% buffered design was based on the hypothesis that subtherapeutic doses formalin for 48 to 72 hours. Standard 2-mm thick blocks of the of MSCs and atorvastatin when administered together become rat brains were cut on a rodent brain matrix (a total of seven blocks from A to G) and embedded with paraffin. A series of therapeutic. All procedures were approved by the Henry Ford µ Hospital IACUC. adjacent 6- m thick sections were cut. Three sections with 50-µm intervals from Block E were dewaxed and rehydrated with xylene and graded ethanol and subsequently digested MATERIALS AND METHODS with pronase K (100 µg/ml) for 15 minutes at 37ЊC. The (oligonucleotide probe (5؅-AGATCTTGATTTTTAGTGTTC-3؅ Preparation of Rat MSCs for the Sry gene of the murine sex-determining region carried -Male adult Wistar rat bone MSCs were prepared, frozen in on the Y chromosome was labeled at the 3؅-end with digoxi -liquid nitrogen, and transported to our laboratory by Cognate, genin (DIG)-ddUTP using a DIG oligonucleotide 3؅-end label Inc. (Los Angeles, CA). MSCs were restored and a small sam- ing kit (Roche Pharmaceuticals, Nutley, NJ). After denaturing ple was selected for cell viability counting using trypan blue. the tissue sample, hybridization was performed in a mixture Nucleated marrow cells were counted using a cytometer to consisting of 50% deionized formamide, 10% salmon test ensure adequate cell numbers for transplantation. The viability deoxyribonucleic acid, 10% dextran sulfate, 10% 50 ϫ rate ranged from 87 to 97%; the injected cell number excluded Denhardt’s solution, 10% 20 ϫ standard saline citrate, and dead cells. Rat MSCs suspended in saline were injected via the 500 ng DIG-labeled probe at 42ЊC overnight (5, 8). The DIG- rats’ tail vein (24). labeled Y chromosome was visualized using a fluorescent anti- body enhancer set (Boehringer Mannheim GmbH, Penzburg, Animal Model Germany) under fluorescent microscopy, which resulted in flu- A controlled cortical impact rat model was used as previously orescein isothiocyanate fluorescence (green). The slides were described (6, 27). Female Wistar rats were anesthetized intraperi- then counterstained with 10 ng/ml of propidium iodide (red) toneally with chloral hydrate (350 mg/kg body weight). Rectal for nuclear staining and mounted with antifade solution and temperature was maintained at 37ЊC with a feedback regulated coverslips (24). Negative control sections from each animal water-heating pad. Rats were placed in a stereotactic frame. Two received identical staining preparation, except that the probe or 10-mm diameter craniotomies were performed adjacent to the the antidigoxigenin antibodies were omitted. central suture, midway between the lambda and bregma. The second craniotomy allowed for lateral movement of cortical tis- Immunohistochemistry Combined with sue (27). The dura was kept intact over the cortex. Injury was In Situ Hybridization induced by impacting the left cortex (ipsilateral cortex) with a Immunohistochemistry stain combined with in situ pneumatic piston containing a 6-mm diameter tip at a rate of 4 hybridization was performed on coronal cerebral sections meters per second and 2.5 mm of compression. Velocity was adjacent to the sections for in situ hybridization. Brain sec- measured with a linear velocity displacement transducer (6). tions were initially immunostained with diaminobenzidine (DAB) for detection of the neuronal marker, microtubule asso- Treatment of TBI Rats with MSCs and Atorvastatin ciated protein-2 (MAP-2). MAP-2 is a cytoplasmic protein that One day after TBI, the rats were anesthetized intraperi- is present only in neurons. Its presence indicates phenotypic toneally with chloral hydrate. The suspended MSCs (1 ϫ 106) neuronal differentiation. Subsequently, in situ hybridization in 1 ml of PBS were slowly injected with a 1-ml syringe into the was performed on the same section with fluorescence labeling tail vein of rats. Control animals received an injection of (26). Briefly, 6-µm thick sections from the MSC- and PBS- phosphate-buffered saline (PBS) in their tail veins. Rats also treated groups were deparaffinized and placed in PBS. For received atorvastatin orally (0.5 mg/kg) for 14 days starting identification of neurons, the sections were placed in boiling 1 day after TBI. Atorvastatin was mixed with water and admin- citrate buffer (pH 6) in a microwave oven for 10 minutes. istered directly into the esophagus using a gastric lavage tube. After cooling at room temperature, the sections were incu- The animals were divided into four groups: Group 1 (n ϭ 8), bated overnight in 0.1% saponin-PBS at 4ЊC. After blocking in TBI plus 1 ϫ 106 MSCs; Group 2 (n ϭ 8), TBI plus 0.5 atorvas- normal serum, sections were treated overnight with MAP-2 tatin; Group 3 (n ϭ 8), TBI plus 1 ϫ 106 MSCs plus 0.5 atorvas- (dilution, 1:400) (Chemicon International, Temecula, CA) at tatin; and Group 4 (n ϭ 8), TBI plus PBS. All rats were sacri- 4ЊC. After sequential incubation with biotin-conjugated anti- ficed 35 days after TBI. mouse immunoglobulin G (dilution, 1:100) (Dakopatts,

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Carpinteria, CA), the sections were treated with an avidin- von Willebrand Factor Staining and biotin-peroxidase complex kit (Vector Laboratories, Inc., Measurement of Vascular Density Burlingame, CA). After staining with DAB, these sections von Willebrand Factor (vWF) is a marker of newly formed were processed for in situ hybridization as previously endothelial cells. vWF staining was used to identify newly described. The slides were mounted with antifade solution formed vessels (9). Five sections with 50-µm intervals through and observed under light and fluorescent microscopy (BH-2; Block E were stained for vWF, and the images were digitized Olympus Optical Co., Tokyo, Japan). with a light microscope at 400ϫ magnification at the interau- Estimates of Positive Cell Number ral 5.20-mm levels. The Microcomputer Imaging Device sys- tem was used to count the vWF-positive vessels in the bound- Y chromosome positive cells in the brains of rats receiving ary zone of the lesion and the CA3 region of the MSCs were identified via fluorescence in situ hybridization; hippocampus. The vascular density in both regions was deter- slides were analyzed using fluorescent microscopy. This cellu- mined by dividing the immunoreactive vessels by the corre- lar analysis was performed on Block E, which contains the sponding area (13) and using the resulting computation as a lesion core. The total number of Y chromosome-positive cells parameter of angiogenesis. on three sections from one rat brain were counted manually with a 40 objective under a fluorescent microscope and used for statistical analysis. Three additional slides from Block E were Modified Neurological Severity Scores stained with DAB for MAP-2 and were processed for in situ Neurological functional analysis was performed using the hybridization for Y chromosome identification. The number of modified neurological severity score, which is a composite of Y chromosome-positive cells expressing MAP-2 was counted in motor, sensory, reflex, and balance tests. A detailed description the MSC-treated groups using light and fluorescent microscopy. of this functional test has been published previously (12, 29). This number was then divided by the total number of Y Rats were tested before TBI and at regular intervals after TBI. chromosome-positive cells and expressed as a percentage of All measurements were performed by observers (CQ, AG) total Y chromosome cells. To reduce the biases introduced by blinded to individual treatment. sampling parameters, all sections for Y chromosome identifica- tion from rats were stained simultaneously. The criteria (green Spatial Learning Tested by the Morris Water Maze Test in the nuclei) for Y chromosome-positive cells were defined The Morris water maze testing procedure has been before the cells were counted by observers (DL, CQ, AG) described previously (17). Briefly, the experimental apparatus blinded to the individual treatment. consists of a circular water tank 140 cm in diameter and 45 cm Bromodeoxyuridine Immunohistochemical Staining high. An invisible platform measuring 15 cm in diameter and 35 cm high is placed 1.5 cm below the surface of the water. The Bromodeoxyuridine (BrdU) is incorporated into the newly water temperature is maintained at 30ЊC. The pool is located in formed deoxyribonucleic acid and is a marker of newly gen- a large test room in which there are many cues external to the erated endogenous cells (20). Single staining with DAB was maze (e.g., pictures, lamps, etc.) that are visible from the pool performed to identify BrdU-labeled cells and to detect the and used by the rats for spatial orientation. The position of the distribution of these newly generated endogenous cells. For cues remains unchanged throughout the task. When the plat- single staining, brain sections were deparaffinized and incu- form is removed for the occasional brief probe trial, the animal bated in 50% formamide-2xSSC at 60ЊC for 30 minutes, treated quickly discovers its absence and may spend only a small with 2 N HCI at 37ЊC for 10 minutes to denature the deoxyri- amount of time searching for it again in that location. In each bonucleic acid, and then incubated in 0.1 mol/L boric acid at training session, the latency to escape onto the hidden plat- room temperature for 3 minutes to neutralize the residual form is recorded. If the animal finds the platform, it is allowed acid. After blocking in normal serum, sections were incubated to remain there for 15 seconds and then returned to its home overnight with mouse anti-BrdU antibody (Calbiochem, San cage. If the animal is unable to find the platform within 90 sec- Diego, CA) diluted at 1:100 in PBS at 4ЊC. After sequential onds, the training is terminated and a maximum score of 90 incubation with biotin-conjugated anti-mouse immunoglobu- seconds is assigned. The percentage of time traveled within lin G (dilution, 1:100) (Dakopatts), the sections were treated the northeast (correct) quadrant is calculated relative to the with an avidin-biotin-peroxidase system (ABC kit, Vector total amount of time spent swimming before reaching the plat- Laboratories, Inc.). DAB was used as a sensitive chromogen form and is used for statistical analysis. for light microscopy. An average number of five equally spaced slides (approximate interval, 100-µm) were obtained from brain Blocks D and E, which contained the subventricu- Statistical Analysis lar zone, lesion boundary zone, and dentate gyrus. BrdU- Data were analyzed by analysis of variance for multiple com- reactive cells were also counted (20). The number of BrdU- parisons. Paired t tests were used to test the difference in cell positive cells was counted in the ipsilateral hemisphere using counts between the ipsilateral and contralateral hemispheres or the Microcomputer Imaging Device system (Imaging between different groups. The behavioral and histological Research, Inc., St. Catharine’s, Canada) (20). assays were performed in a completely blinded manner.

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RESULTS A Modified Neurological Severity Scores There was no improvement in the modified neurological severity scores of animals treated with monotherapy of MSCs and atorvastatin. However, a statistically significant improve- ment was seen in those treated with combination therapy (MSCs and atorvastatin) (Table 1). This improvement was first visible on Day 28 and persisted until Day 35. This clearly shows that MSC and atorvastatin combination therapy is more effec- tive than either therapy alone.

Spatial Learning Rats were tested with the Morris water maze test during the last five days (Days 31–35) of the trial. The rats were sup- B posed to swim to a submerged platform in the correct quad- rant. There was no difference in the performance of rats receiving PBS (control) and those receiving 1 ϫ 106 MSCs or 0.5 mg/kg atorvastatin, indicating persistent impairment of the spatial learning process. However, among rats receiving combination treatment of 1 ϫ 106 MSCs plus 0.5 mg/kg ator- vastatin, there was significant improvement in the spatial learning process (Table 2).

Distribution and Identification of MSCs in the Rat Brain Y chromosome-positive cells were detected in the brain of rats receiving MSCs and a combination of MSCs and atorvas- tatin using fluorescence in situ hybridization. Cells were prima- rily seen in the lesion boundary zone (Fig. 1), although some FIGURE 1. Microphotograph showing Y chromosome-positive MSCs (arrows) were also found in other areas of both the ipsilateral and con- in the lesion boundary zone in the MSC- (A) and MSC plus atorvastatin- tralateral cortices. Significantly more Y chromosome-positive treated (B) groups. Scale bar, 25µm; original magnification, ϫ 400.

TABLE 1. Modified neurological severity scores after marrow stromal cell and atorvastatin treatment of traumatic brain injurya Day 1 Day 4 Day 7 Day 14 Day 28 Day 35 1 million MSCs 9.13 Ϯ 1.25 7.71 Ϯ 1.38 6.29 Ϯ 0.76 5.86 Ϯ 1.07 3.43 Ϯ 1.99 2.67 Ϯ 1.37 1 million MSCs plus 0.5 mg/kg atorvastatin 9.50 Ϯ 1.69 8.38 Ϯ 1.19 6.25 Ϯ 1.16 5.00 Ϯ 1.53 1.88 Ϯ 0.83b 1.00 Ϯ 0.53b,c 0.5 mg/kg atorvastatin 9.38 Ϯ 1.51 7.50 Ϯ 2.78 6.13 Ϯ 0.99 3.75 Ϯ 1.58 3.75 Ϯ 3.01 3.25 Ϯ 2.71 PBS 8.13 Ϯ 0.83 8.00 Ϯ 1.83 6.29 Ϯ 1.70 6.14 Ϯ 1.07 4.43 Ϯ 1.13 4.00 Ϯ 1.41

a MSCs, marrow stromal cells; PBS, phosphate-buffered saline. All data is provided as mean Ϯ standard deviation. b P Ͻ 0.05 compared with the 0.5 mg/kg atorvastatin and PBS groups. c P Ͻ 0.05 compared with the 1 million MSCs group.

TABLE 2. Morris water maze test 31 to 35 days after traumatic brain injurya Day 31 Day 32 Day 33 Day 34 Day 35 1 million MSCs 24.8 Ϯ 4.70 27.55 Ϯ 3.00 29.54 Ϯ 3.28 33.14 Ϯ 2.82 37.22 Ϯ 6.49 1 million MSCs plus 0.5 mg/kg atorvastatin 25.7 Ϯ 4.73 28.14 Ϯ 6.10 33.7 Ϯ 4.88 38.57 Ϯ 6.33 45.78 Ϯ 3.34b 0.5 mg/kg atorvastatin 26.23 Ϯ 5.70 29.18 Ϯ 6.29 32.01 Ϯ 4.17 35.11 Ϯ 8.12 37.07 Ϯ 4.19 PBS 24.43 Ϯ 4.20 28.52 Ϯ 4.28 30.0 Ϯ 3.83 33.59 Ϯ 4.52 36.95 Ϯ 3.27

a MSCs, marrow stromal cells; PBS, phosphate-buffered saline. All data is provided as mean Ϯ standard deviation. b P Ͻ 0.05 compared with the 1 million MSCs, 0.5 mg/kg atorvastatin, and PBS groups.

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TABLE 3. Microtubule associated protein-2/Y chromosome double staininga MAP-2/Y chromosome- MAP-2/Y positive cells expressed chromosome- as the percentage positive of the total number cell number of Y chromosome- positive cells TBI plus MSCs 6.3 Ϯ 3.5 3.2 Ϯ 1.1 FIGURE 2. Bar graph showing the number of Y chromosome-positive TBI plus MSCs plus 17.4 Ϯ 5.7b 3.6 Ϯ 1.3 cells (MSCs) in the MSC- and MSC plus atorvastatin-treated groups. atorvastatin Asterisk, P Ͻ 0.05. a MAP-2, microtubule associated protein-2; TBI, traumatic brain injury; MSCs, marrow stromal cells. All data are provided as mean Ϯ standard deviation. A b P Ͻ 0.05 versus the TBI plus MSCs group.

BrdU-positive Cell Identification Treatment with a combination of atorvastatin and MSCs sig- nificantly increases the number of BrdU-labeled cells in both the lesion boundary zone (Fig. 4) and the dentate gyrus at Day 35 compared with treatment with PBS, atorvastatin, or MSCs alone (Table 4). These cells were Y chromosome-negative, indi- cating their origin from endogenous cells and not from male donor cells. These data demonstrate that combination treat- ment increases the number of newly generated cells. B Vessel-to-tissue Area Change after Combination MSC and Atorvastatin Treatment Treatment with MSCs and atorvastatin significantly increases vascular density in the lesion boundary zone and hippocampus when compared with all other groups (Fig. 5), demonstrating that the combination treatment may enhance angiogenesis.

DISCUSSION

Our results show that subtherapeutic doses of MSCs and atorvastatin, when given in combination, produce a statisti- FIGURE 3. Coronal brain sections of rats treated with MSCs (A) and MSCs plus cally significant improvement in functional outcome after TBI. atorvastatin (B) stained by double immunostaining to show the expression of We also observed significantly more MSCs in the animals neuronal marker (MAP-2) in Y chromosome-positive cells (arrows). Y chromo- receiving combination therapy than in those receiving MSCs somes (white) are seen within the red nucleus surrounded by cytoplasm showing alone, significantly more endogenous cellular proliferation in positive signal (black) for MAP-2. Cells that are positive only for MAP-2 (green the animals receiving the combination therapy than in those arrowhead) represent the endogenous neuronal cells, whereas those positive for receiving the single therapies, and significantly more neovascu- Y chromosomes alone represent donor cells (white arrowheads) without neu- lar proliferation in the combination therapy group than in the µ ϫ ronal differentiation. Scale bar, 25 m; original magnification, 400. monotherapy groups. Our previous studies have shown that the minimally effec- cells were identified in the lesion boundary zone of the combi- tive dose of MSCs that provides therapeutic benefit after TBI nation treatment group than in that of the MSC only group is 2 ϫ 106 (21, 24) and that the minimally effective dose of (Fig. 2). Double staining with MAP-2 (Fig. 3) showed that the atorvastatin is 1 mg/kg (13, 17). We administered subthera- total number of Y chromosome-positive cells expressing this peutic doses of MSCs (1 ϫ 106) and atorvastatin (0.5 mg/kg) neuronal marker was significantly greater in the combination individually after TBI and found them to be ineffective. treatment group than in the monotherapy group (Table 3). However, when administered together, the same subthera- However, the percentage of cells was the same in both groups. peutic doses of MSCs and atorvastatin significantly improved

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A

FIGURE 5. Bar graph showing the density of vessels in the lesion bound- ary zone. Asterisk, P Ͻ 0.05.

effect on cerebral microvasculature and intravascular throm- B bosis after TBI. Treatment of TBI with statins increases the cerebral microvascular patency by increasing the density and diameter of vessels in the lesion boundary zone (17). It causes proliferation of endothelial cells (13) and induces resolution of microvascular microthrombi (16, 17). These changes subse- quently lead to increased perfusion in the injured areas, as shown by fluorescein isothiocyanate-dextran perfusion stud- ies (17). This enhanced regional blood flow can increase the access of agents such as MSCs into the injury zone. One of the limiting factors with MSC therapy is that only a small per- centage of injected cells reach the injured brain (21, 24). Therefore, if statins can increase the delivery of MSCs to the target tissue, they can significantly increase their therapeutic effect. Our data showed that the number of MSCs in the rats FIGURE 4. Coronal brain sections showing newly regenerating BrdU-positive treated with combination therapy was significantly greater cells (arrows) in the lesion boundary zone of MSC- (A) and MSC plus than in those receiving MSCs alone. Our data also showed µ ϫ atorvastatin-treated (B) rats. Scale bar, 100 m; original magnification, 100. that MSCs enhance the angiogenic effect of statins because the vessel-to-tissue ratio was significantly increased in the combi- nation therapy group. Therefore, MSCs exert an autoinductive TABLE 4. Bromodeoxyuridine-positive cellsa effect. They promote the statins’ angiogenic effect, which then Dentate gyrus Boundary zone leads to their increased delivery into the injured brain. In (cells/mm) (cells/mm2) addition, this angiogenic effect can serve as a priming event for MSCs by increasing their survival and efficacy once they TBI plus saline 7.04 Ϯ 2.90 45.86 Ϯ 14.95 have reached the injury zone. Newly proliferating vascular TBI plus atorvastatin 16.70 Ϯ 3.30b 87.27 Ϯ 15.27b endothelial cells are known to produce an array of factors, TBI plus MSCs 17.31 Ϯ 5.40b 104.31 Ϯ 31.50b including brain-derived neurotrophic factor (BDNF) (11), TBI plus MSCs plus 33.70 Ϯ 9.20b,c 174.3 Ϯ 23.70b,c which likely promote the survival of MSCs. It has been well atorvastatin recognized that trophic factors enhance the survival and sub- a TBI, traumatic brain injury; MSCs, marrow stromal cells. All data are sequent differentiation of transplanted stem cells into neu- Ϯ provided as mean standard deviation. rons and glia (34). Our previous studies have shown that cul- b P Ͻ 0.05 versus the TBI plus saline group. c P Ͻ 0.05 versus the TBI plus atorvastatin and TBI plus MSCs groups. turing MSCs with neurotrophic factors (i.e., BDNF and nerve growth factor [NGF]) increases their survival and neuronal differentiation (23). Also, the functional outcome of rats the functional outcome after TBI. This improvement was not treated with MSCs cultured with growth factors is signifi- visible until Day 28, suggesting that time is needed for the cantly better than those treated with MSCs alone (23). synergistic interaction between the two agents to be clearly Therefore, statins can potentiate the effect of MSCs by not visible in the functional outcome. The reasons for this only increasing their delivery into the injury zone, but also enhanced functional recovery after combination therapy are enhancing their effect once they have reached the target tis- probably multifold. The statins likely increase the access of sue. In the present study, the percentage of MSCs showing MSCs to the injured tissue and also prime the tissue to the neuronal differentiation was the same in the combination and effects of MSCs. Statins have been shown to have a distinct monotherapy groups even though the total number of donor

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cells showing neuronal differentiation was significantly more 6. Dixon CE, Clifton GL, Lighthall JW, Yaghmai AA, Hayes RL: A controlled cor- in the combination therapy group because this is simply a tical impact model of traumatic brain injury in the rat. J Neurosci Methods function of a larger number of Y chromosome-positive cells. It 39:253–262, 1991. 7. Dixon CE, Flinn P, Bao J, Venya R, Hayes RL: Nerve growth factor attenuates has long been our contention that MSCs influence the func- cholinergic deficits following traumatic brain injury in rats. Exp Neurol tional outcome not by differentiating into nerve cells but 146:479–490, 1997. rather by enhancing intrinsic neurorestorative functions of 8. Eglitis MA, Mezey E: Hematopoietic cells differentiate into both microglia the injured brain (15). In the present study, the dose of ator- and macroglia in the brains of adult mice. Proc Natl Acad Sci U S A vastatin was very small, and we cannot rule out the possibil- 94:4080–4085, 1997. 9. Fernandez Pujol B, Lucibello FC, Zuzarte M, Lutjens P, Muller R, Havemann ity that larger doses may enhance the differentiation of donor K: Dendritic cells derived from peripheral monocytes express endothelial MSCs into neurons. markers and in the presence of angiogenic growth factors differentiate into Our data also showed that significantly increased endoge- endothelial-like cells. Eur J Cell Biol 80:99–110, 2001. nous cellular proliferation was induced by combination ther- 10. Huang EJ, Reichardt LF: Neurotrophins: Roles in neuronal development and function. Annu Rev Neurosci 24:677–736, 2001. apy compared with monotherapies. Our previous studies 11. Leventhal C, Rafii S, Rafii D, Shahar A, Goldman SA: Endothelial trophic sup- have demonstrated that both MSCs and statins enhance port of neuronal production and recruitment from the adult mammalian endogenous cellular proliferation, thereby promoting intrinsic subependyma. Mol Cell Neurosci 13:450–464, 1999. neural plasticity (13, 17, 20). This effect is probably mediated 12. Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, Katakowski M, Zhang LJ, by the production of neurotrophic growth factors. Multiple Lu M, Janakiraman N, Chopp M: Human marrow stromal cell therapy for stroke in rat: Neurotrophins and functional recovery. Neurology 59:514–523, growth factors have been identified but the ones shown to be 2002. most vital for neural development and regeneration include 13. Lu D, Goussev A, Chen J, Pannu P, Li Y, Mahmood A, Chopp M: Atorvastatin NGF, BDNF, and vascular endothelial growth factor. MSCs reduces neurological deficit and increases synaptogenesis, angiogenesis, and produce and induce intrinsic parenchymal cells to produce neuronal survival in rats subjected to traumatic brain injury. J Neurotrauma 21:21–32, 2004. growth factors such as NGF and BDNF (19), whereas statins 14. Lu D, Li Y, Wang L, Chen J, Mahmood A, Chopp M: Intraarterial administra- induce increased production of vascular endothelial growth tion of marrow stromal cells in a rat model of traumatic brain injury. J factor and BDNF (4). Therefore, if used together, more growth Neurotrauma 18:813–819, 2001. factors are likely to be produced providing additional ration- 15. Lu D, Mahmood A, Chopp M: Biologic transplantation and neurotrophin- ale for combining MSC and statin therapies. Growth factors induced neuroplasticity after traumatic brain injury. J Head Trauma Rehabil 18:357–376, 2003. influence different aspects of neurogenesis, synaptogenesis, 16. Lu D, Mahmood A, Goussev A, Qu C, Zhang ZG, Chopp M: Delayed throm- and angiogenesis. Vascular endothelial growth factor is an bosis after traumatic brain injury in rats. J Neurotrauma 21:1756–1766, 2004. angiogenic factor and has multiple effects, e.g., neurogenesis 17. Lu D, Mahmood A, Goussev A, Schallert T, Qu C, Zhang ZG, Li Y, Lu M, and axonal outgrowth (26, 30). BDNF regulates different Chopp M: Atorvastatin reduction of intravascular thrombosis, increase in cerebral microvascular patency and integrity, and enhancement of spatial aspects of neuronal survival, migration, morphological dif- learning in rats subjected to traumatic brain injury. J Neurosurg 101:813–821, ferentiation, and synaptic function (2, 10). NGF is another 2004. important growth factor that plays a major role in neural 18. Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M: Adult bone marrow stro- repair and restoration after injury (7, 31, 32). mal cells administered intravenously to rats after traumatic brain injury In summary, treatment of TBI with MSC and atorvastatin migrate into brain and improve neurological outcome. Neuroreport 12:559–563, 2001. combination therapy has a superior effect on the reduction of 19. Mahmood A, Lu D, Chopp M: Intravenous administration of marrow stromal neurological deficits compared with single therapies. As dis- cells (MSCs) increases the expression of growth factors in rat brain after trau- cussed above, the reasons for this response, although based on matic brain injury. J Neurotrauma 21:33–39, 2004. scientific data, are still unproven. We acknowledge that addi- 20. Mahmood A, Lu D, Chopp M: Marrow stromal cell transplantation after tional research is needed to provide insight into how statins traumatic brain injury promotes cellular proliferation with the brain. 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Sinson G, Voddi M, McIntosh TK: Nerve growth factor administration atten- not the statin agents have an effect on other cell lines. uates cognitive but not neurobehavioral motor dysfunction or hippocampal Douglas Kondziolka cell loss following fluid-percussion brain injury in rats. J Neurochem 65:2209–2216, 1995. Pittsburgh, Pennsylvania 33. Vescovi AL, Gritti A, Galli R, Parati EA: Isolation and intracerebral grafting of nontransformed multipotential embryonic human CNS stem cells. J ahmood et al.’s study suggests that intravenous bone MSC ther- Neurotrauma 16:689–693, 1999. Mapy synergizes with oral statin therapy. They have previously 34. Yurek DM, Lu W, Hipkens S, Wiegand SJ: BDNF enhances the functional demonstrated that both individual therapies carry potential advantage reinervation of the striatum by grafted fetal dopamine neurons. Exp Neurol in the functional recovery from cortical contusion injury. In the present 137:105–118, 1996. study, half of the therapeutic dose of cells was combined with half the therapeutic dose of atorvostatin, resulting in improved post-injury COMMENTS memory and motor function. In addition, dual therapy increased the number of MSCs in the perimeter of the lesions, increased hippocam- erhaps someday we will see statins in the drinking water alongside pal and lesional neurogenesis, and increased neovascularity in both the Pfluoride. There seems to be no end to the positive effects of the 3- hippocampus and lesion regions. Microtubule-associated protein-2 hydroxy-3 methyl-glutaryl-coenzyme A reductase inhibitors. staining, indicative of neuronal differentiation in MSCs, increases in The authors of this study have experience with both experimental proportion to the increase in total MSCs. agents and previously determined minimally effective doses. They The authors propose a mechanism whereby atorvostatin increases intentionally looked for an additive or synergistic effect, and indeed the delivery of MSCs through neovascularization, whereas MSCs they found one. They noted improvements only in the combination increase atorvostatin-dependent neovascularization through an group, which demonstrated improved modified neurological severity unknown inductive pathway. Moreover, atorvostatin and MSC- scores and water maze performance. Furthermore, they observed sig- dependent neovascularization is purported to provide trophic factor nificantly higher numbers of stem cells and increased endogenous cel- support for the observed MSCs. This mechanism provides an elegant lular and vascular proliferation in the combination group. explanation for the apparent synergy between the two therapies but These results are preliminary and will require replication. Exploring seems to overstep the limited data presented in the current report. It is a possible dose-response relationship will be crucial. The possible true that microvasculature can produce growth factors which, in turn, mechanisms for this synergy advanced by the authors are highly con- have been shown to promote stem cell survival and neuronal differen- jectural but also highly feasible. A beneficial role for statins in stem cell- tiation. This is, however, somewhat circumstantial evidence. The mediated approaches to tissue repair is theoretically grounded in pub- authors present no evidence that neovascularization induces MSC neu- lished data from cardiac and vascular research in which one might ronal differentiation and survival. anticipate such an idea to originate. The real mystery that must be pondered from a mechanistic perspec- It is interesting that benefits were noted in a delayed fashion after tive is how increased MSC-derived cells, which predominantly popu- therapy. Such delayed improvement may be indicative of meaningful late the periphery of a lesion, can mediate improved neural function in repair processes such as axonal regrowth and enhanced plasticity, both the short time frame that is examined. The authors show that atorvo- of which would require some time to be seen. This will be important to statin increases the number of these cells that become neurons (MAP- explore. It is also worth noting that the experimental regime is clinically 2 positive). It seems implausible, however, that these new neurons relevant in that the agents are administered within 24 hours after injury, somehow integrate into the circuits that support memory and enhance which would be achievable in many neurotrauma patients. function in the period of a month. Likewise, they demonstrate that This study is important because it combines cell-replacement and neurogenesis is activated locally. The role of these cells in improved pharmacological approaches with ameliorating the effects of neuro- acute recovery is similarly mysterious. To truly provide a benefit, they trauma. Monotherapies currently demonstrate only modest benefits, would have to stabilize neurons or axonal pathways that are hanging and combined treatments will very likely be required to achieve mean- in the balance. The present study teaches us little about the timeframe ingful repair in neurologically injured patients. This study raises the over which these cells appear. I am left wondering whether they form

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quickly enough to play this role. If not, then the formation of new neu- assays is reason for a healthy skepticism. No doubt, we will see further rons may be unrelated to the observed behavioral improvement. work from this group that will support these exciting findings. The study reports the findings of a single time point and single dose Lastly, the literature is rife with interventions capable of neuropro- of MSCs. A better understanding of the effect would be provided by tection in rodent models. These interventions are difficult to translate dose-response work focusing on the primary behavioral outcome. That into human closed head injury. Nonetheless, intravenous cell thera- is to say that, although the authors have done a good deal of work on pies with or without adjuvant drugs will be relatively easy to bring to this problem in the past, the fact that the first dose and time point cho- the clinic in comparison with direct transplant strategies. sen had such an impressive impact should beg the need for replication and more in depth study. Similarly, the positive impact of MSCs and Nicholas M. Boulis atorvostatin on such a wide variety of histological and behavioral Cleveland, Ohio

Diagram demonstrating distribution of organ involvement with light-chain amyloidosis in 445 patients. Typically, a bone mar- row plasma-cell clone (center, immunofluorescence assay) synthesizes monoclonal light chains (center, immunofixation of serum and urine) which can deposit amyloid, infiltrating most organs with the exception of parenchymal brain tissue. Percentages are indicative of the frequency of the dominant organ involved. The soft tissue polarized light microscopy image (lower left) shows amyloid infiltration of vessel walls. Courtesy of Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. N Engl J Med 349:583–596, 2003. SPECIAL ARTICLE

EVOLUTION OF THE HUMAN BRAIN: CHANGING BRAIN SIZE AND THE FOSSIL RECORD

Min S. Park, M.D. ALTHOUGH THE STUDY of the human brain is a rapidly developing and expanding Division of Neurological Surgery, science, we must take pause to examine the historical and evolutionary events that University of California, helped shape the brain of Homo sapiens. From an examination of the human lineage San Diego Medical Center, San Diego, California to a discussion of evolutionary principles, we describe the basic principles and theo- ries behind the evolution of the human brain. Specifically, we examine several theo- Andrew D. Nguyen, M.D., Ph.D. ries concerning changes in overall brain size during hominid evolution and relate them Division of Neurological Surgery, to the fossil record. This overview is intended to provide a broad understanding of some University of California, of the controversial issues that are currently being debated in the multidisciplinary field San Diego Medical Center, San Diego, California of brain evolution research. KEY WORDS: Allometry, Brain, Encephalization quotients, Evolution, Hominids, Humans Henry E. Aryan, M.D. Division of Neurological Surgery, Neurosurgery 60:555–562, 2007 DOI: 10.1227/01.NEU.0000249284.54137.32 www.neurosurgery-online.com University of California, San Diego Medical Center, San Diego, California hroughout much of recorded history, H.M.S. Beagle, Darwin put forth several obser- poets, philosophers, and artists have vations and deductions that would form the Hoi Sang U, M.D. attempted to codify their identity and foundation for his theory of evolution. First, Division of Neurological Surgery, T place in the known and unknown worlds. It is he noted that all organisms must struggle for University of California, San Diego Medical Center, likely that this intellectual endeavor began the scarce resources in their environment. He San Diego, California long before recorded history. In one of the ear- also observed a wide variety of differences in liest attempts at taxonomy, Aristotle devel- nature, even between animals of the same Michael L. Levy, M.D., Ph.D. oped his “Great Chain of Being” in the 4th species. Darwin deduced that some of these Division of Neurological Surgery, century BC. He placed all living things in an variations must be more suited for a particular University of California, orderly, hierarchical ladder with humans as environment and, thus, have a higher chance San Diego Medical Center, and the dominant and perfect form occupying the of being selected for in future generations, a Department of Neurological Surgery, top rung. The relationship of all living things process he termed natural selection. Children’s Hospital San Diego, San Diego, California was considered to be preordained and fixed, Since that time, the study of evolution has arising from Aristotle’s belief in the “immuta- expanded exponentially with the advent of Katerina Semendeferi, Ph.D. bility” of species. multiple disciplines examining the questions From that time, the idea that species develop of human origin and evolution. We build on Department of Anthropology, University of California at San Diego, and adapt to their surroundings over time and these foundations to describe the current state San Diego, California generations has been proposed and refined. In of study into the evolution of the human brain. Philosophie Zooligique, published in 1809, Jean- This article is intended to provide individuals Reprint requests: Baptiste Lamarck described his theory of the who are naïve in evolutionary brain science Katerina Semendeferi, Ph.D., inheritance of acquired characteristics. Lamarck with a first look at this rapidly expanding and Department of Anthropology, University of California at San Diego, proposed that as an animal physically adapted developing field; it is not meant to represent a 9500 Gilman Drive, to its environment, the changes could be passed complete overview. We have chosen a sam- La Jolla, CA 92093-0532. directly to their progeny. His theory was pling from the multitude of theories and argu- Email: [email protected] remarkable for its recognition of the relation- ments that offer a glimpse into this dynamic ship between the environment and the organ- area of scientific investigation. Received, September 26, 2006. ism. However, as revolutionary as this idea was Accepted, October 31, 2006. at the time, it presumed that evolution could A HISTORICAL VIEW occur within the lifetime of one individual. OF QUANTIFYING BRAIN Charles Darwin published his famous trea- SIZE CHANGES tise, On the Origin of Species, in 1859, describing his theory of evolution by natural selection. On The study of brain evolution is inherently the basis of his work as a naturalist on the driven by the desire to uncover the evolution-

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ary principles that determine intelligence. To begin, we must sizes of our extinct ancestors. Together with evidence of “intel- first determine what constitutes intelligence. Harold Jerison ligent” behaviors (i.e., tool making and the use of fire) from the (20), in his study of the evolution of intelligence, defines “bio- paleoarchaelogical record, we can speculate a certain level of logical intelligence” as the ability to integrate various sensory “intelligence” among these extinct hominids. modalities regarding objects in space and time to construct a With contemporary animals, the measurements are much perceptual world. Based on Jerison’s definition, it seems intu- easier to obtain. When comparing extant vertebrates, we note itive that humans exhibit more intelligence than primates and that blue whales have a brain five times the size of a human other mammals. However, even the measurement of intelli- brain. Although marine mammals are known to be very intel- gence within our own species is a daunting task with critics in ligent animals, we would be hard pressed to find an individual scientific, political, and sociological circles assailing any to argue that this confers on the whale five times human intel- attempts to quantify it. ligence. Likely, the whale has a larger brain because of its larger Regarding animal intelligence, the question becomes more body. However, when we directly scale brain size to body size, clouded. Different species experience identical experimental we find that a blue whale’s brain comprises only 0.01% of its tasks in completely different manners (41). Because of this total body weight. Humans, on the other hand, have a brain-to- difficulty in defining general intelligence across species, we body ratio of 2% (39). Conversely, small mammals such as examine ”domain-specific” intelligence in the laboratory set- pocket and harvest mice demonstrate brain-to-body ratios of ting, i.e., the learning of navigational skills in homing pigeons nearly 10% (27). Obviously, by itself, a simple brain-to-body (15, 39). Thus, animals are often examined in the scope of their ratio does not make intuitive sense with respect to intelligence natural behaviors and abilities. Rodents perform better using between species. food as a reward, whereas reptiles generally perform much Researchers then turned to scaling or allometry, the study of better in learned tasks using warmth as an incentive (39). differential proportions among various anatomic structures and Despite all of the inherent difficulties in defining and measur- related consequences, to explore the relationship between brain ing intelligence, researchers continue to examine its possible size and intelligence. Plotting a logarithmic scale of brain and correlation with both behavior and the brain. body weights for many mammals demonstrates a negative The long-standing interest in determining brain size among allometric relationship with a slope of less than one (39). This humans, primates, other mammals, and the extinct hominids indicates that, among animals, an increase in body size is lies in the attempt to correlate intelligence to some aspect of the accompanied by small increases in brain size in a proportion- brain as a structure and vice versa. Initial attempts at forging ate manner. We can clearly define and compare this mathemat- relationships relied on measurements of absolute brain size as ical relationship between the brain and body sizes of several a marker for intelligence. By examining the fossil record, we animals or species. Considering these relationships to be repre- can determine the cranial vault capacities of our ancestors. sentative of the intelligence differences between species, how- Endocasts, fossilized or human-made casts of the cranial vault, ever, is much more problematic and does not sufficiently provide a fairly accurate representation of brain size, as well as explain the differences in humans, primates, and other mam- a general look at superficial brain anatomy (Fig. 1). Along with mals (3, 13, 18, 37). reconstructions of the postcranial skeleton, we can determine, This led Jerison (19) to develop the encephalization quotient with some degree of certainty, the absolute and relative brain (EQ) in 1973, which calculates the departure of the observed brain size from what would be expected for an individual based on a reference group of animals (EQ ϭ actual brain mass divided by estimated brain mass). This allowed Jerison to circumvent one of the inherent diffi- culties in allometry, namely comparing brain size across species independent of its primary correlation with body size (14). Jerison then correlated EQ across many different species with certain behavioral variables, such as intelligence. On the basis of these studies, we find that humans have both the highest absolute brain size and the highest EQ among primates, a very reassuring finding (38). At first glance, we can speculate on the relationship between brain and body size and intelligence in animals; however, there are several criticisms of using EQ in this manner. EQ is a rela- tive measurement based on a chosen data set and is ultimately derived from a mathematical relationship between brain and FIGURE 1. A and B, views of the “Taung” child, an Australopithecus body size. The difficulty is apparent in attempts to use simple africanus, showing a partial skull and fossilized endocast. Cast from measurements and calculations (i.e., EQ) to predict and quan- the Department of Anatomic Sciences, Witswatersrand Medical School, tify complex behaviors and attributes (i.e., intelligence). Also, South Africa. evolution plays a part in the selection of both brain and body

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size (22). Very small monkeys have EQs that are much higher require more intelligence to navigate the vagaries of a social than our closest extant relatives, the gorillas and chimpanzees lifestyle and to increase their reproductive fitness. The obvious (Fig. 2). Few would argue, however, that squirrel monkeys are benefits of a more social group can be enjoyed by all of its more intelligent than chimpanzees. Because of the selection for members, whereas those clever enough to exploit and manip- a smaller body size in some monkeys, the EQ, by nature of its ulate certain situations and alliances profit more. Thus, social calculation, seems high. In addition, smaller dogs, such as chi- animals such as manta rays, hammerhead sharks, and ele- huahuas and other miniature breeds, have a higher EQ than phants are generally more encephalized when compared with larger breeds, such as German shepherds. Again, few would their closest, less social cousins (39). claim that chihuahuas represent the pinnacle of canine intelli- Because brain size is constrained by several anatomic and gence. Rather, their body types have been selected, although in physiological factors, several theories have been proposed a less natural fashion, leading to an artificially high EQ (38). regarding how such constraints may have been overcome. These “release mechanism” theories describe the anatomic EVOLUTIONARY PRINCIPLES OF changes identified within extant primates and the fossil record BRAIN SIZE CHANGE that either allowed for or resulted from the increase in brain size. The “expensive tissue” hypothesis argues that because There are multiple theories concerning the development of the brain has such a high energy requirement relative to its certain behaviors that may have led to increasing intelligence size, it is, metabolically speaking, a very expensive organ (1). and brain size. The “clever foraging” hypothesis examines the The only other organ system with a comparable energy interplay between diet, accessibility of food resources, and demand is the intestinal tract. Because of the competition brain size (31). We find that filter-feeding sharks and whales are between the two organ systems, a change to a more easily generally less encephalized than other members of their genus digestible and nutrient-rich diet allowed for shortening of the who hunt individually for prey (39). Among primates, leaf intestinal tract, thus freeing up limited, valuable resources for eaters tend to be less encephalized than insectivores and frugi- the brain (1). vores (9). Thus, species that are more encephalized tend to for- Scientists have also examined the role of a more energy-rich, age or hunt strategically, taking into account the tendencies carnivorous food source on increasing body and brain size in and location of their prey, whereas species that are less hominids (29). On the basis of an anatomic and kinetic study of encephalized tend to graze or feed opportunistically (39). carnivores, extant great apes, and human intestinal tracts, we The social intelligence model of encephalization, also known note differences in the proportion of the relative components of as the “Machiavellian intelligence” hypothesis, examines the their intestines. In humans, the small intestine occupies the role of social organizations on behavior (7, 17). We find that diet majority of the digestive tract, whereas in apes, the colon occu- and food resources do not adequately explain intelligent behav- pies the most space (29). This evolutionary change in relative iors in all animals. However, highly social animals tend to proportions presumably allows humans to easily extract nutri- ents from a more energy-rich animal food source. Thus, researchers postulate that early hominids required a change from a predominantly plant-based diet to a meat-based one to provide enough nutrition to accommodate the larger body and brain size (26, 29). In contradiction to the previous hypothesis, other researchers propose that cooking had a more profound impact on human evolution than eating meat (44). They argue that changes in the digestive tract of humans resulted not from an increase in pro- tein (i.e., meat) in their diet, but from an increased reliance on cooking to maximize the nutritional value of meats and vege- tation, particularly underground tubers (44, 45). We note that chimpanzees require an inordinate amount of time to chew and swallow raw meat. Because of this, researchers propose that hominids solved the problem of inefficient digestion of certain plant materials and raw meat by applying cooking tech- niques (44). Furthermore, the addition of cooked tubers to the hominid diet provided the higher-quality diet necessary for brain expansion (45). The fossil record seems to lend some sup- port to this contention with the identification of controlled fire possibly as early as 1.6 million years ago (mya), a time of remarkable brain size increase (34). FIGURE 2. Lateral (A) and ventral (B) views of a chimpanzee brain. Lateral Another type of “release mechanism” not directly related to (C) and ventral (D) views of a gorilla brain. energy and diet is the “radiator” theory (11). After study of the

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differences between fossil remains of some early hominid ancestors, researchers identified a statistically significant differ- ence in the occurrence of an occipital/marginal sinus between early hominid representatives (11). We find that certain extinct hominids from our direct lineage evolved a network of emis- sary veins along the parietal and mastoid regions for drainage of venous blood, a system retained in modern day humans. Other extinct hominids, representing evolutionary dead ends, lacked this adaptation and retained a system of occipital/mar- ginal sinuses to drain venous blood. This network of emissary veins created “thermoregulatory adaptations” that allowed for a more rapid and selective cooling of the human brain in the hyperthermic state (8). Although the “radiator” theory and the occurrence of selective brain cooling in humans is hotly debated (4, 5, 30), it proposes that an increased efficiency of the brain in the paleoecological niche of our early ancestors allowed for the rapid expansion of the hominid brain that is readily identifiable in the fossil record (11). FIGURE 4. Representative species of Old World monkeys. A, red colobus Which of these hypotheses accurately describe the evolution monkey. B, baboons. of brains within the hominid line is very difficult to answer. The theories described above are not without their detractors and are certainly not the only theories regarding evolutionary changes in behavior and other anatomic structures that allowed the hominid brain to expand. In addition, because these views are not necessarily mutually exclusive, a combination of factors may have allowed us to branch out on the phylogenetic tree and find a new niche in primate evolution.

CHANGES IN HOMINID BRAIN SIZE IN THE FOSSIL RECORD

Before we can fully understand human brain evolution, we must have a perspective of our standing within the phyloge- netic tree (Fig. 3). The primate order, of which we are a mem- ber, can be further divided into prosimians and anthropoids. Prosimians encompass the lemurs and their closely related kin. Anthropoids encompass the New and Old World mon- keys (Fig. 4) and the apes, including gibbons, gorillas, orang- utans, chimpanzees, and humans. The hominid family

FIGURE 5. Partial hominid phylogenetic tree. Timeline scale in millions of years ago. H., Homo; A., Australopitecus.

includes only the bipedal apes, namely humans and our extinct direct ancestors. As we attempt to link ourselves with our ancestors, we iden- tify certain characteristics that are deemed significant and, evo- lutionarily speaking, necessary in developing the human form. These attributes allow us to identify with, and distinguish our- FIGURE 3. Partial primate phylogenetic tree. selves from, previous hominids and place fossil specimens in their appropriate position on the phylogenetic tree (Fig. 5). Of

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course, there is still much and chimpanzees (22, 23, 33). However, recent biomechanical debate regarding the phylo- models and evolutionary robotics studies based on her lower genetic relationships of the extremity skeletal morphology and contemporary fossilized fossil specimens. The diffi- footprints suggest that she was fully bipedal (36). Despite con- culty lies in defining the troversy, she was given the species name Australopithecus anatomic features that serve afarensis and has become the standard-bearer for the Australo- as the hallmarks of a particu- pithecus genus. lar species. However, recent There are, of course, multiple other species within the comparative anatomic stud- Australopithecus genus. Earlier specimens have been identified, ies and molecular genetic evi- as have contemporary and later species assigned to the same dence are helping scientists genus. Some of these later species, such as the robust australo- make more informed classifi- pithecines, demonstrated increasing anatomic specializations cations. and seem to represent divergence within the Australopithecus It is easier to identify dis- genus. Likely, they also represent an evolutionary dead end tinguishing attributes in (38). Further discussion of the diverse australopithecine radia- modern day representatives. tion falls outside the scope of this article. Humans have evolved pre- FIGURE 6. “Lucy,” an Australopithe- Scientists have been able to calculate cranial capacities from dominantly bipedal locomo- cus afarensis. Reconstruction by many australopithecine fossils (Table 1). A. afarensis had an tion and have lost the oppos- William Munns. intracranial volume of approximately 342 to 350 cm3, similar to able big toe, traits not shared that of chimpanzees, orangutans, and female gorillas (Fig. 7) with our extant cousins. The development of language is also (28). In the later robust australopithecines, we find a trend not found among our brethren. Whether these evolutionary toward larger volumes of 494 to 537 cm3, roughly the size of a developments induced changes within the hominid brain or male gorilla brain (28). It is difficult to conclude that the robust whether changes in the brain allowed for these developments australopithecines were more encephalized than the early ones is a question that is not easily answered and falls outside the because determinations of body size from fragmented skeletal scope of this article. remains pose some difficulty. Errors may also be introduced by Returning to the fossil record, we estimate the origin of the the selection of a modern reference standard for comparative primate lineage to be at least 50 mya. With evidence from modeling (16). Despite these concerns, it is generally accepted genetic analyses of modern day primates, it is conceivable that that the members of the genus Australopithecus were smaller our last common ancestors originated as early as 65 to 60 mya, than modern apes. Given that they have comparable brain during the late Cretaceous period. This makes our most distant sizes, we can assume that the australopithecines were more primate ancestors the contemporaries of dinosaurs (12, 40). encephalized than modern apes (38). The earliest known fossil specimen of hominids belongs to Approximately 2 mya, the members of the genus Homo Sahelanthropus tchadensis, found in northern Chad in 2001. This appeared. A juvenile partial skull discovered in the 1960s by specimen, dated to approximately 6 to 7 mya, exhibits charac- Louis and Mary Leakey led to the identification of Homo habilis, teristics found in both apes and hominids, although its exact place on the phylogenetic tree is still a matter of debate (38, 42). Unfortunately, the fossil record for the ape ancestors during TABLE 1. Comparison of cranial capacities and encephalization this period is poorly represented, making an accurate determi- quotients between sample hominidsa nation of the ape-hominid split difficult. Molecular genetic evi- Dates Cranial Estimated dence, however, points to approximately 5 to 8 mya as the time Specimen (mya) capacity (cm3)EQ of last common ancestor between hominids and our closest extant relatives, the chimpanzees (12, 42). Australopithecus 3.9–3.0 342–350 2.5 The australopithecines represent one of the older, more com- afarensis plete members of the hominid family. Arguably, the most Robust 2.3–1.4 494–537 2.7–3.0 famous member of this family is “Lucy,” the diminutive fossil australopithecines discovered in 1974 by Donald Johanson (Fig. 6). At the time of Homo habilis 1.9–1.6 509–775 2.7–3.3 her discovery, “Lucy” represented the earliest hominid fossil, Homo erectus 1.6–0.25 727–1225 3.3 exhibiting a mosaic of ape and human characteristics. With Archaic Homo 0.6–0.13 1100–1586 3.5 more than 40% recovered, she also remains one of the most sapiens complete skeletons (21). Her cranium and dentition share char- Neandertals 0.15–0.027 1200–1750 4.0 acteristics between living apes and humans with a cranial vault Modern day Present 1349 5.3 size similar to that of modern great apes. Although she seems Homo sapiens to exhibit lower extremity skeletal evidence of bipedalism, a mya, million years ago; EQ, encephalization quotient. Data compiled from study of her radius and wrist morphology suggests more of a Leigh (25), McHenry and Coffing (28), Ruff et al. (35), and Stanford et al. (38). knuckle-walking locomotive pattern, similar to modern gorillas

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purportedly the first stone tool makers of the hominid lineage 1225 cm3 (average, 900 cm3) (Fig. 7) (24). This skull possessed a brain larger than any known (25, 38). Cranial capacities of australopithecine and most modern apes (10, 28). The smallest the larger-brained H. erectus members of this family have brain sizes that overlap with the even begin to approach val- largest brains found in gorillas. Given the relatively slight ues found in modern human stature of H. habilis, we can again assume that they were rela- brains (32). Evidence also tively more encephalized than both their predecessors and points to their dispersal away modern apes (38). Oldowan tools, consisting of stone flakes from the African continent as and cores, from approximately 2.5 mya are clearly associated early as 1.7 mya, the first of for the first time with these early hominids (38). However, sig- several hominid species to do nificant controversy exists regarding the make-up of H. habilis. so (2). H. erectus is also associ- Because of the morphological diversity found among the fossil ated with a more complex specimens, some authors have had difficulty justifying their stone tool technology than inclusion into only one species (42, 43). H. habilis. This is the first The identification of fossil remains of H. erectus dated to instance in hominid history approximately 1.8 mya at the Koobi Fora in Kenya reveals a in which we identify stone FIGURE 8. H. heidelbergensis recon- major adaptive shift in hominids. The fossil record reflects an tools, including hand axes struction based on fossil specimens discovered in Heidelberg, Germany. increase in body size, lengthening of the femur in association and cleavers, that required a Reconstruction by A. Mascres, ca. with a more efficient stride, and increasing brain size in this mental template for stan- 1912, for the 1915 Panama-California species (38). H. erectus cranial capacities, which were generally dardization and the creation Exposition in San Diego. larger than H. habilis and australopithecines, ranged from 700 to of symmetrical objects (38). As we continue to analyze the Homo genus, we begin to iden- tify fossil specimens that likely form a bridge to the modern H. sapiens. Some, such as H. erectus and H. heidelbergensis (Fig. 8), more clearly form a direct link to our ancestors, whereas others, such as H. neandertalensis or Neandertals, arguably represent an evolutionary dead end (38). We continue to find a trend in increasing cranial capacities and greater encephalization in archaic H. sapiens, Neandertals, F6 and modern H. sapiens (Fig. 9) (35). In fact, Neandertals exhibit brain sizes that surpass that of even modern day humans, whereas the brain sizes of H. sapiens have decreased during the past 35,000 years (35, 38). Presumably, the larger Neandertal brain is simply caused by allometric scaling resulting from a larger body habitus and cold weather adaptations (38). The decrease in the brain size of H. sapiens was coupled with a decrease in body mass, resulting in an overall increase in EQ during this period (35). Furthermore, increasing encephaliza- tion found in Neandertals and H. sapiens occurred by different morphological trajectories, with humans exhibiting larger development of the parietal region (6). We have presented species from the hominid phylogenetic tree as representatives along the evolutionary timeline. How- ever, it is important to note that there have been numerous other specimens representing hominid radiations that may or may not be part of the direct ancestral lineage. In addition, it would be erroneous to think that only a single species of hominid existed at a single place and time. With the development of modern dat- ing techniques, we can clearly identify multiple hominid species coexisting throughout Africa, Asia, and Europe. The place of one species either in an evolutionary dead end (i.e., extinction) or as distant, direct ancestors, is a matter of significant debate in the anthropological world. Certainly, evolution does not follow a FIGURE 7. A, anteroposterior view of an A. afarensis skull. Anteroposterior simple unidirectional progression but is more halting and spo- (B) and lateral (C) views of a H. habilis skull. Sculptural reconstructions by radic, using nature and the environment to select for the most Bones Clones, Inc., Canoga Park, CA. favorable attributes in a population of almost infinite variations.

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2. Anton SC, Swisher CC: Early dispersal of Homo from Africa. Annu Rev Anthropol 33:271–296, 2004. 3. Armstrong E: Brains, bodies, and metabolism. Brain Behav Evol 36: 166–176, 1990. 4. Braga J, Boesch C: The “radiator” bias: A response to Falk and Gage. J Hum Evol 33:503–506, 1997. 5. Brengelmann GL: Specialized brain cooling in humans. FASEB J 7:1148– 1153, 1993. 6. Bruner E, Manzi G, Arsuaga JL: Encephalization and allometric trajectories in the genus Homo: Evidence from the Neandertal and modern lineages. Proc Natl Acad Sci U S A 100:15335–15340, 2003. 7. Byrne RW, Whiten A: Machiavellian Intelligence: Social Expertise and the Evolution of Intellect in Monkeys, Apes, and Humans. Oxford, Clarendon Press, 1988. 8. Cabanac M: Human Selective Brain Cooling. Austin, Landes Publishing Co., 1995. 9. Clutton-Brock TH, Harvey PH: Primates, brain, and ecology. J Zool Lond 190:309–323, 1980. 10. Day MH, Leakey RE, Walker AC, Wood BA: New hominids from East Turkana, Kenya. 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Hens SM, Konigsberg LW, Jungers WL: Estimating stature in fossil hominids: It would be simplistic and erroneous to claim that brain evo- Which regression model and reference sample to use. J Hum Evol 38:767–784, lution is the sole reason humans have become what they are 2000. today. The development of bipedalism and the reliance on a 17. Humphrey NK: The social function of intellect, in Bateson PP, Hinde RA(eds): more varied diet are a few of the many factors that necessitated Growing Points in Ethology. Cambridge, Cambridge University Press, 1976. 18. Jerison HJ: Brain size and the evolution of the mind: The 59th James Arthur Lecture significant changes in skeletal morphology. These changes are on the Evolution of the Human Brain. New York, American Museum of Natural also readily identifiable in the fossil record and likely influ- History, 1991. enced changes in hominid brains. Likewise, the increasing 19. Jerison HJ: Evolution of the Brain and Intelligence. New York, Academic intellectual capacity of the hominid brain allowed for the devel- Press, 1973. opment of social groups, culture, and language. 20. Jerison HJ: Paleoneurology and the evolution of the mind. Sci Am 234:90–91, 94–101, 1976. This interplay between behavior, intelligence, and brain evo- 21. Johanson DC, Lovejoy CO, Kimbel WH, White TD, Ward SC, Bush ME, lution is likely very tightly woven. Extricating any one single Latimer BM, Coppens Y: Morphology of the Pliocene partial hominid skele- fiber from this tangled web is a difficult process and one that ton (AL 288–1) from the Hadar Formation, Ethiopia. Am J Phys Anthropol would be subject to criticisms from multiple fronts. We have 57:403–451, 1982. 22. Latimer B, Lovejoy CO: The calcaneus of Australopithecus afarensis and its presented some of the current thoughts and beliefs regarding implications for the evolution of bipedality. Am J Phys Anthropol 78:369–386, changes in overall brain size in relation to human brain evolu- 1989. tion. Although it is historically one of the earliest topics to be 23. Latimer B, Lovejoy CO: Metatarsophalangeal joints of Australopithecus explored, it is definitely not the only avenue of research within afarensis. Am J Phys Anthropol 83:13–23, 1990. the field of brain evolution. As we develop a more sophisti- 24. Leakey LS, Tobias PV, Napier JR: A new species of the genus Homo from Olduvai Gorge. Nature 202:7–9, 1964. cated understanding of the organization of the brain, intelli- 25. Leigh SR: Cranial capacity evolution in Homo erectus and early Homo sapi- gence, and behavior, we will come to a more complete under- ens. Am J Phys Anthropol 87:1–13, 1992. standing of our own evolution. 26. Leonard WR, Robertson ML: Comparative primate energetics and hominid evolution. Am J Phys Anthropol 102:265–281, 1997. Acknowledgments 27. Mace GM, Harvey PH, Clutton-Brock TH: Brain size and ecology in small mammals. J Zool 193:333–354, 1981. We thank Ken Hedges and Rose Tyson of the San Diego Museum of Man for 28. McHenry HM, Coffing K: Australopithecus to Homo: Transformations in Figures 1, 4, 5, their generous assistance with the illustrations and figure legends. body and mind. Annu Rev Anthropol 29:125–146, 2000. 6, and 7 are currently on display at the San Diego Museum of Man. The authors 29. Milton K: A hypothesis to explain the role of meat-eating in human evolution. have not received any financial support in the preparation of this article. Evol Anthropol 8:11–21, 1999. 30. Nelson DA, Nunneley SA: Brain temperature and limits on transcranial cool- REFERENCES ing in humans: Quantitative modeling results. Eur J Appl Physiol Occ Physiol 78:353–359, 1998. 1. Aiello LC, Wheeler P: The expensive-tissue hypothesis: The brain and the 31. Parker ST, Gibson KR: Object manipulation, tool use, and sensorimotor intel- digestive system in human and primate evolution. Curr Anthrop ligence as feeding adaptations in cebus monkeys and great apes. J Human 36:199–221, 1995. Evol 6:623–641, 1977.

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32. Redcay E, Courchesne E: When is the brain enlarged in autism? A meta- misguided attempts to relate cranial capacity to human intelligence analysis of all brain size reports. Biol Psychiatry 58:1–9, 2005. during the 19th and early 20th centuries. The willful and inadvertent 33. Richmond BG, Strait DS: Evidence that humans evolved from a knuckle- examples of observer bias that plagued those pseudoscientific studies walking ancestor. Nature 404:382–385, 2000. are a lesson for all of us who consider ourselves dispassionate 34. Rowlett RM: Fire control by Homo erectus in East Africa and Asia. Acta observers of fact. The results were inextricably entwined with the sor- Anthropol Sin 19:198–208, 2000. did history of social eugenics, which, in turn, contributed to the worst 35. Ruff CB, Trinkaus E, Holliday TW: Body mass and encephalization in Pleistocene Homo. Nature 387:173–176, 1997. political excesses of the 20th century. 36. Sellers WI, Cain GM, Wang W, Crompton RH: Stride lengths, speed and Paul H. Chapman energy costs in walking of Australopithecus afarensis: Using evolutionary robotics to predict locomotion of early human ancestors. J R Soc Interface Boston, Massachusetts 2:431–441, 2005. 37. Smith RJ: Biology and body size in human evolution: Statistical inference misapplied. Curr Anthropol 37:451–460, 1996. 1. Gould S: The Mismeasure of Man. New York, W.W. Norton & Co., 1996. 38. Stanford C, Allen JS, Anton SC: Biological Anthropology: The Natural History of Humankind. New Jersey, Pearson Prentice Hall, 2006. 39. Striedter GF: Principles of Brain Evolution. Massachusetts, Sinauer Associates, his article is a piece of rare genius. The authors, a group from Inc., 2005. very mixed educational and medical backgrounds, have put 40. Tavare S, Marshall CR, Will O, Soligo C, Martin RD: Using the fossil record T together a most remarkable piece of reading examining the historical to estimate the age of the last common ancestor of extant primates. Nature 416:726–729, 2002. and evolutionary events that led to the present shape and form of the 41. Tinbergen N: The Study of Instinct. New York, Oxford University Press, 1951. human brain. To neurosurgeons, this might seem to be just a bit of 42. Wood B: Human Evolution: A Very Short Introduction. New York, Oxford boring evolution and with little application to their day-to-day prac- University Press, 2005. tice. I would like to state that this is clearly not the case. This article 43. Wood B, Collard M: The human genus. Science 284:65–71, 1999. reveals a treasure trove of information on brain size, body size, and 44. Wrangham R, Conklin-Brittain N: Cooking as a biological trait. Comp lineage in the evolutionary tree, as well as other concepts. As I was Biochem Physiol A Mol Integr Physiol 136:35–46, 2003. reviewing this article, there were a number of points at which I had 45. Wrangham RW, Jones JH, Laden G, Pilbeam D, Conklin-Brittain N: The raw to stop and digest what had been written. I cannot imagine that any- and the stolen: Cooking and the ecology of human origins. Curr Anthropol one interested in neurosurgery, the history of evolution, and under- 40:567–594, 1999. standing man in general will not find this piece of work both interest- ing and enjoyable. My compliments to the authors for their efforts in COMMENTS putting together a work of remarkable scholarship; this article was truly a treasure to read. his is a thoroughly entertaining and informative review of the sub- Tject. In addition to the articles cited by Stephan Gould, I also recom- James T. Goodrich mend his book, The Mismeasure of Man (1), in which he recounts the Bronx, New York

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LANCISI’S NERVES AND THE SEAT OF THE SOUL

Antonio Di Ieva, M.D. THE STRIÆ LONGITUDINALES mediales corporis callosi, or medial longitudinal striae Department of Neurosurgery, of the corpus callosum, are two slender bands of myelinated fibers that form longitu- Istituto Clinico Humanitas, dinal ridges in the indusium griseum on the superior aspect of each half of the corpus Milan, Italy callosum. They were first described by the Italian physician Giovanni Maria Lancisi, Manfred Tschabitscher, M.D. who served as the personal physician of three successive Popes. This essay offers an Center of Anatomy and Cell Biology, account of this eminent physician, his era, and his philosophical background, as well Medical University of Vienna, as a description of the anatomic structures that bear his name. Vienna, Austria KEY WORDS: Corpus callosum, Giovanni Maria Lancisi, Lancisi’s nerves, Longitudinal striae Riccardo Rodriguez y Baena, Neurosurgery 60:563–568, 2007 DOI: 10.1227/01.NEU.0000249283.46514.93 www.neurosurgery-online.com M.D. Department of Neurosurgery, Istituto Clinico Humanitas, Milan, Italy “Is the hard problem too hard for us?” cedon (335–280 BC), who is considered the Reprint requests: — Colin McGinn, father of modern anatomy (18) and a pioneer Antonio Di Ieva, M.D., The Problem of Consciousness, 1991 in neuroscience (1). Department of Neurosurgery, According to this theory, the body contains Istituto Clinico Humanitas IRCCS he description of the dorsal area of the natural, vital, and animal spirits that fluctuate Via Manzoni 56, 20089 Rozzano, Milan, Italy. corpus callosum in Gray’s Anatomy in the body until they reach the brain where, Email: [email protected] Treads, “Along the middle line, is a linear after being slowed and mixed by the different depression, the raphe, bounded laterally by blood flow, they are purified in the cerebral Received, May 30, 2006. two or more slightly elevated longitudinal ventricles, subsequently flow out through the Accepted, November 1, 2006. bands, called the striæ longitudinales, or nerves nerves to the periphery, and then return into of Lancisi; and, still more externally, other circulation. Thus, Galen saw the brain as an longitudinal striæ are seen, beneath the con- organ that purifies the blood of an excess of volution, which rests on the corpus callosum. spirits and theorized that an imbalance in this These are the striæ longitudinales laterales” system could cause human diseases, particu- (Fig. 1) (11, p 462). larly insanity, depression, melancholy, despair, However, is every neurosurgeon really fa- and, sometimes, death. Furthermore, he miliar with the striae longitudinales? Why are believed in the existence of the rete mirabile, a the medial striae longitudinales called the plexus of veins at the cranial base in which the “nerves of Lancisi?” And, who was Lancisi? animal spirit formed, although he could never This essay will try to answer these questions prove this theory by means of an autopsy per- by looking at the life and times of Giovanni formed on a human being (19). Maria Lancisi, who served as the personal Although human dissections in the Middle physician of three successive Popes who lived Ages have been documented, autopsies were a in Rome in the 17th century, and describing religiously forbidden practice until the 16th these interesting but neglected structures. century. The restrictions on human dissection meant that Galen’s belief survived the Middle Neuroanatomy in Rome in the Ages and, although modified by some authors 16th to 18th Centuries: Seeking of the 17th Century, the ventricles continued the “Seat of the Soul” to be thought of as the site of the movement Before the Age of the Enlightenment, “brain and mixing of the humors and spirits and science” was based on proving and/or con- were considered the seat of the soul and all futing the theories of Galen, which permeated superior functions such as cognition, imagi- the culture of the Middle Ages until the 16th nation, and memory. and 17th centuries. Many of Galen’s theories The theory was eventually dismantled by were based on the theory of animal spirits Descartes (1596–1650) and his dualistic vision originally proposed by Herophilus of Chal- of res cogitans (the soul) and res extensa (the

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to the surrounding anatomic structures. Also, Malpighi (1628–1694), in his books De Cerebro and De cerebri cortice, belied Descartes’ conception by asserting that the seat of the superior functions was the brain cortex. In 1705, Antonio Pacchioni (1665–1726) described the gran- ulations of the dura mater in his Dissertatio epistolaris de glan- dulis conglobatis Durae Meningis humanae (6) and De durae meningis fabbrica et usu disquisito anatomica (Rome, 1701), pos- tulated that the diastolic-systolic movement of the meninges could force nervous fluid through the brain nerves toward the periphery by means of a kind of “squeezing function.” A dis- pute about the originality of this idea arose because Giorgio Baglivi (1669–1707) had arrived at a similar conclusion in his work De fibra motrice (17). Baglivi, in his De praxi medica, invited the princes to establish an academy (Medicorum Collegium) at every “University” Hospital, where it would be possible to discuss the clinical aspects of medical problems by emphasizing the epistemological differences between experien- tia (knowledge based on comparing texts) and experimentum (clinical observation) (3). This was the cultural context in which Giovanni Maria Lancisi found himself. Like Galileo, Lancisi skimmed Nature’s book rather than man’s opinions to reveal the truth and, there- fore, performed many anatomic dissections of humans and ani- FIGURE 1. Schematic drawing of a section of the brain on a level with the mals. The “fashion” of the anatomy of the time was to find the corpus callosum showing the striae longitudinales mediales (nerves of Lancisi), the striae longitudinales laterales, and their relationship with seat of the soul. Following Descartes’ view that it was impos- the corpus callosum (from, Traité d’Anatomie Humaine, Poirier P, Tome sible to consider mere rational activity as object of observation, Troisième, Ed. A Charpy, Paris, 1904). Lancisi explained his purpose in describing the anatomy of the soul by quoting Plato’s Alcibiades: “In illum maxime animae locum intueri oportet, in quo virtus animae ac sapientia ipsa inest” matter), which formed the basis of the mechanistic theory. (“We must turn our eyes to the point where the faculty of the Descartes was not an expert anatomist, but he claimed that soul is knowledge itself”) (13, p 411). blood reached the brain through the carotid arteries, passed through increasingly smaller blood vessels at the choroid Giovanni Maria Lancisi plexus, and targeted the pineal gland where res cogitans and res Giovanni Maria Lancisi (Fig. 2) was born in Rome in 1654 extensa could readily interact. He chose the pineal gland, a uni- and died in 1720. He was a very famous Italian physician who tary, unpaired organ in the middle of the brain, as the seat of attended three Popes (Innocent XI, Innocent XII, and Clement the soul and thought that blood passing through the pores of XI). He also served as Archiater of the Papal State and Canon the tissue was sent to the body through the nerves and habenu- of the Church of San Lorenzo, Professor of Surgery, Anatomy lae, depending on the inclination of the gland itself. and Theoretical and Practical Medicine at Rome University These became the main concepts of neurology and neu- from 1684 to 1719 (8), a member of the Collegio Romano from roanatomy in Rome, where the study of the anatomy had 1689, and a representative of the Repubblica Letteraria Italiana. begun when Pope Paul III instituted the Chair of Anatomy Lancisi was also well-known as a cardiologist, forensic physi- (associated with that of Surgery) in 1539 (17). Subsequently, cian, and epidemiologist. Arcangelo Piccolomini (1525–1586) described the origins of the In 1689, Lancisi performed the autopsy of Pope Innocent XI. intracranial nerves, and Costanzo Varolio (1543–1575) the for- Pope Innocent XII granted him the title of Noble with the mation of the pons; Bartolomeo Eustachio (1520–1574) pre- addition to his coat of arms (represented by a “lance” or pike) pared his famous engravings; and Domenico Mistichelli of the Pope’s family blazon symbolized by three mountains (1675–1715) described the crossing of the nerve fibers in the and three stars. oblong medulla by comparing it with a woman’s plait. Lancisi, in his book De motu cordis et aneurysmatibus, pub- Iatromechanical theories led anatomists to consider the nervous lished posthumously in 1728, was the first person to formulate system as a means of allowing the soul to communicate motion the hypothesis of arterial aneurysms. His book about the phys- to the peripheral organs. iological mechanisms of urine formation and excretion Descartes’ theory also came under considerable criticism. (Tractatus de urinis, 1696) was the first detailed publication on Between 1665 and 1669, Stenone (1638–1686) asserted that it the subject (10). He made an important contribution to veteri- was impossible for the pineal gland to incline as it was attached nary medicine by describing the characteristics of rinderpest, a

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FIGURE 3. Title page of the book Dissertatio de sede cogitantis animae, pub- lished in 1712 and dedicated to the physician Giovanni Fantoni.

themselves, which the great 18th century anatomist Albinus, like most historians, considered to be vastly superior to the better known engravings by Andreas Vesalius (9). In 1715, the Bibliotheca Lancisiana became the site of the Academy of Medicine and Surgery. The library, with its 23,000 volumes and approximately 375 published and unpublished manuscripts, FIGURE 2. Portrait of Giovanni Maria Lancisi, painted by Angelo Masseriotti (from, Direzione Generale del Complesso Monumentale di S. Spirito, Rome). still exists today. Lancisi thought that studying medicine required time, and that the ignorance of physicians could cause great harm to soci- cattle plague affecting Europe in the 18th century, and how to ety. In the field of neuroscience, Lancisi wrote Dissertatio control it by slaughtering each infected animal; the practice of Physiognomica (1710), in which he described the relationship “stamping out” is still used today (15). He also studied the epi- between the mimicry of the frontal muscle and the fibers of the demiological aspects of malarial fevers. meninges and brain (13) and Dissertatio de sede cogitantis animae His De subitaneis mortibus, which was published in 1706, (1712), dedicated to the physician Giovanni Fantoni (1675– described the cardiovascular causes of sudden death, including 1758), in which he considered the problem of the cerebral local- angina pectoris (“Cordis angor”), heart infarction, ruptured izations and specificity of the cortical functions (Fig. 3). The aortic aneurysms, and cardiovascular malformations, and latter also includes some “phrenological” intuitions, although involved him in a not very edifying episode. Having been he had been preceded in these ideas by the French physician asked by Domenico Mistichelli to comment on his book about Francois Gigot de La Peyronnie (1678–1747) (13). apoplexy, which, among other topics also studied by Lancisi, Lancisi shared Pacchioni and other authors’ concept of fibers included the description of the crossed nervous fibers in the crossing in the corpus callosum, as well as Pacchioni’s iatrome- oblong medulla, Lancisi did not return his comment before chanical concept of liquid “squeezing” in the neurons caused publishing De subitaneis mortibus, which thus came out 2 years by the movement of the meninges. before Mistichelli’s book (17). In Dissertatio de sede cogitantis animae, he agreed with On May 14, 1714, Lancisi inaugurated his medical library, the Descartes that the seat of the soul and superior psychic func- Bibliotheca Lancisiana, in Santo Spirito Hospital in Rome. Its tions should be a median and unpaired organ, but favored the structure reflected the scientific and medical culture of its corpus callosum over the pineal gland. On the other hand, he founder by offering young apprentices, either physicians or thought the epiphysis played an important part, as it was con- surgeons, the means for a rational medical education based on nected to the thalami through the habenulae; it is interesting to “plenty of patients” and a good choice of books (7), as well as note that Lancisi’s theory was refused in 1749 by Zinn, who a place where professors and physicians could gather (2, 10). performed a series of split-brain experiments on dogs. During the inauguration, he presented a silver case containing Lancisi’s anatomic studies were very meticulous, and he pro- the Eustachian anatomic plates that had been lost since 1552, vided an excellent description of the corpus callosum: the year in which they were drawn. This was a great contribu- tion to medical science because only eight small plates had “By corpus callosum we mean that medullary surface, been printed under the title Barthol. Eustachii Opuscolo similar to a white strip, one finger and half in breadth, Anatomica (Venice, 1564) (14), whereas the 39 folio works had which, in its superior part, runs almost horizontally under disappeared until Lancisi found them in the keeping of an the sagittal suture. It is narrower in its front part, and Urbino family and published the prints from the original cop- larger in its back part. Being shaped like fornix and per engravings with his personal comments. The importance of columns, it bends by assuming an elliptical shape: in this this discovery was owing to the importance of the engravings way it joins and connects the major cerebral hemispheres.

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The Septum [pel]lucidum, on the other hand, is nothing not covered with dura mater, but with the only arach- else than an interior prolongation of the corpus callosum noidal membrane run along the corpus callosum forwards and fornix, also located in the median medullary part of and backwards, being almost in contact” (13, p 417). the brain. It goes down in a vertical way, from the superior section of corpus callosum, separating and dividing…the In brief, he described the “Nervali longitudinales ab anterioribus cavities of the ventricles” (13, p 412). ad posteriora excurrentes,” which are still called the “medial lon- gitudinal striae of corpus callosum,” or nerves of Lancisi (Fig. He clearly recognized, particularly in horse brain speci- 4). In his dissections, he also noticed the presence of striae lon- mens, the fibers crossing the corpus callosum and connecting gitudinales laterales, although he thought that “it was more the two cerebral hemispheres. After the removal of the hemi- probable those were not proper nerves, but edges of the corpus spheres and the pia mater, he wrote that “medullary nerves in callosum which were raised slightly from the medullary plane” a transversal direction and parallel to each other will be seen” (13, p 417). (13, p 414). However, the originality of his neuroanatomic The text continues with a detailed anatomic description of studies lies in his first description of the structures bearing his the route of these structures: name. “The nerves running along the median line of the corpus Nerves of Lancisi callosum, after having crossed all the horizontal plane The Dissertatio de sede cogitantis animae continues: almost in contact among them, then deviate by diverging, and bend down subsequently upon the columns of the “. . . In the superior part of the corpus callosum, . . . fornix; on the contrary, even if a little later they seem to I observed one thing completely disregarded or unob- disappear, however they reappear and proceed in a very served until now: each medullar transversal fiber is inter- evident way upon the columns themselves, where they sected at a right angle to two nerves, which are medullary, join by forming the third ventricle; at the end, they pen- round, and have a changeable diameter. These ones are etrate and disperse into the thalami of the optic nerves, in the point where the last ones are facing the front of ven- tricles….In the front part of the corpus callosum these nerves trace a route which is identical to the previous one: in fact, they bend down upon its external surface, called the anterior column of the fornix and, under the chiasma of the optic nerves, they bend outwards near the hole of the infundibular recess, then they seem to disap- pear where the medullary substance constitutes the basis of the thalami, which are the beginning of the spinal cord” (13, pp 417, 418).

He also explained why these “nerves” are not covered with dura mater; holding fast to Pacchioni’s iatromechanical theory, he thought the spirits flowing in such a crucial anatomic zone should be slow, bland, and moderate in order to avoid meningeal traction, like in the other parts of the brain. Lancisi’s description of the corpus callosum was more anatomic than functional, and his ideas were not original. However, in his conception of the corpus callosum as the seat of the soul and the nerves as the fibers in which the spirits could flow, he interpreted the medial striae that he described as a “pathway” for the stream of the soul (or perhaps conscious- ness) between the anterior part of the corpus callosum and the FIGURE 4. Original drawing from the Dissertatio de sede cogitantis ani- anterior columns of the fornix and the posterior part of the cor- mae by Giovanni Maria Lancisi showing a section of the brain with the pus callosum and the thalami, a sort of connection between corpus callosum and the striae. A, schematic brain section above the cor- the seat of the soul and the peripheral organs, between the soul pua callosum; b, white cortical bands running through the corpus callo- and the body. sum, C, anterior part of the corpus callosum under the sagittal suture; d, The difficulty of explaining Lancisi’s only original neu- small longitudinal nerves running from forwards to backwards; c, medu- roanatomic description is summarized in the final sentence of larry striae like combs running transversely from side to side in both parts his work: “…it is what I could conjecture, among the thick under the longitudinal nerves; f, edges of the corpus callosum similar to nerves; g, posterior part of the corpus callosum under the sagittal and coro- darkness of these abstruse problems, about the shop, seat, and nal sutures. domicile of the rational, perceiving, and deliberating soul, that is about the most difficult problems of physiology” (14, p 429).

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FIGURE 5. Formalin-fixed specimen of human brain (previously frozen using Klinger’s technique) cut sagittally in the middle of the corpus callosum. A, stria longitudinalis lateralis; B, stria longitudinalis medialis (nerve of Lancisi); FIGURE 6. Specimen of human brain showing the medial and lateral longi- CR, corona radiata; CC, corpus callosum; IG, indusium griseum. tudinal striae above the corpus callosum.

Striae Longitudinales Mediales Corporis Callosi Today especially after the description of Papez’s circuit. However, it is The medial longitudinal striae (nerves of Lancisi) and lateral very difficult to understand how it functions. longitudinal striae are two pairs of myelinated fiber bands Concerning the seat of consciousness, we are still at the same found in the gray matter of the indusium griseum on the dor- crucial point as Lancisi was 300 years ago when, quoting Descartes and Plato, he said it was very difficult, if not impos- sal aspect of the corpus callosum (Figs. 5 and 6), which are also sible, to consider rational activity an object of observation in called the peduncles of the corpus callosum. They are related itself; it is impossible to study the brain by means of a brain, to to the indusium in the same way that the cingulum is related search the soul by means of the same soul, by being satisfied to the gyrus cinguli (12). The longitudinal striae consist of with the morphological (anatomic) description of the container, fibers connecting the septal area, located on the medial side of as the contents cannot be known “by conjecturing, among the the frontal lobe, to the hippocampus in the temporal lobe (5). thick darkness of these abstruse problems, about…the most In addition, axons from the indusium griseum pass into the difficult problems of physiology” (15, p 429). longitudinal striae, curving downward to join the fornix and the anterior commissure (12). They enter the corpus striatum where they join the olfactory projection-path. REFERENCES The indusium griseum and longitudinal striae are dorsal 1. Acar F, Naderi S, Guvencer M, Türe U, Arda MN: Herophilus of Chalcedon: remnants of the archicortex of the hippocampus and fornix and A Pioneer in neuroscience. Neurosurgery 56:861–867, 2005. are minor components of the limbic system. From the hip- 2. Angeletti LR, Gazzaniga V, Conforti M, Fiorilla M, Marinozzi S: Giovanni Maria Lancisi and the Academy which does not exist [in Italian]. XLII pocampal formation, the efferent fibers enter Papez’s circuit Congress of the Italian National Society of the History of Medicine, Bologna, (16), including the hippocampus, fornix, mammillary bodies, October 24–26, 2002. anterior thalamic nuclei, cyngulum, cingulated gyrus, parahip- 3. Angeletti LR: Lancisi, Baglivi and the medical academies in Rome [in Italian]. pocampal gyrus, and amygdala. Related fibers projecting to Med Secoli 12:29–47, 2000. 4. Arroyo-Guijarro J, Prats-Galino A, Ruano-Gil D, Costa-Llobet C: Comparative wide areas of the neocortex are also found here. study of the medial longitudinal striae of the hippocampus (formerly called This circuit seems to be involved in the acquisition of new “nerves of Lancisi”) in the fighting bull and domestic bull [in French]. Bull data in the mechanism of memory; it also seems that the struc- Assoc Anat (Nancy) 72:15–19, 1988. tures of the limbic system are involved with some higher cog- 5. Barr ML, Kirnan JA: Anatomy of the Human Nervous System [in Italian]. Milan, McGraw-Hill, 1995, pp 232 and 257. nitive functions (i.e., emotional behavior). A comparative study 6. Brunori A, Vagnozzi R, Giuffre R: Antonio Pacchioni (1665–1726): Pioneer of bulls has shown that Lancisi’s nerves may be related to studies on the dura mater. Ann Ital Chir 63:579–586, 1992. mechanisms controlling aggressive behavior, as the authors 7. Conforti M, Fiorilla M: The Lancisiana library as a resource for the transmis- sion of medical culture [in Italian]. Med Secoli 14:499–513, 2002. found that the striae longitudinales mediales were more devel- 8. Conte A(ed): Teachers of the University “La Sapienza” in Rome since 1514 to 1787: oped in fighting bulls than in the domestic variety (4). Rotuli and other sources [in Italian]. Rome, Istituto Storico Italiano per il In conclusion, in the three centuries since Lancisi described Medioevo, 1991. Archivio di Stato di Roma, Fondo Università, b. 94 and b. 213. these nerves for the first time, nothing more has been learned 9. Fahrer M: Bartholomeo Eustachio—The Third Man: Eustachius published by Albinus. ANZ J Surg 73:523–528, 2003. about the real functions of Lancisi’s nerves. The limbic system 10. Gazzaniga V: Giovanni Maria Lancisi and urology in Rome in early modern seems to be very complex from an anatomic point of view, age. J Nephrol 16:939–944, 2003.

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11. Gray H: Anatomy descriptive and surgical. London, Promotional Reprint ing article because I was not previously familiar with the nerves of Company Ltd., 1997, pp 461–462. Lancisi and some of Lancisi’s other contributions. To most historians 12. Gray H: Anatomy of the Human Body. Philadelphia, LEA & Febiger, 1918, p 868. and certainly to neurosurgeons, Lancisi’s great contribution was to bring 13. Grondona F: The dissertation of Giovanni Maria Lancisi about the seat of the to light Eustachius’ great anatomical contribution, the Tabulae Anatomi- rational soul [in Italian]. Physis 7:401–430, 1965. carum. Many historians believe that, if the anatomical drawings of 14. Jourdan AC: Medical Biography [in French]. Paris, Panckouke, 1820. 15. Mantovani A, Zanetti R: Giovanni Maria Lancisi: De bovilla peste and stamp- Eustachius had emerged when they were drawn, they would have chal- ing out. Hist Med Vet 18:97–110, 1993. lenged Andreas Vesalius’ position as the “Father of Modern Anatomy.” 16. Papez JW: A proposed mechanism of emotion. Arch Neurol Psychiatry The authors nicely feature this anatomical contribution and provide 38:725–743, 1937. interesting contemporary details on Lancisi’s library, of which I was 17. Pazzini A: Neurology in XVII and XVIII centuries in Rome [in Italian], in previously unaware. The anatomical jewel of this article is the original Belloni L (ed): Essay of the History of Italian Neurology. Proceedings of the illustrations revealing the striae longitudinales mediales corporis callosi International Symposium on the History of Neurology. Varenna, 1961, pp 43–49. and the anatomical preparations shown in situ. The authors are to be 18. Singer C, Underwood EA: A short History of Medicine. Oxford, Clarendon complimented on a remarkable article and one that I thoroughly Press, 1962, pp 48–49. 19. Viale G: The rete mirabile of the cranial base: A millenary legend. enjoyed reading. Neurosurgery 58:1198–1208, 2006. James T. Goodrich Bronx, New York Acknowledgments We thank Dr. Leonarda Vanessa Di Ieva, Ph.D., for the correction of this arti- he authors call attention to small structures associated with the lim- cle and Saverio Marco Fiorilla, Ph.D., Director of the Bibliotheca Lancisiana Tbic system as an introduction to early neuroanatomy efforts in (Rome), for the retrieval of the bibliographic sources necessary for compiling this Rome between the 16th and 18th centuries. Beginning with the theory essay and for the copy of G.M. Lancisi’s portrait. of animal spirits, as espoused by Herophilus of Chalcedon in the 4th century B.C., which was carried well into the 17th and 18th centuries as an important part of Galen’s teachings, the authors provide a suc- COMMENTS cinct history of neuroanatomy and Lancisi’s role and anatomical con- tribution to its development. his article is a compilation of information collected from previously Tpublished books concerning the history of medicine in Italy Lycurgus M. Davey between the 16th and 18th centuries and serves as an article of curios- New Haven, Connecticut ity for the contemporary reader. The article offers a combination of the philosophy and scientific knowledge of a very fruitful period of iovanni Lancisi was a talented Italian clinician and anatomist. The anatomical research. Before reading this article, I had poor knowledge Gauthors’ passing mention of his role in the publication of Tabulae of “the nerves of Lancisi.” This article seems to have reached its goal of Anatomicae by Bartolomeo Eustachio (Eustachius), deserves elabora- sharing and popularizing the interest for structures with functions that tion. Eustachius, a contemporary of Vesalius, discovered the Eustachian still remain unknown. In the future, perhaps functional neuroimaging tube, the thoracic duct, and the abducens nerve. In 1552, he completed and tractography will disclose the “enigma” and give merit to Lancisi. the production of 47 superbly engraved copper plates. These anatom- ical depictions, drawn by Eustachius himself, have been judged by Giovanni Broggi some as superior to those published by Vesalius. For unknown reasons, Milan, Italy they were never printed. However, they were deposited for more than a century and a half in the Vatican Library before Pope Clement XI pre- his is an interesting article that deals with an unknown anatomical sented them to his personal physician, Lancisi, who arranged for their landmark involving the corpus callosum and the indusium griseum, T publication in 1714, accompanied by his own annotations. which were first described by the prominent Italian physician, Giovanni Maria Lancisi. The authors nicely outline the history behind this anatom- Norman H. Horwitz ical discovery and describe the anatomical format. This was an interest- Washington, District of Columbia

568 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com CASE REPORTS

AN ASTROBLASTOMA MIMICKING A CAVERNOUS MALFORMATION: CASE REPORT

Luis M. Tumialán, M.D. OBJECTIVE: Astroblastomas are rare glial neoplasms that usually occur in young adults Department of Neurosurgery, and have a predilection for the cerebral hemispheres. Patients typically present with Emory University School of Medicine, signs of increased intracranial pressure and seizures. Imaging studies reveal circum- Atlanta, Georgia scribed, contrast-enhancing tumors that contain both cystic and solid components with variable peritumoral edema. Hemorrhage, which suggested the presence of a vascular Daniel J. Brat, M.D., Ph.D. lesion in this patient, has not been previously described as a feature of this neoplasm. Department of Pathology and CLINICAL PRESENTATION: The authors report the case of a 33-year-old woman who Laboratory Medicine, Emory University presented with spontaneous intraparenchymal hemorrhage. The collective radiographic School of Medicine, data suggested the presence of a cavernous malformation. Atlanta, Georgia INTERVENTION: A right frontotemporal craniotomy was performed under frameless stereotactic image guidance. An astroblastoma was diagnosed after resection and neu- Arthur J. Fountain, M.D. ropathological examination. Department of Radiology, Section of Neuroradiology, CONCLUSION: A rare radiological to pathological correlation of astroblastoma is pre- Emory University sented in which the evolving hematoma, as observed on magnetic resonance imaging School of Medicine, Atlanta, Georgia scans, complicated the radiographic diagnosis of this lesion. The clinical, radiographic, and pathological features of astroblastomas, as well as the natural history of these rare Daniel L. Barrow, M.D. glial neoplasms, are reviewed. This case illustrates the capacity of astroblastomas to Department of Neurosurgery, hemorrhage, disguising the classic radiographic findings typical of this glial neoplasm. Emory University School of Medicine, KEY WORDS: Astroblastoma, Cavernous malformation, Intraparenchymal hemorrhage Atlanta, Georgia Neurosurgery 60:E569–E270, 2007 DOI: 10.1227/01.NEU.0000255336.80285.70 www.neurosurgery-online.com Reprint requests: Daniel L. Barrow, M.D., Department of Neurosurgery, The Emory Clinic, ailey and Cushing first described astrob- Patients present with nonspecific symptoms 1365-B Clifton Road, N.E., lastomas in their 1924 classification of such as seizures, headaches, and signs of Suite 6400, central nervous system neoplasms (17). increased intracranial pressure (20). Radio- Atlanta, GA 30322. B Email: daniel_barrow@emory Although neither “astrocytic” nor “blastic,” graphically, astroblastomas are large, lobulated, healthcare.org astroblastomas are typically solid and well cir- and supratentorial, with both cystic and solid cumscribed, with the characteristic histological components (1, 3, 19). The current body of liter- Received, July 5, 2005. features of astroblastic pseudorosettes and ature indicates that prognosis is best predicted Accepted, November 7, 2006. perivascular hyalinization (3). There has been by histology (2, 22). Well-differentiated astrob- much controversy regarding the question of lastomas may be successfully treated with gross whether astroblastomas are a subtype of total resection without the need for adjuvant ependymomas or astrocytomas. Although therapy. Treatment for anaplastic astroblas- astroblastomas demonstrate many clinical and tomas, which requires surgery, remains contro- histopathological features of ependymomas and versial, and the roles of adjuvant chemother- astrocytomas, the two have been clearly differ- apy and radiation are ill defined (2). entiated with immunohistochemical, ultrastruc- The authors present a patient with an acute tural, and chromosomal studies (3, 18). The intraparenchymal hemorrhage who was ini- most recent World Health Organization classifi- tially thought to have a cavernous malforma- cation of central nervous system tumors recog- tion based on computed tomographic (CT) nizes astroblastomas as a distinct entity (2). scans, magnetic resonance imaging (MRI) Astroblastomas typically present in older scans, and conventional and CT angiography. children or young adults and have a predilec- After craniotomy and resection of the lesion, tion for the cerebral hemispheres (2, 24). neuropathological examination established the

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diagnosis of astroblastoma. To our knowledge, this case repre- AB sents the first example of an astroblastoma presenting as an intra- cranial hemorrhage and mimicking a vascular malformation. CASE REPORT A 33-year-old woman with a medical history significant for mitral valve prolapse experienced the sudden onset of headache, nausea, and imbalance. She presented to an outside institution, where she was noted to have left-sided facial weak- ness. A noncontrast CT scan of the head demonstrated a large right frontal intracranial hemorrhage (Fig. 1). The patient was managed with phenytoin and intravenous steroids. FIGURE 2. Anteroposterior (A) and lateral (B) projections of the right inter- Conventional four-vessel cerebral angiography did not reveal nal carotid artery on conventional angiography without evidence of a vascu- the source of the hemorrhage (Fig. 2) and MRI scans with and lar lesion or blush that would suggest a neoplastic lesion. without gadolinium demonstrated only a partially resolving hematoma (Fig. 3). During her hospitalization, she did not AB exhibit any seizure activity or altered level of consciousness. After an uncomplicated hospital stay with complete resolution of her neurological symptoms, the patient was discharged. Two months after her initial hemorrhage, the patient pre- sented electively to our institution for further recommenda- tions. At the time of her evaluation, the patient remained neu- rologically intact. Because the results of her studies suggested the possibility of a cavernous malformation, a craniotomy for exploration of the hematoma cavity was planned. A right frontotemporal craniotomy was performed under frameless stereotactic image guidance (Fig. 4). After the dura was opened, an abnormal area on the surface of the brain became obvious. Stereotactic guidance was used to confirm that this area corresponded with the site at which the hematoma came closest to the brain’s surface. A cortical FIGURE 3. MRI scans of the brain C incision was made and the performed 24 hours after the initial hematoma cavity was entered. hemorrhage demonstrating an intra- After elements of an organizing parenchymal hematoma. A, T2- weighted image demonstrating a hematoma were evacuated, ab- large, well-circumscribed peripheral normal appearing diaphanous mass with heterogeneous hyperin- vessels were identified entering tense signal. There is very little evi- the hematoma cavity and lead- dence of vasogenic edema. Astro- ing to a small, tan-red nodular blastomas are typically isointense on mass. Using microsurgical tech- T2-weighted images. B, T1-weighted niques, the presumed malfor- image without contrast revealing het- mation, which measured app- erogeneous signal intensity hypo- roximately 1.5 cm in diameter, intense with respect to gray matter. was circumferentially excised C, T1-weighted image with gadolin- ium demonstrating homogeneous and sent to pathology. All enhancement of the rim portion with remaining abnormal vessels heterogeneous enhancement of the solid portion, and the previously reported entering the lesion were coagu- “bubbly appearance” at the center. lated and divided. After the FIGURE 1. Noncontrast head CT hematoma cavity was explored scan at the time of the initial hemor- Histological sections revealed a well-differentiated astrob- under high magnification with- rhage demonstrating heterogeneous lastoma and adjacent brain tissue with evidence of recent and signal intensity within the hema- out evidence of additional remote hemorrhage and reactive gliosis. The astroblastoma toma, which is indicative of acute abnormal vessels, the walls of hemorrhage. The lateral component showed classic features, including numerous astroblastic the cavity were lined with of hematoma with a hyperattenuated rosettes formed by elongated tumor cells containing abundant Surgicel (Ethicon, Inc., Somer- signal is suggestive of either suba- eosinophilic cytoplasm extending a single prominent process to ville, NJ) and the wound was cute hemorrhage or the solid compo- a central blood vessel (Fig. 5). In contrast to ependymoma, closed. nent of a neoplasm. these rosettes are not fibrillar but rather are formed by colum-

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nar or cuboidal cells. Typical A of astroblastomas, perivascu- lar hyalinization was also prominent and, in some regions, the hyalinization coa- lesced to occupy large zones of the tumor (3, 12). The tumor was graded as a well-differ- entiated astroblastoma be- cause the mitotic rate was low (0–1 in 10 high-power fields and there was no evidence of vascular proliferation or tumor necrosis. The MIB-1 FIGURE 4. Axial T1-weighted MRI index was slightly elevated scan of the brain with gadolinium (6–8%) compared with most performed 3 months after the initial well-differentiated astroblas- B hemorrhage for frameless stereotactic tomas. A well-defined border guidance on the day of surgery show- was noted at the interface of ing a completely evolved hematoma the tumor with adjacent brain with little enhancement of the rim compared with previous studies. tissue. No diffuse infiltration Heterogeneous enhancement is lim- of the surrounding paren- ited to the mural nodule. chyma by tumor cells was identified. The tumor was strongly immunoreactive for glial fibrillary acidic protein, S-100 protein, vimentin, and epithelial membrane antigen (Fig. 5). The patient awoke from anesthesia with no neurological deficits. Postoperatively, the patient had a focal motor seizure. After her antiepileptic medication was adequately dosed, she had no further seizure activity and was discharged on the third postoperative day. The patient was initially thought to C have a gross total resection, but surveillance imaging sug- gested the presence of persistent tumor. The patient under- went another craniotomy at an outside facility 3 months after her initial surgery and a well-differentiated astroblastoma was confirmed. Gross total resection was not achieved and the patient underwent partial brain radiation (daily dose, 180 cGy; total dose, 3600 cGy) followed by three-dimensional intensity modulated radiation therapy (daily dose, 180 cGy; total dose, 1980 cGy). Two years after her initial surgery, the patient has no evidence of residual or recurrent disease on surveillance imaging.

DISCUSSION

Astroblastomas are rare primary central nervous system FIGURE 5. Histopathology of a well-differentiated astroblastoma. The histo- tumors with a reported incidence of 0.45 to 2.8% of primary logical hallmark of astroblastomas is the astroblastic pseudorosette, composed brain gliomas (9). Since Bailey and Cushing introduced the of elongated tumor cells with columnar or tapering processes oriented to a cen- term astroblastoma in 1924, there has been much confusion tral vessel (A and B, arrows). Low magnification demonstrates a well- differentiated, noninfiltrative tumor containing repeating units of astroblastic regarding their natural history, diagnostic criteria, and cell of rosettes (A, original magnification, ϫ200). Higher magnification demon- origin (3, 5, 7, 18). In fact, astroblastomas are not accepted by all strates the wide, columnar structure of individual cell processes that extend to neuropathologists as a unified clinicopathological entity central blood vessels in astroblastic pseudorosettes (B, original magnification, because of the inability to fully distinguish this glial neoplasm ϫ600). Immunostaining for glial fibrillary acidic protein is positive in tumor from ependymal or astrocytic neoplasms (2). During the past cells of astroblastic rosettes and highlights the perivascular orientation (C, several years, a body of literature has arisen that defines astro- arrow; original magnification, ϫ400).

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blastomas in the context of their natural history, radiographic signal intensities, indicating hemorrhage at different stages of features, and histopathological findings (7, 13). Although astro- evolution, which, in the context of an angiographically silent cytomas and ependymomas may share many of these features, lesion, would suggest a cavernous malformation. Further stud- recent immunohistochemical, ultrastructural, and chromoso- ies demonstrated this lesion to be angiographically occult on mal studies further establish astroblastomas as distinct from conventional angiography, reinforcing the presumptive diagno- these neoplasms (3, 5, 8–10, 20). However, there are no pathog- sis of cavernous malformation. Retrospective review of the pre- nomonic genetic alterations for astroblastomas, and previous operative MRI scan (Fig. 4) performed for image guidance 2 studies have only described genetic alterations as a means for months after her initial hemorrhage, however, seemed more distinguishing astroblastomas from ependymomas as a patho- suggestive of a neoplasm. Intraoperative findings did not logical entity. These alterations seem to have no positive predic- reveal the discrete multilobulated berry-like lesion expected tive value for diagnosis. with a cavernous malformation but, rather, a well-defined tan Although astroblastomas may occur in patients of any age, nodule within the hematoma cavity. Previous authors have older children and young adults are more commonly affected; reported similar macroscopic findings of astroblastomas in the there is also a slight female predominance (2, 5, 9, 16). absence of hemorrhage (5, 21, 25). Astroblastomas tend to occur in the supratentorial brain as The finding of a glial neoplasm at surgery prompted further well circumscribed tumors, but have also been described in the retrospective review of the findings of the preoperative imag- cerebellum, brainstem, and cauda equina (11). ing. When a cavernous malformation is in the differential diag- Radiographic imaging demonstrates many classic features nosis, an MRI scan sequence sensitive to dephasing should be of this tumor, which may aid the pathologist in making the used to look for other areas of focal signal loss in the brain. diagnosis once a histological sample has been obtained. CT These signal losses represent hemosiderin deposits from previ- scanning depicts a large cystic lesion with occasional calcifica- ous bleeds at other sites; 25 to 50% of cavernous malformation tions in the cerebral hemispheres, as well as associated mass cases have multiple sites, as do 75% of hereditary lesions (14). effect. The solid component may demonstrate a slightly In addition, the MRI scan spin echo sequences that are most increased attenuation. MRI scanning typically reveals a spher- sensitive involve a long echo time, as in a T2-weighted image ical mass with both cystic and solid components (1). The solid with a prolonged echo time. The signal loss is more apparent at components of the mass are hypointense with respect to gray high field strengths than at low field strengths. More sensitive matter on T1-weighted images and isointense on T2-weighted yet are gradient echo sequences in which the T2-weighted sig- images (17, 19). Despite the potential large size of astroblas- nal loss is more profound because of the less-efficient signal tomas, there is relatively little vasogenic edema observed on refocusing. Thus, gradient echo sequences are capable of demon- T2-weighted images. The cyst walls, along with the solid com- strating even minute traces of blood, such as those found in cav- ponent of the tumor, exhibit heterogenous enhancement with ernous malformations (4, 14, 23). gadolinium (Fig. 4) (1, 25). The rarity of this tumor has prevented the generation of large In the setting of acute hemorrhage, as observed in the trials to develop conclusive treatment protocols (2, 6, 8). Thus, patient presented in this report, these characteristic neu- the treatment of astroblastomas remains controversial and is roimaging findings of astroblastoma become obfuscated and based primarily on several small case series in the literature (2, a vascular lesion seems more likely on the basis of the initial 6). Several investigators have found that prognosis seems to be imaging. In a 33-year-old woman, the presence of acute hem- predicted by histology (10, 15, 21, 22). Bonnin and Rubinstein orrhage on CT scans (Fig. 1) and a resolving hematoma with (2) identified anaplastic features that were distinct from a more elements of enhancement on MRI scans (Fig. 2) are suggestive differentiated growth pattern in their series of 23 patients with of a cavernous or arteriovenous vascular malformation or a astroblastomas. These authors reported a worse prognosis in neoplastic process. The propensity of intracranial metastatic patients with anaplastic lesions, despite adjuvant therapy. lesions to bleed initially placed a metastatic process in the Thiessen et al. (22) corroborate this conclusion in their series of differential. However, with negative routine breast examina- seven patients, in which they observed that recurrences were tions, a negative family history of breast, lung, and colon common in the patients with anaplastic features, despite gross cancer, no history of bloody stools, no history of weight loss, total resection, radiotherapy, and chemotherapy. Conversely, no history of smoking, and a negative chest x-ray, a metasta- the patients with well-differentiated features remained disease tic evaluation was thought to be of lower yield than a surgi- free after gross total resection alone (22). cal procedure. The current literature indicates that gross total resection has The initial unenhanced CT scan (Fig. 1) shows a heteroge- the greatest impact on the survival of patients with well- neous signal within the hematoma cavity, which may be differentiated astroblastomas (2, 6). There is little evidence to observed in cavernous malformations or neoplastic lesions. suggest that adjuvant chemotherapy or radiation improves sur- Even in retrospect, when compared with the location of the vival in these patients (22). Although aggressive therapy is indi- nodular component of the preoperative MRI scan (Fig. 4), the cated in anaplastic astrocytomas in the form of surgery, radia- isodense-to-moderately hyperintense signal in this study is tion, and chemotherapy, it has been difficult to assess how each consistent with a cavernous malformation. The MRI scans of these modalities has altered survival (22). Nevertheless, the revealed a well-delineated complex reticulated core of varying radiosensitivity and chemosensitivity of astroblastomas have

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been established by previous cases in the literature (6). With 18. Rubinstein LJ, Herman MM: The astroblastoma and its possible cytogenic regard to the patient in this report, the inability to achieve gross relationship to the tanycyte. An electron microscopic, immunohistochemical, total resection with the second craniotomy prompted the tissue- and organ-culture study. Acta Neuropathol (Berl) 78:472–483, 1989. 19. Sener RN: Astroblastoma: Diffusion MRI, and proton MR spectroscopy. options of another craniotomy, continued surveillance, radia- Comput Med Imaging Graph 26:187–191, 2002. tion, and chemotherapy. The patient elected to undergo radia- 20. Shuangshoti S, Mitphraphan W, Kanvisetsri S, Griffiths L, Navalitloha Y, tion therapy after her second craniotomy. Two years after her Pornthanakasem W, Mutirangura A: Astroblastoma: Report of a case with initial surgery, the patient remains disease free. microsatellite analysis. Neuropathology 20:228–232, 2000. 21. Sugita Y, Terasaki M, Shigemori M, Morimatsu M, Honda E, Oshima Y: Astroblastoma with unusual signet-ring-like cell components: A case report CONCLUSION and literature review. Neuropathology 22:200–205, 2002. 22. Thiessen B, Finlay J, Kulkarni R, Rosenblum MK: Astroblastoma: Does histol- Astroblastomas are rare glial tumors that are generally non- ogy predict biologic behavior? J Neurooncol 40:59–65, 1998. 23. Wurm G, Fellner FA: Implementation of T2*-weighted MR for multimodal infiltrative and well circumscribed in relation to the surround- image guidance in cerebral cavernomas. Neuroimage 22:841–846, 2004. ing brain tissue. This case illustrates the capacity of astroblas- 24. Yamashita J, Handa H, Yamagami T, Haebara H: Astroblastoma of pure type. tomas to hemorrhage, disguising the classic radiographic Surg Neurol 24:218–222, 1985. findings typical of this glial neoplasm. 25. Yunten N, Ersahin Y, Demirtas E, Yalman O, Sener RN: Cerebral astroblas- toma resembling an extra-axial neoplasm. J Neuroradiol 23:38–40, 1996.

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Brunereau L, Leveque C, Bertrand P, Tranquart E, Cordoliani Y, Rouleau P, he authors present a case report describing a patient who appeared Labauge P: Familial form of cerebral cavernous malformations: Evaluation of Tto have a frontal cavernous malformation that was ultimately gradient-spin-echo (GRASE) imaging in lesion detection and characterization revealed to be an astroblastoma. It is likely that the presence of a at 1.5 T. Neuroradiology 43:973–979, 2001. hematoma in the tumor made the lesion appear to resemble a cav- 5. Cabello A, Madero S, Castresana A, Diaz-Lobato R: Astroblastoma: Electron ernous malformation. In either case, the large size of the lesion and its microscopy and immunohistochemical findings: Case report. Surg Neurol superficial location justified surgical intervention. This report reminds 35:116–121, 1991. 6. Caroli E, Salvati M, Esposito V, Orlando ER, Giangaspero F: Cerebral astro- us that certain hemorrhagic tumors can mimic vascular malformations blastoma. Acta Neurochir (Wien) 146:629–633, 2004. and should be kept in the differential diagnosis. 7. de Reuck J, van de Velde E, vander Eecken H: The angioarchitecture of the Steven D. Chang astroblastoma. Clin Neurol Neurosurg 78:89–98, 1975. Stanford, California 8. Hoag G, Sima AA, Rozdilsky B: Astroblastoma revisited: A report of three cases. Acta Neuropathol (Berl) 70:10–16, 1986. 9. Husain AN, Leestma JE: Cerebral astroblastoma: Immunohistochemical and his report presents a unique occurrence of hemorrhage associated ultrastructural features. Case report. J Neurosurg 64:657–661, 1986. Twith an astroblastoma, which has not been previously reported. 10. Jay V, Edwards V, Squire J, Rutka J: Astroblastoma: Report of a case with Several features of this case make it instructive. For instance, the ultrastructural, cell kinetic, and cytogenetic analysis. Pediatr Pathol authors note that a T2-weighted gradient echo sequence in suspected, 13:323–332, 1993. but uncertain, cases of cavernoma can be helpful because of the high 11. Kim BS, Kothbauer K, Jallo G: Brainstem astroblastoma. Pediatr Neurosurg 40:145–146, 2004. multiplicity incidence of cavernomas. Because the lesion itself is rare, 12. Kubota T, Hirano A, Sato K, Yamamoto S: The fine structure of astroblastoma. the occurrence of hemorrhage further compounded preoperative diag- Cancer 55:745–750, 1985. nosis. This case is somewhat difficult from the perspective of preoper- 13. Kujas M, Faillot T, Lalam T, Roncier B, Catala M, Poirier J: Astroblastomas ative imaging because a routine consideration of diagnostic possibilities revisited. Report of two cases with immunocytochemical and electron micro- would not likely include astroblastomas; however, the possibility of scopic study. Histogenetic considerations. Neuropathol Appl Neurobiol underlying neoplasm, whether primary or metastatic, should not be 26:295–298, 2000. overlooked. There is some tendency for hematomas derived from neo- 14. Lehnhardt FG, von Smekal U, Ruckriem B, Stenzel W, Neveling M, Heiss plasms to demonstrate more heterogeneity than hemorrhages associ- WD, Jacobs AH: Value of gradient-echo magnetic resonance imaging in the ated with vascular malformations. Therefore, whereas vascular malfor- diagnosis of familial cerebral cavernous malformation. Arch Neurol 62:653–658, 2005. mation remains one of the primary diagnostic considerations, the 15. Mierau GW, Tyson RW, McGavran L, Parker NB, Partington MD: Astro- somewhat heterogeneous appearance of the hematoma on both com- blastoma: Ultrastructural observations on a case of high-grade type. puted tomographic and magnetic resonance imaging scans in this case Ultrastruct Pathol 23:325–332, 1999. brings the possibility of an underlying neoplasm into greater consider- 16. Pizer BL, Moss T, Oakhill A, Webb D, Coakham HB: Congenital astroblastoma: ation. In summary, this is a good discussion of classic features and a An immunohistochemical study. Case report. J Neurosurg 83:550–555, 1995. newly recognized atypical feature of astroblastomas. 17. Port JD, Brat DJ, Burger PC, Pomper MG: Astroblastoma: Radiologic- pathologic correlation and distinction from ependymoma. AJNR Am J Paul E. Kim Neuroradiol 23:243–247, 2002. Los Angeles, California

NEUROSURGERY VOLUME 60 | NUMBER 3 | MARCH 2007 | E570 CASE REPORTS

CEREBELLAR CRYPTOCOCCOMA IN A PATIENT WITH UNDIAGNOSED SARCOIDOSIS: CASE REPORT

Charles W. Kanaly, M.D. OBJECTIVE: We describe a patient with undiagnosed sarcoidosis who presented with Department of Surgery, a rare isolated cerebellar cryptococcoma masquerading as a metastatic brain tumor. Division of Neurosurgery, Duke University Medical Center, CLINICAL PRESENTATION: A 58-year-old man with a history of resected squamous cell Durham, North Carolina carcinoma of the larynx and pulmonary nodules was found to have a left cerebellar lesion on neuroimaging after presenting with a 4-month history of occipital headaches. Neuroimaging Lee A. Selznick, M.D. revealed a large, lobulated, intra-axial, left cerebellar hemispheric mass with peripheral nodu- Department of Surgery, lar enhancement, mild adjacent edema, and dense focal areas of calcification. Division of Neurosurgery, Duke University Medical Center, INTERVENTION: The patient underwent a left suboccipital craniotomy for gross total Durham, North Carolina resection of the left cerebellar mass. Pathological examination of the resected speci- men demonstrated a cryptococcoma, which was confirmed with a positive cerebrospinal Thomas J. Cummings, M.D. fluid cryptococcal antigen. Postoperative evaluation revealed pulmonary sarcoidosis. Department of Pathology, Duke University Medical Center, CONCLUSION: Central nervous system cryptococcoma is a rare infection that may Durham, North Carolina present in a patient with no known history of immunosuppression and no clinical signs of infection. Diagnostically, this can be difficult to distinguish from a brain tumor. Central D. Cory Adamson, M.D., nervous system cryptococcoma is an opportunistic infection that typically occurs in Ph.D., M.P.H. the presence of an immunosuppressed state. Sarcoidosis should be considered a pre- Department of Surgery, disposing factor because patients with this underlying disease have an increased sus- Division of Neurosurgery, Duke University Medical Center, ceptibility to this central nervous system fungal infection. Durham, North Carolina KEY WORDS: Cerebellum, Cryptococcoma, Cryptococcus, Neurosarcoidosis, Sarcoid, Sarcoidosis

Reprint requests: Neurosurgery 60:E571, 2007 DOI: 10.1227/01.NEU.0000255338.18404.C1 www.neurosurgery-online.com D. Cory Adamson, M.D., Ph.D., M.P.H., Department of Surgery, Division of Neurosurgery, entral nervous system (CNS) cryptococco- mous cell carcinoma of the larynx 4 months Duke University Medical Center, Research Drive, MSRB 479, Box 2624, mas typically occur in patients who are before admission. He was diagnosed with Durham, NC 27710. Cimmunosuppressed, such as those with interstitial lung disease 13 years earlier as an Email: [email protected] acquired immunodeficiency syndrome, those incidental finding on chest x-rays. This had who have received organ transplants, or those been followed without significant change at an Received, May 24, 2006. with lymphoproliferative disorders. It is much outside hospital. A positron emission tomo- Accepted, November 1, 2006. more common for cryptococcal infections of the graphic scan was performed as part of a stag- CNS to present with meningitis rather than cryp- ing workup for his cancer and showed hyper- tococcomas, and it is rare for cryptococcal infec- metabolic activity in bilateral lungs. Fine tions of the CNS to occur in patients without needle aspiration of a right upper lobe lesion marked immunosuppression. Sarcoidosis, how- was biopsied at an outside hospital and exhib- ever, is a systemic granulomatous disease of ited noncaseating granulomatous inflamma- unknown etiology that can alter the host tion. The patient was treated for his laryngeal immune response and increase susceptibility to carcinoma with resection followed by 6 weeks cryptococcal infections. Sarcoidosis should be a of localized radiation therapy. diagnostic consideration in a patient with CNS After presenting to his primary care physi- cryptococcoma, particularly in the setting of cian with a 4-month history of occipital underlying lung disease. headaches, nausea, and vomiting (previously thought to be caused by his radiation therapy), CASE REPORT a computed tomographic scan of his brain revealed a left cerebellar lesion with focal areas Our patient is a 58-year-old man diagnosed of hyperdensity consistent with calcification. with T1N0M0 moderately differentiated squa- Magnetic resonance imaging (MRI) scans of

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ϫ ϫ the brain showed a large, lobulated 2.6 2.6 2.3 cm intra- A axial, left cerebellar hemispheric mass with large central hypointensity on T1-weighted images and peripheral multi- loculated ring enhancement (Fig. 1). There was mild adjacent edema without significant mass effect on the vermis or fourth ventricle. This lesion had dark signal intensity on fluid- attenuated inversion recovery-weighted MRI scans. Neuro- logical examination of the patient was notable only for a slightly positive Romberg test. Preoperative laboratory values were remarkable only for a decreased white blood cell count of 3.1 with a normal white blood cell differential. Because of the patient’s medical history and neuroimaging results, a metasta- tic tumor in the cerebellum was highly suspected. The patient was taken to the operating room for diagnosis and resection of the mass via a left suboccipital craniotomy. On initial inspection, the yellowish mass was solid with a dense, firm nodular component. A soft, thick, cheesy material surrounded the solid mass. The mass was resected en bloc using microsurgical technique with an easily identified plane. The soft, cheesy surrounding material was gently aspirated and the B edge of the cavity was dissected until normal cerebellum was encountered on all margins, achieving gross total resection. Pathological evaluation demonstrated an encapsulated abscess-like cavity with acute and granulomatous inflammation, as well as focal areas of calcification (Fig. 2A). Gomori Methenamine Silver stain for identifying fungi histochemical stain showed numerous budding yeasts present with mostly narrow-based buds, chains of organisms, and abundant mucin consistent with Cryptococcus neoformans (Fig. 2B). The diagnosis of a cryptococcoma was made. No neoplasm was observed. Intraoperative microbiology cultures were remarkable for coagulase-negative staphylococcus grown from broth, which was thought to be a contaminant. Gram stain and India ink were neg- ative. Cerebrospinal fluid was positive for cryptococcal antigen. Postoperatively, the patient’s hospital course was initially uneventful and he remained FIGURE 2. A, histological sample demonstrating a zone of necrosis with cal- neurologically intact. He had cifications (purple) and numerous yeast forms (hematoxylin and eosin, orig- an extensive medical work- inal magnification, ϫ40). B, the cryptococcus yeasts are identified with a up, which was negative for Gomori methenamine silver histochemical stain (original magnification, ϫ40). underlying immunosuppres- sion, including human and his CD4 to CD8 ratio was low (0.46). The findings of the immunodeficiency virus and initial right upper lobe lung fine needle aspiration were purified protein derivative of thought to represent pulmonary sarcoidosis, although tuberculin. Because of the angiotension-converting enzyme levels were not initially pathological findings, he was obtained at the outside facility. Thus, the leukopenia was treated with amphotericin B explained by his active sarcoidosis. Steroids were started for his plus flucytosine; however, he sarcoidosis and 200 mg fluconazole was administered daily for developed acute renal failure his cryptococcal infection. After 1 year, fluconazole will be and was changed to 400 mg FIGURE 1. T1-weighted MRI scan with contrast revealing a large, lobu- weaned to a dosage of 100 mg daily for as long as he continues fluconazole daily for 8 weeks. lated 2.6 ϫ 2.6 ϫ 2.3 cm intra-axial, on steroids. The patient developed left cerebellar hemispheric mass with leukopenia, which was ini- large central hypointensity with mild DISCUSSION tially attributed to the ampho- adjacent edema and no significant tericin and flucytosine. His mass effect. Multilocated rim CNS cryptococcus is an opportunistic infection that usually CD4 count was noted to be 85 enhancement is also seen. occurs in the setting of immunosuppression. Cryptococcal

E571 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com CEREBELLAR CRYPTOCOCCOMA IN UNDIAGNOSED SARCOIDOSIS: CASE REPORT

infection has a predilection for the CNS. In a study of patients appearance. Computed tomographic and MRI scan characteris- negative for human immunodeficiency virus who were tics of cryptococcomas can overlap with both tumors and infected with Cryptococcus neoformans, 51% were found to have abscesses, including infections such as toxoplasmosis (14). On CNS disease (11). Cryptococcal disease has previously been computed tomographic scans, these lesions typically appear as documented in the presence of underlying sarcoidosis (9, 13). isolated hypodense mass lesions with surrounding rim There are few case reports in the literature regarding cryptococ- enhancement (3, 8). On MRI scans, they typically possess low comas found in patients who are thought to be immunocompe- signal intensity on T1-weighted imaging, high signal intensity tent. A few studies have suggested that the Cryptococcus neofor- on T2-weighted imaging, and may have uniform or ring mans variant gattii, which is more prevalent in tropical and enhancement (5, 7). They occur most commonly in the cerebel- temperate climates, is more likely to cause cryptococcomas in lum, brainstem, basal ganglia, and temporoparietal regions. To immunocompetent patients (2, 10). help diagnose these masses radiographically, Ho et al. (5) sug- Cryptococcal infections are typically associated with deficien- gest looking for hypointensity on diffusion-weighted MRI scans cies in cell-mediated immunity, such as sarcoid and systemic and hyperintensity on apparent diffusion coefficient maps. lupus erythematosus (6, 12). The connection between sarcoid, Histological examination is, therefore, necessary to make the which has its highest prevalence rates among the African definitive diagnosis of cryptococcal infection. In cerebrospinal American population in the United States (15), and Cryptococcus fluid specimens from patients with cryptococcal meningitis, neoformans is thought to be explained by glucocorticoid usage India ink will show the yeast in approximately 80% of acquired during treatment of sarcoid and deficient cell-mediated immu- immunodeficiency syndrome patients and 50% of patients who nity. The exact nature of the immunosuppression caused by sar- do not have acquired immunodeficiency syndrome (16). On coidosis is unknown, but it is thought that there is a reversal of examination of tissue sections, the yeast typically appears the ratio of CD4 to CD8 T-cells in the blood caused by sequestra- encapsulated, pleomorphic, 5 to 10 µm in diameter, and pos- tion of helper T-cells in the organ involved with sarcoid. Ross sesses narrow-based buds. The capsule does not stain with and Katz (13) reported on a patient similar to ours; both patients hematoxylin or eosin; therefore, when examining tissue sec- were noted to have a low CD4 count, but their patient presented tions, one will often see the yeast surrounded by the empty with meningitis and not a cryptococcoma. Before the diagnosis of space of the capsule. Mucin stains, such as mucicarmine and sarcoidosis, our patient was initially thought to have idiopathic Alcian blue, can stain the polysaccharide capsule of Cryptococcus CD4 T-cell lymphocytopenia. This disease has also been shown neoformans. Fontana-Masson stain identifies melanin and to predispose patients to Cryptococcus neoformans and other argentaffin and can be used to selectively stain the cell wall of opportunistic infections (3). However, an underlying etiology Cryptococcus neoformans black. Gomori methenamine silver stain must be excluded. In the setting of pulmonary abnormalities, a can be used to identify yeast; however, it is not selective for diagnosis of sarcoidosis must be considered, as in this case. Cryptococcus neoformans because it can also identify Pneumocystis Even when the diagnosis of sarcoidosis is known, recogniz- carinii and other fungi. With this stain, the organisms are often ing cryptococcal infection is further complicated by the fact outlined in brown to black. The diagnosis of CNS cryptococcal that neurosarcoidosis can be difficult to distinguish from cryp- infection was confirmed in our patient by the presence of typi- tococcal meningitis (8). Awareness of this combination of dis- cal yeast on histological sections and the presence of cryptococ- eases is critical because early treatment is essential to avoid cal antigen in the cerebrospinal fluid. the possibly fatal complications that can occur. Conversely, cases describing the diagnosis of sarcoidosis after the patient CONCLUSION presents with cryptococcal meningitis have rarely been reported in the literature (1, 4). To our knowledge, this case CNS cryptococcomas are opportunistic infections and have report presents the first description of the diagnosis made after rarely been reported to occur in otherwise immunocompetent presentation with a cryptococcoma. patients. As observed in our patient after his cryptococcus diag- Our patient was a diagnostic challenge. Because the patient nosis, a source of immune deficiency must be investigated. initially presented to our clinic with a known diagnosis of squa- Sarcoidosis is a common systemic disease that may increase mous cell carcinoma of the larynx, the initial unifying diagnosis host susceptibility to CNS cryptococcal infection without any for his lung nodules and CNS mass lesion were metastases. When other signs or symptoms of host immunosuppression. In a an isolated cryptococcoma presents in a patient who is thought to patient previously thought to be immunocompetent with be immunocompetent, it can easily be misdiagnosed as a brain newly diagnosed cryptococcoma of the CNS, it is important to tumor both clinically and radiographically. In one published consider sarcoidosis before assuming that the patient has no report, a parasellar cryptococcoma in an immunocompetent underlying risk factors because failure to treat the underlying patient appeared radiologically indistinguishable from a pitu- predisposing condition may lead to adverse outcomes. itary adenoma on MRI scans, with low signal intensity on T1- weighted imaging, high signal intensity on T2-weighted imaging, and uniform contrast enhancement of the mass (16). REFERENCES Radiological evaluation alone cannot convincingly diagnose 1. Botha RJ, Wessels E: Cryptococcal meningitis in an HIV negative patient with cryptococcoma because there is no pathognomonic radiological systemic sarcoidosis. J Clin Pathol 52:928–930, 1999.

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2. Correa Mdo P, Severo LC, Oliveira Fde M, Irion K, Londero AT: The spectrum role of undiagnosed sarcoidosis as a source of occult immunocompro- of computerized tomography (CT) findings in central nervous system (CNS) mise is an excellent one. infection due to Cryptococcus neoformans var. gattii in immunocompetent children. Rev Inst Med Trop Sao Paulo 44:283–287, 2002. Robert Breeze 3. Duncan RA, von Reyn CF, Alliegro GM, Toossi Z, Sugar AM, Levitz SM: Denver, Colorado Idiopathic CD4ϩ T-lymphocytopenia—Four patients with opportunistic infections and no evidence of HIV infection. N Engl J Med 328:393–398, 1993. he authors describe the case of a patient with a solitary cerebellar 4. Giner V, Casademont J, Cardellach F: Cryptococcal meningoencephalitis and Tlesion that was surgically resected. Although the nature of the mass sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 16:229–230, 1999. was uncertain before surgery, the posterior fossa location and large 5. Ho TL, Lee HJ, Lee KW, Chen WL: Diffusion-weighted and conventional size of the lesion made the decision to resect an appropriate one. magnetic resonance imaging in cerebral cryptococcoma. Acta Radiol Clearly, any large cerebellar lesion of unknown etiology should be 46:411–414, 2005. resected for diagnosis. Large posterior fossa brain metastases may swell 6. Huang JL, Chou ML, Hung IJ, Hsieh KH: Multiple cryptococcal brain abscesses in systemic lupus erythematosus. Br J Rheumatol 35:1334–1335, 1996. during or after whole brain radiation therapy, which would lead to 7. Kesler R, Maertens P: Pontine cryptococcoma in a nonimmunocompromised obstructive hydrocephalus, and should be removed. Any fungal individual: MRI characteristics. J Neuroimaging 9:118–121, 1999. abscess in the posterior fossa, as this mass was found to be, should be 8. Lane H, Browne L, Delanty N, Neill SO, Thornton J, Brett FM: July 2004: 40- excised. Even though a metastatic brain tumor was highly suspected in year-old man with headaches and dyspnea. Brain Pathol 15:89–90, 95, 2005. this patient, it should be noted that squamous cell carcinoma from the 9. Mehrany K, Kist JM, Gibson LE: Cryptococcal infection in sarcoidosis. Int J head and neck rarely metastasize to the brain. Dermatol 41:773–774, 2002. This patient was thought to be immunologically competent, although 10. Mitchell DH, Sorrell TC, Allworth AM, Heath CH, McGregor AR, I am not sure this assumption is entirely accurate because he developed Papanaoum K, Richards MJ, Gottlieb T: Cryptococcal disease of the CNS in squamous cell carcinoma of the larynx, a cryptococcal brain abscess, and immunocompetent hosts: Influence of cryptococcal variety on clinical mani- festations and outcome. Clin Infect Dis 20:611–616, 1995. pulmonary sarcoidosis. The immune defect may not be apparent when 11. Pappas PG, Perfect JR, Cloud GA, Larsen RA, Pankey GA, Lancaster DJ, the hematological parameters are analyzed from a purely numerical Henderson H, Kauffman CA, Haas DW, Saccente M, Hamill RJ, Holloway point of view; however, the presence of cancer and an intracranial fun- MS, Warren RM, Dismukes WE: Cryptococcosis in human immunodeficiency gal infection suggest the abnormal function of those immune cells that virus-negative patients in the era of effective azole therapy. Clin Infect Dis are present. The known defect in cell-mediated immunity associated 33:690–699, 2001. with sarcoidosis presumably predisposed this patient to developing the 12. Perfect JR, Casadevall A: Cryptococcosis. Infect Dis Clin North Am cryptococcus neoformans brain abscess. Whether or not an altered 16:837–874, 2002. immune system was partly responsible for the development of laryn- 13. Ross JJ, Katz JD: Cryptococcal meningitis and sarcoidosis. Scand J Infect Dis geal squamous cell cancer is a question left open to conjecture. 34:937–939, 2002. 14. Schmidt S, Reiter-Owona I, Hotz M, Mewes J, Biniek R: An unusual case of Walter A. Hall central nervous system cryptococcosis. Clin Neurol Neurosurg 97:23–27, 1995. 15. Wu JJ, Schiff KR: Sarcoidosis. Am Fam Physician 70:312–322, 2004. Minneapolis, Minnesota 16. Yu YQ, Jiang XX, Gao YJ: MRI of a pituitary cryptococcoma simulating an adenoma. Neuroradiology 37:449–450, 1995. his unusual case of cryptococcoma highlights the importance of good Tintraoperative pathology assistance in patient management. The diagnosis of cryptococcoma probably could not have been made preop- COMMENTS eratively, although strong indications to the sarcoid diagnosis were avail- analy et al. provide an interesting case report of a 58-year-old able. It is worth remembering that regional failure of laryngeal carcinoma Kman who presented with signs and symptoms of a mass lesion in is more common than distant metastasis, that brain metastases from the clinical setting of a recently treated malignancy and known pul- laryngeal carcinoma are unusual, and that most fungal brain abscesses monary nodules. The authors initially considered a diagnosis of are bright on diffusion-weighted magnetic resonance imaging (1). metastatic disease, but the mass proved to be a cryptococcal brain Frederick G. Barker II abscess in a patient with chronic pulmonary sarcoidosis. Large cryp- Boston, Massachusetts tococcal abscesses do not usually present a significant challenge in management because the mass effect alone usually prompts surgical resection, and the diagnosis is easily made with appropriate analysis 1. Gaviani P, Schwartz RB, Hedley-Whyte ET, Ligon KL, Robicsek A, Schaefer P, of the specimen. Small lesions in apparent immunocompetent indi- Henson JW: Diffusion-weighted imaging of fungal cerebral infection. AJNR viduals can be more problematic. The authors’ position regarding the Am J Neuroradiol 26:1115–1121, 2005.

E571 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com CASE REPORTS

GIANT, PARTIALLY THROMBOSED ANEURYSM DEVELOPS AFTER REMOTE ANGIOGRAPHICALLY NEGATIVE SUBARACHNOID HEMORRHAGE: CASE REPORT

Udaya K. Kakarla, M.D. OBJECTIVE: This is the first report of the rupture of a giant aneurysm in a patient who Division of Neurological Surgery, sustained a remote angiographically negative subarachnoid hemorrhage (SAH). Barrow Neurological Institute, St. Joseph’s Hospital and CLINICAL PRESENTATION: A 62-year old woman initially presented with a Fisher Medical Center, Grade III SAH 9 years ago. Her evaluation, which included cerebral angiography, Phoenix, Arizona magnetic resonance imaging scans, and magnetic resonance angiography of the head and neck, failed to reveal the cause of the hemorrhage. Nine years after her initial Peter H. Maughan, M.D. hemorrhage, the patient presented with a Fisher Grade IV SAH and a giant right supra- Division of Neurological Surgery, Barrow Neurological Institute, clinoid internal carotid artery aneurysm. St. Joseph’s Hospital and INTERVENTION: Computed tomographic and catheter angiography showed a par- Medical Center, tially thrombosed giant aneurysm of the right supraclinoid internal carotid artery. Phoenix, Arizona She underwent clip reconstruction and obliteration of the aneurysm. Review of her Vivek R. Deshmukh M.D. previous angiograms and magnetic resonance imaging scans did not show an aneurysm Department of Neurosurgery, in its nascency. George Washington University, CONCLUSION: Initial catheter angiography and magnetic resonance imaging scans Washington, D.C. may fail to disclose a subtle dissection or blister aneurysm as a cause for SAH. As in our case, the dissection or blister may progress to a giant aneurysm with time. Robert F. Spetzler M.D. Division of Neurological Surgery, KEY WORDS: Aneurysm, Subarachnoid hemorrhage Barrow Neurological Institute, St. Joseph’s Hospital and Neurosurgery 60:E572–E573, 2007 DOI: 10.1227/01.NEU.0000249285.92255.A4 www.neurosurgery-online.com Medical Center, Phoenix, Arizona

Reprint requests: he incidence of subarachnoid hemor- SAH with findings that raised suspicions of Robert F. Spetzler, M.D., rhage (SAH) from unknown causes is a giant aneurysm (Fig. 1). CT and catheter c/o Neuroscience Publications, estimated to range between 5 and 15% of angiography showed a giant, partially Barrow Neurological Institute, T all patients with SAH (7, 11). A subset of these thrombosed aneurysm involving the supra- 350 West Thomas Road, Phoenix, AZ 85013. patients sustains a nonaneurysmal perimesen- clinoid portion of the internal carotid artery Email: [email protected] cephalic hemorrhage. A small percentage, (ICA). The anterior choroidal or posterior however, harbor an aneurysm that is occult communicating arteries were not clearly Received, September 27, 2005. even on initial angiography and magnetic res- visualized. The anterior cerebral and middle Accepted, November 1, 2006. onance imaging (MRI) scans. We report the cerebral arteries were significantly distorted. case of a patient with a history of a remote Postaneurysmal stenosis of the ICA was also angiographically negative SAH who presented present (Fig. 2). with a giant, partially thrombosed aneurysm 9 The patient’s family stated that the patient years later. had experienced progressive visual loss dur- ing the course of several months and had CASE REPORT been complaining of worsening headaches. A 62-year-old woman presented with an She had previously been treated at our institu- acute deterioration of consciousness. On tion, but the family did not know the nature of admission, she had a Glasgow Coma Scale her previous hospitalization. Review of old score of 5 and a Hunt and Hess Grade of V. records revealed that the patient had experi- In our emergency room, computed tomo- enced a Fisher Grade III SAH 9 years earlier. An graphic (CT) scan showed a Fisher Grade IV extensive evaluation at that time was negative.

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The patient was then lost to Our policy for patients follow-up and failed to with angiographically nega- undergo the recommended tive SAH is to perform an 1-month follow-up angio- MRI scan of the entire cra- gram. niospinal axis. Angiography The patient’s previous CT is repeated 7 days after scan showed a Fisher Grade SAH. The follow-up angio- III SAH, perhaps eccentric to gram serves the twofold the right side (Fig. 3). Angio- purpose of evaluating for an graphy showed no aneur- aneurysm and vasospasm. If ysm or obvious dissection the hemorrhage pattern is of (Fig. 4). MRI scans of the concern (e.g., Fisher Grade brain and neck also failed to III diffuse), a third angio- indicate the source of the gram is repeated 1 month FIGURE 1. Axial noncontrast CT scan patient’s SAH (Fig. 5). showing diffuse SAH with a mass FIGURE 3. Axial noncontrast CT scan later on an outpatient basis. The patient underwent an lesion within the subarachnoid space. showing diffuse SAH with blood pre- If this study is also negative, urgent modified orbitozygo- dominating on the right side. no further studies are ob- matic craniotomy, and the atherothrombotic dome of the tained. The literature sup- aneurysm was debulked. Attempts were made to clip recon- ports this algorithm for the management of angiographically struct the vessel, but intraoperative angiography showed high- negative SAH (4, 6, 11, 13, 14). grade stenosis at the distal aspect of the clip (Fig. 6). Given the To our knowledge, the yield of follow-up catheter angiogra- continued filling of the middle cerebral artery and the robust phy in detecting an aneurysm after initial negative examination collaterals present on preoperative angiography, a bypass was has ranged from 11 to 37% in recent series (1, 4, 13). Inamasu not pursued. et al. (4) detected an aneurysm in seven out of 19 patients who Postoperatively, the patient did not improve. In accordance initially had angiographically negative angiograms. They do with her previously stated wishes, care was withdrawn on not mention additional angiographic examinations for patients postoperative Day 3. with two negative angiograms. Kaim et al. (6) detected an intracranial aneurysm in eight out of 42 patients with negative initial angiograms. Bradac et al. (1) found an aneurysm in five DISCUSSION out of 40 patients with initially angiographic negative SAH. Topcuoglu et al. (13) reported that catheter angiography SAH that is negative on initial angiography is typically the showed an aneurysm in four out of 36 patients with nonperi- result of an occult aneurysm, occult vascular malformation, or mesencephalic SAH. This study found that catheter angiogra- a benign perimesencephalic variant of SAH. Perimesencephalic phy was invaluable in the evaluation of these patients. The SAH accounts for a significant percentage of patients with authors compared the usefulness of noninvasive studies in angiographically negative SAH and carries an excellent prog- detecting aneurysms and found that all initially occult nosis (9, 10). Other causes that have been implicated in angio- aneurysms were detected only by catheter angiography (13). graphically negative SAH include arteriovenous malformations The rate of positive follow-up angiography has been esti- of the cervical spine and myxopapillary ependymomas of the mated to range from 5 to 15% (1, 3, 6, 8, 12). The most frequent conus medullaris. cause of initial angiographically negative SAH is an aneurysm

A B A B

FIGURE 2. A, right common carotid angiogram showing a giant, partially thrombosed aneurysm arising from the supraclinoid ICA. B, the posterior FIGURE 4. Angiograms demonstrating that no aneurysm or dissection is communicating and anterior choroidal arteries are not apparent on this lateral observed on posteroanterior (A) and lateral (B) projections with an ICA projection. The distal branches fill sluggishly. injection.

E572 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com ANEURYSM DEVELOPS AFTER REMOTE SUBARACHNOID HEMORRHAGE

5. Iwanaga H, Wakai S, Ochiai C, Narita J, Inoh S, Nagai M: Ruptured cerebral AB aneurysms missed by initial angiographic study. Neurosurgery 27:45–51, 1990. 6. Kaim A, Proske M, Kirsch E, von Weymarn A, Radu EW, Steinbrich W: Value of repeat-angiography in cases of unexplained subarachnoid hemorrhage (SAH). Acta Neurol Scand 93:366–373, 1996. 7. 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 results. J Neurosurg 73:18–36, 1990. 8. Khan N, Schuknecht B, Yonekawa Y: Presentation and management of patients with initial negative 4-vessel cerebral angiography in subarachnoid hemorrhage. Acta Neurochir Suppl 82:71–81, 2002. 9. Rinkel GJ, Wijdicks EF, Hasan D, Kienstra GE, Franke CL, Hageman LM, Vermeulen M, van Gijn J: Outcome in patients with subarachnoid haemor- rhage and negative angiography according to pattern of haemorrhage on computed tomography. Lancet 338:964–968, 1991. 10. Rinkel GJ, Wijdicks EF, Vermeulen M, Ramos LM, Tanghe HL, Hasan D, Meiners LC, van Gijn J: Nonaneurysmal perimesencephalic subarachnoid hemorrhage: CT and MR patterns that differ from aneurysmal rupture. AJNR FIGURE 5. Proximal (A) and distal (B) axial T2-weighted MRI scans show- Am J Neuroradiol 12:829–834, 1991. ing no evidence of an intracranial aneurysm in the region of the right ICA. 11. Schwartz TH, Solomon RA: Perimesencephalic nonaneurysmal subarachnoid hemorrhage: Review of the literature. Neurosurgery 39:433–440, 1996. at the anterior communicat- 12. Tatter SB, Crowell RM, Ogilvy CS: Aneurysmal and microaneurysmal ing artery complex (2). A ”angiogram-negative” subarachnoid hemorrhage. Neurosurgery 37:48–55, subtle dissection of the ICA 1995. is also a known cause (4, 5). 13. Topcuoglu MA, Ogilvy CS, Carter BS, Buonanno FS, Koroshetz WJ, Singhal AB: Subarachnoid hemorrhage without evident cause on initial angiography Our case is disconcerting studies: Diagnostic yield of subsequent angiography and other neuroimaging because there was no evi- tests. J Neurosurg 98:1235–1240, 2003. dence of an abnormality 14. Urbach H, Zentner J, Solymosi L: The need for repeat angiography in sub- on angiography or high- arachnoid haemorrhage. Neuroradiology 40:6–10, 1998. resolution MRI scans at the time of the patient’s first COMMENTS hemorrhage. We suspect that the patient likely had a he authors describe the presentation of a patient with a giant rup- FIGURE 6. Intraoperative angiogram subtle dissecting or blister Ttured aneurysm in the setting of subarachnoid hemorrhage (SAH) confirming complete obliteration of the aneurysm that may or may 9 years after a negative angiogram. Because very little is known about aneurysm. A high-grade stenosis of the not have been visible on a the genesis of giant aneurysms, this case report is a welcome addition ICA is present. delayed angiogram, which to the literature. Unfortunately, the patient refused a short-term follow- we requested but the patient failed to obtain. This dissection up angiogram. Although this case report is interesting, it does not sup- port follow-up imaging beyond what is outlined as the author’s insti- likely progressed with laminations of thrombus and atheroma- tutional protocol, particularly because the patient refused the protocol. tous debris to form a giant aneurysm. Of the fairly high number It would be interesting to study delayed magnetic resonance angiogra- of SAH patients with negative findings on angiography or MRI phy at 1, 5, and 10 years after angiographically negative SAH. scans, how many have a subtle dissection or blister aneurysm Joseph G. Adel that could easily be missed? This case affirms the need for Bernard R. Bendok repeated late (several months after ictus) follow-up catheter or Chicago, Illinois magnetic resonance angiography in patients with an SAH that causes concern and initially negative evaluation. he authors have reported a rare and troublesome scenario in which Ta patient with SAH of unknown etiology later presented with lethal SAH from a giant intracranial aneurysm despite a thorough work-up REFERENCES at the time of the initial hemorrhage. As stated by the authors, patients with SAH and negative initial angiography typically undergo repeat 1. Bradac GB, Bergui M, Ferrio MF, Fontanella M, Stura G: False-negative angiography and magnetic resonance imaging scans of the entire cra- angiograms in subarachnoid haemorrhage due to intracranial aneurysms. nial spinal axis. If these follow-up studies are negative, there is a very Neuroradiology 39:772–776, 1997. low yield of further diagnostic work-up in this group of patients. In 2. Di Lorenzo N, Guidetti G: Anterior communicating aneurysm missed at general, these patients are considered to fare well with a very low risk angiography: Report of two cases treated surgically. Neurosurgery 23:494–499, of subsequent SAH. 1988. The aneurysm that was subsequently discovered in this patient 3. Farres MT, Ferraz-Leite H, Schindler E, Muhlbauer M: Spontaneous sub- has a very unusual configuration; I agree with the authors that this arachnoid hemorrhage with negative angiography: CT findings. J Comput Assist Tomogr 16:534–537, 1992. was probably a “blister” aneurysm of the dorsal wall of the internal 4. Inamasu J, Nakamura Y, Saito R, Horiguchi T, Kuroshima Y, Mayanagi K, Orii carotid artery that was simply below the resolution of conventional M, Ichikizaki K: “Occult” ruptured cerebral aneurysms revealed by repeat angiography 9 years earlier. Based on this experience, the authors angiography: Result from a large retrospective study. Clin Neurol Neurosurg question whether or not long-term follow-up angiography should be 106:33–37, 2003. performed routinely in all patients with SAH of unknown etiology.

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Our current protocol for managing such patients includes the routine aneurysms detected on follow-up angiography 3 to 6 months later; use of three-dimensional rotational angiography, a technique that ele- however, it is rare to see an occult aneurysm progress to a giant gantly demonstrates these blister-like aneurysms. The routine use of aneurysm. The fusiform aneurysm morphology and intraluminal three-dimensional rotational angiography may identify those rare thrombus suggest dissection as the underlying etiology. Arterial dissec- patients with subtle abnormalities and obviate the need for long-term tions can be subtle at presentation and difficult to detect on angiogra- follow-up angiography. phy, particularly when compared with saccular aneurysms with intra- Daniel L. Barrow luminal thrombus, which often have some angiographic signs. This Atlanta, Georgia patient’s failure to undergo follow-up angiography proved costly and emphasizes the authors’ conclusion that surveillance catheter angiog- his report is a unique case of a patient with an angiographically- raphy is essential after an initially negative evaluation and a clinical Tnegative SAH that developed into a giant, thrombotic aneurysm of history suggestive of arterial rupture. the supraclinoid internal carotid artery over the following 9 years. I Michael T. Lawton often see patients with angiographically-negative SAH who have small San Francisco, California

E572 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com CASE REPORTS

INTRACAVERNOUS TRIGEMINAL GANGLION AMYLOIDOMA: CASE REPORT

Markus J. Bookland, M.D. OBJECTIVE: Isolated amyloidomas rarely manifest in nervous system tissues. To the Department of Neurosurgery, authors’ knowledge, there have been 52 documented cases of primary amyloid tumors The Johns Hopkins School of Medicine, Baltimore, Maryland of the central nervous system and closely associated structures. The authors present a case of a woman with a history of presumptive trigeminal neuralgia who was found to Carlos A. Bagley, M.D. have an amyloidoma of the trigeminal ganglion. Department of Neurosurgery, CLINICAL PRESENTATION: A 32-year-old Caucasian patient presented with a chief The Johns Hopkins School of Medicine, complaint of severe numbness and pain throughout the right side of her face. Her symp- Baltimore, Maryland toms had been progressive over the previous 3 years. Medical management of her pre- Jacob Schwarz, M.D. sumptive diseases with Zoloft (Pfizer Inc., New York, NY) and Neurontin (Pfizer Inc.) failed Department of Neurosurgery, to improve or halt her right facial numbness and pain. Brain magnetic resonance imag- The Johns Hopkins School of Medicine, ing was acquired, demonstrating abnormal contrast enhancement and enlargement of Baltimore, Maryland the right trigeminal ganglion. The lesion abutted and indented the right internal carotid artery and extended from Meckel’s cave into the inferior cavernous sinus and distally Peter C. Burger, M.D. to the foramen ovale. Department of Pathology, The Johns Hopkins School of Medicine, INTERVENTION: The patient underwent a right frontotemporal craniotomy for resec- Baltimore, Maryland tion of the gasserian ganglion lesion. A delicate incision was made in the wall of the cav- ernous sinus, allowing confirmatory biopsy of the lesion. With the site of the tumor Henry Brem, M.D. within the cavernous sinus verified by pathology, the remainder of the tumor was Department of Neurosurgery, removed. A final pathological review of the resected tumor confirmed a diagnosis of The Johns Hopkins School of Medicine, Baltimore, Maryland amyloidoma of the trigeminal ganglion. CONCLUSION: We present the case of a patient with a rare trigeminal ganglion amy- Reprint requests: loidoma that closely mimicked idiopathic trigeminal neuralgia. Even in the absence of Carlos A. Bagley, M.D., The Johns Hopkins University systemic signs of amyloidosis, this benign protein deposition disease should be con- School of Medicine, sidered in the differential for atypical dysesthesias of the trigeminal dermatomes. Department of Neurosurgery, Furthermore, central and peripheral nervous system amyloidomas respond well to sur- 600 North Wolf Street, Meyer 8-161, gical resection and rarely recur. Baltimore, MD 21287. KEY WORDS: Amyloidoma, Intracavernous, Trigeminal ganglion Email: [email protected]

Neurosurgery 60:E574, 2007 DOI: 10.1227/01.NEU.0000255361.32689.B3 www.neurosurgery-online.com Received, August 20, 2006. Accepted, January 8, 2007. ervous system amyloidomas are rare loidoma in a 32-year-old woman who pre- tumors (13). To the authors’ knowl- sented with trigeminal neuralgia. edge, there have been 52 documented N Patient Presentation cases of primary amyloid tumors of the central nervous system (CNS) and closely associated A 32-year-old Caucasian patient presented structures; 23 involved the cerebral paren- with severe numbness and pain throughout the chyma (4, 7, 8, 14, 17, 19, 23, 27, 28, 30, 33, 37, right side of her face. Her symptoms had been 46, 47,50, 52, 53), eight involved the spinal cord progressive over the previous 3 years; she had or spinal column (3, 13, 24, 29, 32, 35, 40, 41, visited multiple physicians during this time 44), three involved the pituitary gland (2, 26, period. After extensive examination and tests, 38), four involved the cranial base (9, 18, 27, including lumbar puncture and magnetic reso- 54), and 13 involved the gasserian ganglion (5, nance imaging (MRI) scans, had failed to 6, 11, 12, 27, 34, 39, 56, 57). We report a case of expose any abnormalities, she was diagnosed primary trigeminal nerve ganglion amy- with fibromyalgia and trigeminal neuralgia.

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ABA

FIGURE 1. Axial (A) and coronal (B) postcontrast T1-weighted MRI scans demonstrating the enhancing lesion in the right cavernous sinus. B

However, medical management of her presumptive diseases with Zoloft (Pfizer Inc., New York, NY) and Neurontin (Pfizer Inc.) failed to improve or halt her right facial numbness and pain. Her past medical history was otherwise unremarkable. At the time of her initial presentation, the patient reported complete loss of sensation over the right side of her face, with periods of severe, diffuse right-sided facial tingling not associ- ated with any recognizable triggers. The patient also noted hav- ing persistent headaches. No further symptoms were reported. Examination On examination, the patient had perturbed appreciation of light touch throughout all three trigeminal distributions on the FIGURE 2. A, hematoxylin and eosin stain of trigeminal ganglion amy- right side. Cranial Nerves II through XII, with the above excep- loidoma with distinctive amorphous, eosinophilic, hyalinaceous material and tion, were normal. She displayed no motor weakness, cerebel- minimal inflammatory reaction. B, polarized light microscopy image of Congo lar tests were normal, and there was no evidence of gross cog- red-stained tumor. Note the green birefringence of the amyloid protein. nitive deficits. Cardiopulmonary examination was normal, and there was no evidence of macroglossia or hepatosplenomegaly. the right cavernous sinus, which was somewhat plump. A BrainLab frameless stereotactic navigation system (Heim- Imaging stetten, Germany) was used to localize the lesion within the Brain MRI scans were acquired, despite past reports of nor- cavernous sinus. A delicate incision was made in the wall of mal brain imaging. These scans showed abnormal contrast the cavernous sinus at the site indicated by the navigation enhancement and enlargement of the right trigeminal ganglion system. This provided a confirmatory biopsy of the lesion. (Fig. 1). The lesion abutted and indented the right internal With the site of the tumor within the cavernous sinus verified carotid artery and extended from Meckel’s cave into the infe- by pathology, the remainder of the tumor was removed using rior cavernous sinus and distally to the foramen ovale. Given Yas¸argil and Rhoton tumor forceps. The portion of the sinus the new lesion, the patient’s previous MRI scans were also containing the tumor was relatively avascular, allowing min- reviewed. Careful examination identified the same trigeminal imal blood loss during resection. ganglion lesion on multiple previous images. No abnormalities were identified in the contralateral ganglion. Pathological Findings A final pathological review of the resected tumor confirmed Operation a diagnosis of amyloidoma of the trigeminal ganglion. The tis- The patient underwent a right frontotemporal craniotomy sue samples consisted of amorphous material with little inter- for resection of the gasserian ganglion lesion. After the bone vening inflammatory tissue (Fig. 2). Samples of the amorphous flap was elevated, the dura was incised in a curvilinear fash- material stained positively with Congo red and displayed ion and the frontal and temporal lobes were gently elevated apple-green birefringence under polarized lighting, consistent with Leila self-retaining retractors. The Sylvian fissure was with amyloid protein. Immunostaining for κ and λ light chains then split using microdissectors, allowing an ample view of proved the amyloid to consist predominantly of λ light chains.

E574 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com INTRACAVERNOUS TRIGEMINAL GANGLION AMYLOIDOMA

Postoperative Course cores found in the neuritic plaques of patients with Alzheimer’s Given the unusual nature of the patient’s diagnosis and her disease derive from a specific chain of processing events otherwise benign medical history, a workup for systemic causes involving the amyloid precursor protein (15). of amyloidosis began. However, thorough blood work and urine testing for elevated serum protein failed to demonstrate Pathological Characteristics a systemic source of amyloid production. Serum protein Although the appearance of amyloid-infiltrated tissues is not electrophoresis, serum free light chain assays, quantitative consistent on gross inspection, some generalizations can be immunoglobulins, and 24-hour urine protein tests showed made. Affected tissues will often appear bulging and waxy on no evidence of M-spikes, altered κ-to-λ ratios, elevated gross inspection, and palpation sometimes finds these tumors immunoglobulin, or proteinuria. A fat pad biopsy with Congo gritty with imbedded osseous pockets (1, 54). red staining showed no amyloid deposits. A definitive diagnosis must be made by microscopic exami- The patient was discharged in good health 4 days after her nation and Congo red staining. Serological tests for elevated operation. She had a slight right Cranial Nerve III palsy imme- serum proteins can hint at the diagnosis of systemic amyloido- diately after the operation, which steadily improved over the sis. However, elevated light chain serum proteins are rarely subsequent weeks. At the time of her 2-month follow-up exam- detected in cases of amyloid tumors, and their absence cannot ination, the patient reported no pain or numbness across all rule out the presence of an amyloid pathology (22). A biopsy trigeminal divisions. sample of suspect tumors or of adipose tissue provides the best opportunity for diagnosis. The classic microscopic appearance DISCUSSION of amyloid impregnated tissues stained with hemotoxylin and eosin is an amorphous, eosinphilic, extracellular hyaline sub- Amyloid is an amorphous and heterogenous protein stance. Occasionally, inflammatory infiltrates may be seen amid deposit associated with a variety of inflammatory and non- amyloid pockets but this is an unreliable finding (1). Foci of cal- inflammatory conditions, such as plasmacytomas, chronic cification have also been reported in several instances of renal failure, rheumatoid arthritis, and familial transthyretin intracranial amyloidomas, likely forming when calcium, mutations (25, 31, 40, 45, 49, 55). In rare instances, amyloido- released from bone eroded by these osteolytic protein deposits, mas, consisting of β-pleated proteins with variable amounts binds to fibrils in the amyloidoma (11, 13, 27, 34, 54). The most of N-terminal digestion, may arise in the absence of any striking microscopic feature of amyloidomas, however, is the β obvious sources of exuberant protein production (14, 30, 51). apple-green birefringence that amyloid’s -pleated proteins Instances of localized amyloid formation associated with give off under polarized light and Congo red staining. This systemic plasma cell dyscrasias occur in the context of amy- appearance is consistent for all forms of amyloid (1). Immuno- histochemical studies for λ and κ light chains in nervous tissue loid light-chain amyloidoses, which may produce systemic λ or local disease, usually involving the kidney (48). A fluores- amyloidomas have nearly universally been positive for light cent in situ hybridization study of patients with systemic chains, including the case reported here (4, 6, 8, 17, 27, 30, 34, amyloid light-chain amyloidosis has demonstrated frequent 47, 50, 52, 57). chromosomal abnormalities that enhance plasma cell light- Imaging chain production. However, patients with localized amyloid tumors in the same study did not show similar chromosomal Amyloid deposits on brain imaging can be quite variable in abnormalities (20). Most commonly, these isolated amyloid their appearance, depending on the density of protein deposi- tumors arise in the respiratory tracts of afflicted patients; tion and the presence or absence of edema (27). Most com- however, they may also be found in the skin and genitouri- monly, these lesions involve the cerebral parenchyma, particu- nary tract (22). larly the periependymal white matter of the lateral ventricles In contrast, nervous tissues, both peripheral and central, are (4, 7, 14, 17, 27, 28, 52). On computed tomographic scans, amy- rare locations for amyloidoma formation. Laeng et al. (27) have loidomas appear hyperintense and readily enhance with con- theorized that amyloidomas may arise by way of monotypic trast medium. Depending on their protein concentration, amy- λ-producing B-cells, perhaps in reaction to unique antigens. loidomas can appear hyper- to hypointense on T1-weighted Cohen et al. (8) have put forth a similar theory, suggesting that MRI scans, whereas T2-weighted images tend to demonstrate genetically predisposed microglia may be sources of amyloid intermediate intensities owing to varied protein content (17, when challenged by certain antigens. Such mechanisms might 28). Gasserian ganglion amyloidomas, in particular, appear as explain why CNS amyloidomas are so rare, as the CNS is an brightly enhancing and swollen segments of Cranial Nerve V immunologically protected site and would only be exposed to within Meckel’s cave (27, 34, 39). triggering antigens in rare instances (27). However these amyloid tumors form, they are distinct from Presentation the much more common amyloid cores found in Alzheimer’s Reported cases of amyloidomas of the brain and cranial disease and some elderly patients. Unlike the conjectured nerves have generally occurred in middle-aged patients (mean mechanisms of protein production in amyloidomas, amyloid age, 48.4 yr), with a slight bias toward women (male-to-female

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ratio, 0.85). They most often occur as single lesions, but as of focused radiotherapy, steroids, or colchicine have not many as one-third of the patients in the literature had multiple detailed any positive results (2, 27, 39). In the case of the patient amyloidomas (2, 4–9, 11, 12, 14, 16–19, 26–28, 20, 33, 34, 37, 39, treated with 4500 rads of local radiation, the patient died after 46, 47, 50, 52–54, 56, 57). Most intracranial amyloidomas occur his radiation treatments (2). in the white matter of the brain (22 out of 40 cases) (2, 4–9, 11, 12, 14, 16–19, 26–28, 30, 33, 37, 39, 46, 47, 50, 52–54). When CONCLUSION peripheral nerves are involved, the gasserian ganglion is almost invariably the culprit site (13 out of 17 cases) (5, 6, 10 to We present the case of a patient with a rare trigeminal gan- 12, 21, 27, 34, 36, 39, 42, 43, 56, 57). The reason for this predilec- glion amyloidoma that closely mimicked idiopathic trigeminal tion for trigeminal nerve involvement has not been clarified; neuralgia. Even in the absence of systemic signs of amyloido- however, it is suspected that latent infections of the ganglion sis, this benign protein deposition disease should be considered might provide cryptogenic antigens that stimulate amyloid- in the differential for atypical dysesthesias of the trigeminal forming B-cells. dermatomes. Furthermore, peripheral and CNS amyloidomas Although it is sparse, the literature on gasserian ganglion respond well to surgical resection and rarely recur. amyloidomas is consistent in describing the common symp- toms associated with these tumors. In all cases, the patients REFERENCES had primary complaints of pain and numbness in the distribu- tion of one or more trigeminal branches and were often pre- 1. 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Linke RP, Gerhard L, Lottspeich F: Brain-restricted amyloidoma of amyloid A (apoSAA) expression is up-regulated in rheumatoid arthritis and immunoglobulin lambda-light chain origin clinically resembling multiple induces transcription of matrix metalloproteinases. J Immunol 166:2801–2807, sclerosis. Biol Chem Hoppe Seyler 373:1201–1209, 1992. 2001. 31. Koch KM: Dialysis-related amyloidosis. Kidney Int 41:1416–1429, 1992. 56. Vorster SJ, Lee JH, Ruggieri P: Amyloidoma of the gasserian ganglion. AJNR 32. Mandl J: Ueber lokales Amyloid im Bereiche der Brustwirbelsäule [in Am J Neuroradiol 19:1853–1855, 1998. German]. Virchows Arch 253:639–655, 1924. 57. Yu E, de Tilly LN: Amyloidoma of Meckel’s cave: A rare cause of trigeminal 33. Matsumoto T, Tani E, Fukami M, Kaba K, Yokota M, Hoshii Y: Amyloidoma neuralgia. AJR Am J Roentgenol 182:1605–1606, 2004. in the gasserian ganglion: Case Report. Surg Neurol 52:600–603, 1999. 34. Matsumoto T, Tani E, Maeda Y, Natsume, S: Amyloidomas in the cerebello- pontine angle and jugular foramen. Case report. J Neurosurg 62:592–596, 1985. COMMENTS 35. McAnena OJ, Feely MP, Kealy WF: Spinal cord compression by amyloid tis- sue. J Neurol Neursosurg Psychiatry 45:1067–1069, 1982. his is a nicely written, concise case report and review of intracranial 36. McKechnie S, Yang F, Harper CG, McGee-Collett M, Henderson CJ, Liepnieks Tamyloidomas. These are very rare tumors that can be missed easily, JJ, Yazaki M, Benson, McLeod JG: Amyloidoma of a spinal root. Neurology particularly in the trigeminal ganglion, because it is so common to 61:834–836, 2003. assume enhancing cavernous sinus lesions are either meningiomas or 37. Moreno AJ, Brown JM, Brown TJ, Graham GD, Yedinak MA: Scintigraphic schwannomas. They are, therefore, treated with stereotactic radio- findings in a primary cerebral amyloidoma. Clin Nucl Med 8:528–530, 1983. 38. Mori H, Mori S, Saitoh Y, Moriwaki K, Iida S, Matsumoto K: Growth surgery. hormone-producing pituitary adenoma with crystal-like amyloid immuno- Charles J. Hodge, Jr. histochemically positive for growth hormone. Cancer 55:96–102, 1985. Syracuse, New York 39. O’Brien TJ, McKelvie PA, Vrodos N: Bilateral trigeminal amyloidoma: An unusual case of trigeminal neuropathy with a review of the literature. Case report. J Neurosurg 81:780–783, 1994. his report of an amyloidoma of the gasserian ganglion and cav- 40. O’Hara R, Murphy EP, Whitehead AS, FitzGerald O, Bresnihan B: Local ernous sinus is instructive in warning against irradiation of cav- expression of the serum amyloid A and formyl peptide receptor-like 1 genes T ernous sinus lesions without first obtaining histological confirmation of in synovial tissue is associated with matrix metalloproteinase production in patients with inflammatory arthritis. Arthritis Rheum 50:1788–1799, 2004. presumed tumors such as meningioma or schwannoma. Stereotactic 41. Pawar S, Kay CJ, Anderson HH, Breitfeld V: Primary amyloidoma of the radiosurgery at tumor doses to this mass would likely not have con- spine. J Comput Assist Tomogr 6:1175–1177, 1982. trolled the patient's pain and certainly would not have restored sensa- 42. Pizov G, Soffer D: Amyloid tumor (amyloidoma) of a peripheral nerve. Arch tion. The authors should be congratulated for their successful man- Pathol Lab Med 110:969–970, 1986. agement of this case and for a highly informative review of the 43. Porchet F, Sonntag VK, Vrodos N: Cervical amyloidoma of C2. Case report literature and discussion. and review of the literature. Spine 23:133–138, 1998. 44. Prasad BK, Andrews K, Dutton J, Reid H: Localised amyloid deposit produc- Griffith R. Harsh IV ing paraplegia. Br Med J (Clin Res Ed) 283:1087, 1981. Stanford, California

NEUROSURGERY VOLUME 60 | NUMBER 3 | MARCH 2007 | E574 CASE REPORTS

ACUTE PRESENTATION OF SPINAL EPIDURAL CAVERNOUS ANGIOMAS: CASE REPORT

Giuseppe Caruso, M.D. OBJECTIVE: Spinal extramedullary hematomas stemming from cavernous angiomas in Division of Neurosurgery, the epidural compartment are rare. It is more common for spinal epidural cavernous Villa Maria Cecilia Hospital, angiomas to present with slow and progressive myelopathy or radiculopathy. They sel- Cotignola, Italy dom present with clinical evidence of acute spinal cord or nerve root compression. Marcelo Galarza, M.D. CLINICAL PRESENTATION: Three consecutive cases of acute spinal cavernous angiomas Division of Neurosurgery, with overt neurological deficits were presented. These presentations included acute Villa Maria Cecilia Hospital, onset of neck pain and tetraparesis, bilateral lower extremity pain and paraparesis, and Cotignola, Italy acute sciatic pain with plantar flexor weakness. The lesions were located in the cervi- cal, thoracic, and sacral spine, respectively. The cases included either abrupt lesion Ignazio Borghesi, M.D. enlargement secondary to a pure intralesional hemorrhage or a cavernous hemorrhage Division of Neurosurgery, Villa Maria Cecilia Hospital, that invaded the epidural space. Cotignola, Italy INTERVENTION: All patients were treated with either laminotomy or complete resec- tion of the hematoma and cavernoma within 12 hours after admission. Eugenio Pozzati, M.D. CONCLUSION: Spontaneous spinal epidural hematomas presented with significant Division of Neurosurgery, Ospedale Bellaria, pain and acute spinal cord and nerve root compression may represent the manifesta- Bologna, Italy tion of a cavernous angioma. Appropriate interpretation of preoperative imaging stud- ies may prevent delay in proper management, especially for patients in whom nerve Mario Vitale, M.D. root deficit is the only clinical expression. Division of Neurosurgery, Villa Maria Cecilia Hospital, KEY WORDS: Cavernous angiomas, Nerve root compression, Spinal cord compression, Spontaneous Cotignola, Italy epidural hematoma

Reprint requests: Neurosurgery 60:E575–E576, 2007 DOI: 10.1227/01.NEU.0000255345.48829.0B www.neurosurgery-online.com Marcelo Galarza, M.D., Division of Neurosurgery, Villa Maria Cecilia Hospital, avernomas affecting the spine are most cord impairment with or without acute wors- Viale Corriera 1, commonly located in the vertebral bod- ening is the usual clinical scenario. Cervical 48010 Cotignola, Italy. ies; other locations are rare (12, 25, 26, spinal cavernomas are even more rare, with Email: [email protected] C 33). Although the improvement of magnetic most reports having an acute presentation. A Received, July 25, 2006. resonance imaging (MRI) has led to enhanced thorough review of the literature disclosed a Accepted, November 1, 2006. discovery and more precise detection of caver- predominance of case reports and series with nomas in any part of the central nervous sys- this specific entity from the Italian peninsula tem (CNS), the spinal epidural localization is (21, 25, 26, 30, 31). considered very unusual (9, 26, 30). Caverno- matous hemorrhage may lead to neurological Illustrative Cases deficit by either direct compression of the Patient 1 spinal cord (17, 20, 33) or, more commonly, by A 74-year-old man affected by non-invalidating compression of a nerve root (12, 25, 30, 31). Parkinson’s disease developed sudden and severe The clinical presentation of cavernomas neck pain with interscapular irradiation, which was mimics that of expanding epidural lesions. followed by a right brachiocrural paresis within min- Patients with lumbar lesions who present with utes. Upon admission to the emergency room (ER), the patient was alert and exhibited nuchal rigidity lower back pain usually have lumbar radicu- with neck stiffness and resistance to neck flexion. Deep lopathy caused by the extension of the caver- tendon reflexes of his right arm were absent, whereas noma into the intervertebral foramen. Patients the reflexes in both lower extremities were hyperactive with lumbar localization experience a longer and a bilateral positive Babinski’s sign was present. duration of symptoms (25, 30). In patients who The patient had a deep sensory deficit of his right had thoracic localization, progressive spinal limbs with hypoestesia of the left hemibody below the

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C7 level and myoclonus of the left inferior limb. The patient had no his- T2-weighted hyperintense signal at the C4 segment, corresponding tory of previous neck pain. with the previous vascular event. An emergency computed tomographic scan of the brain was nega- tive. Cervical MRI scans disclosed an acute epidural hematoma at the Patient 2 C4–C5 level (Fig. 1A), which extended toward the right side compress- A 37-year-old man and professional cyclist was referred to our ER ing the cervical spinal cord. The patient was then transferred to our for the acute onset of excruciating leg pain and numbness in the right department 12 hours later. posterior thigh and plantar aspect of the foot involving the S1 der- Upon arrival at the neurosurgical department, a second neurological matome. Pain was also present in the lower lumbar and sacral area. examination revealed that the right hemiparesis had worsened to a Two days before onset, he experienced acute back pain and diffuse right upper extremity palsy, which is associated with severe paresis of paresthesia of the right calf after cycle training. He referred to episodes the right leg, making it impossible to walk and stand. Bowel and blad- of numbness in the right leg that appeared sporadically while cycling der retention were also present. The patient was immediately trans- during the past 6 months. Clinical examination revealed a decreased ferred to the operating room. Laminectomy from C3 to C6 and removal ankle jerk, mild weakness of plantar flexors in the calf, and some sen- of a clot adherent to the posterior right side of the spinal dura mater sory loss of the right calf. Rectal examination was normal. He denied were performed. A grayish and red elastic tissue measuring 2 ϫ 2 ϫ 3 any urinary problems. MRI scans revealed a lobulated oval mass at the cm was discovered in the posterior far side of the dura mater. Small S1–S2 level, which revealed high-level intensity with a ventral area of vessels from the dura mater that circumscribed the lesion were coagu- low-level intensity on T2-weighted imaging (Fig. 2A) and marked high- lated and sectioned. The histological diagnosis revealed a hemorrhagic level intensity on T1-weighted imaging (Fig. 2B). cavernous angioma (Fig. 1B). The mass and ligamentum flavum were resected through the S1–S2 The postoperative course was uneventful. The patient experienced interspace after an S1 laminotomy. A vascular lesion measuring immediate motor function recovery of the upper right arm and hand 2.5 cm in diameter was found attached to the internal aspect of the and complete resolution of his neck pain. The patient was able to right S1 nerve root dura mater with reddish, partially thrombosed walk with a cane on the second postoperative day and was dis- areas. The lesion was located in the outer dura mater layer and was charged with rehabilitation 12 days after surgery. A follow-up exam- quite adherent; however, the dissection was easily achieved after ination 9 months after surgery revealed a positive neurological recov- coagulation and sectioning of tiny afferent vessels that were coming ery with complete sphincter control, mild deficit of the right deltoid from the dura mater itself. There was no communication between the muscle, and sporadic paresthesias in the lower extremities without lesion cyst and the spinal arachnoid space. The lesion was rounded, pain. A control cervical MRI scan revealed a 1-cm intramedullary brownish in color, and contained both fresh and coagulated

A B

FIGURE 1. A, preoperative sagittal T2-weighted MRI scan. Note that the het- demonstrating vascular elements of various dimensions, with some dilated and erogeneous signal abnormality on the posterior epidural space of the cervical papillary endothelial hyperplasia of Masson. Original magnification, ϫ100. spine resembles a subacute hematoma. B, hematoxylin and eosin staining

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AB A

C FIGURE 2. Preoperative coronal T2- weighted (A) and axial T1-weighted (B and C) MRI scans showing an extradural lesion with signal inten- sity similar to a herniated disc com- pressing the nerve root in the S1–S2 B disc space.

hematoma. Histological examination revealed a typical cavernous angioma containing residual bleeding. The postoperative course was uneventful and the patient experienced immediate sensory recovery in his right calf. At the 10-month postoperative follow-up examina- FIGURE 3. Preoperative coronal T2-weighted (A) and axial T1-weighted (B) tion, he was neurologically intact and free of symptoms, without any MRI scans. Note the extradural lesion with a intraspinal, foraminal, and radiculopathy or lower back pain. extraforaminal component, as well as normal signal intensity on the spinal cord. Patient 3 A 68-year-old man presented to the ER with acute worsening of a paraparesis improved after the second month of physiotherapy. At the 1-year history of gait disturbance and sharp diffusion of pain in the 1-year follow-up examination, the patient was able to walk without lower right extremity. He had a previous history of marked spinal assistance and is currently free of pain. stenosis, for which he had undergone operation at the lumbar segment 1 year earlier, and a herniated disc at the thoracolumbar level, for DISCUSSION which he had undergone operation 6 months before presentation at our hospital. After the two previous procedures, he presented with a resid- We present three cases of spinal epidural cavernomas in ual, yet functional, posterior cord syndrome. He was able to ambulate three different segments of the spine with spontaneous hem- with a cane until 2 days before admission. Upon arrival, clinical exam- orrhage and acute neurological deficit from either spinal cord ination revealed a marked paresis on the left thigh and leg, a complete or nerve root compression. After admission to the neurosur- left dorsal and plantar foot palsy, and a marked paresis of the left psoas muscle. Bilateral motor reflexes were absent in the quadriceps and gical department, the patients were treated surgically within Achilles tendon; inferior abdominal reflex was absent on the left side. 12 hours. Complete anesthesia to pain and temperature was evident on the left Cavernous angiomas of the spine most commonly affect the leg. Proprioception was noticeably reduced in both legs. MRI scans vertebral bodies. Although they may present variable extension revealed a high-level intensity, semi-oval intra- and extraforaminal into the epidural space, pure epidural cavernomas are rare, lesion of the right D6 nerve root on T2-weighted imaging (Fig. 3). The constituting approximately 4% of all spinal epidural tumors patient underwent a D6–D7 hemilaminectomy, which revealed an (33). The widespread use of spinal MRI scanning has increased extradural lesion. A reddish-blue, intra- and extraforaminal vascular the number of diagnosed cavernomas (5, 12, 31). The first case lesion measuring 3 cm in diameter was found in the external aspect of of epidural cavernoma was reported in 1938 (16). Epidural cav- the dural sleeve of the D7 nerve root. Although the lesion was adher- ernomas were also described by Wyburn-Mason (32) in his ent to the dura mater, dissection was easily achieved after sectioning a few dural microvessels. There was no communication between the classic work concerning spinal tumors and vascular malforma- lesion and the spinal dural arachnoid space. Pathological examination tions. In 1942, Kaplan (17) reported the first case of acute spinal of the lesion revealed a partially thrombosed cavernous angioma with cord compression caused by an extradural bleeding caver- a tiny portion of dural layer. The postoperative course was uneventful; noma. Thus far, fewer than 60 cases have been reported in the although the pain immediately improved after surgery, the patient’s literature (1, 2, 4, 6, 8–10, 12–17, 20–23, 25, 26, 28–31, 33).

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TABLE 1. Acute presentation of cervical epidural cavernous angiomas in the literaturea Series (ref. no.) Clinical presentation Operative findings Graziani et al., 1994 (9) Acute cervicobrachialgia Extradural hematoma Isla et al., 1993 (15) Sudden tetraparesis None reported Padovani et al., 1997 (26) Acute cervicalgia, tetraparesis, and bladder retention Intralesional hemorrhage Richardson and Cerullo, 1979 (29) Acute cervicobrachialgia Intralesional hemorrhage

a All patients were treated with laminectomy and hematoma drainage and had a positive neurological outcome after surgery.

Pure epidural cavernomas have most often been reported in All three of our patients presented to the ER with either the thoracic or lumbar spine (8, 10, 26, 29, 31). The cervical spontaneous spinal epidural hematomas (Patient 1) or pure localization such as the one described in our first case is intralesional hemorrhage (Patients 2 and 3). At the time of sur- extremely unusual, and only four cases have been reported gery, they presented with either acute or subacute evidence of previously (Table 1) (9, 15, 26, 29). An increased association bleeding. Because of the anatomic localization, two patients with cutaneous vascular nevi, absent in all of our cases, was presented with acute compression of the spinal cord, whereas reported (29). In our opinion, the specific epidural localization the sacral localization presented with acute sciatic nerve deficit. of cavernomas may be explained by the embryological devel- Our patient population may reflect a significant tertiary care opment of the dura mater; the vascular elements from the referral bias for these otherwise rare lesions. Therefore, it is primordial plexus may have some influence in the postnatal unlikely that this selected group reflects the natural history or development of a cavernomatous lesion (11). However, cav- clinical patterns of spinal epidural cavernomas in the general ernous malformations are not necessarily congenital, as some population. We hope this information will be clarified with fur- reports describe de novo cavernomatous lesions (3, 27). The ther clinical reports in the future. genetic factor is a well-known influence in these kinds of lesions (19). We have not encountered associated multiple, Neuroradiological Appearance cerebral, or de novo lesions, and we did not perform genetic MRI scans clearly reveal unruptured spinal epidural caver- studies on our patients. nomas as low-level intensity lesions on T1-weighted images and high-level intensity oval-shaped masses that enhance Clinical Findings homogenously after contrast injection on T2-weighted images Clinical presentation may be slow and insidious in non- (12, 13, 31). This pattern is also seen in intraorbital cavernomas, hemorrhagic cases (14, 15, 33). On the contrary, bleeding cav- whereas intra-axial lesions do not enhance homogenously (31). ernomas often have a dramatic presentation with acute pain Some reports describe an enlargement of the vertebral fora- and neurological deficit. Rarely, cavernous lesions may pres- men (14, 26, 30, 31), which make cavernomas difficult to differ- ent with an abrupt clinical onset after a physical effort, the so- entiate from neurinomas. Type 3 bleeding produces the typical called “spontaneous” spinal epidural hematomas (13). high-level intensity ring in intramedullary or intracerebral cav- However, at least three types of clinical presentations (33) ernomas on T2-weighted images. Although this hemosiderin have been described in most studies, including 1) an acute ring is not usually seen in epidural cavernomas, it may also intralesional bleed, 2) an acute extralesional bleed, and 3) a occur in these lesions primarily because they are histologically slow seepage of blood from the cavernous malformation. The identical to intramedullary cavernomas. In acute hemorrhagic third type of bleeding is thought to lead to myelopathy with cases, epidural bleeding is often the only finding. Spinal an insidious onset or progression of symptoms (5). The angiography is usually negative, but can be indicated if an arte- myelopathy seems to occur less frequently in lesions with riovenous malformation or dural fistula is suspected (22–24). epidural localizations. Certainly, the protective effect of the However, Lawton et al. (20) considered this association to be duramater and the cerebrospinal fluid may play a role in pre- exceedingly rare. In our practice, spinal angiography is not venting spinal cord damage. Nevertheless, our third patient performed in routine emergency cases. had a 1-year history of progressive gait disturbance and had undergone surgery for a lumbar stenosis and for a D12–L1 Surgical Considerations disk herniation 11 and 6 months earlier, respectively. Both Some reports about spinal intramedullary and extramedul- procedures were ineffective regarding his ability to walk. We lary cavernomas describe patients that presented to the ER may consider that he experienced chronic myelopathy, which after hemorrhage had occurred. Of the 60 cases of epidural became worse as a result of intralesional bleeding that cavernoma previously reported, none of the patients were occurred 2 days before admission to our department. In asymptomatic at presentation. Therefore, the published records intramedullary cavernomas, this typical course of progres- only provide enough data to make a conditional statement sive myelopathy followed by acute deterioration has been about patients who presented to the ER with acute bleeding. In properly reported (5). these cases, there is an absolute consensus that urgent spinal

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TABLE 2. Reported cases of spinal epidural cavernomas from Italy in the past 10 years Series (ref. no.) No. of patients Clinical presentation Localization (no.) Padolecchia et al., 1998 (25) 5 Low back pain and lumbar radiculopathy (lumbar), progressive Thoracic (3), lumbar (2) spinal cord impairment (thoracic) Padovani et al., 1997 (26) 2 Acute tetraparesis (cervical), progressive paraparesis (thoracic) Cervical (1), thoracic (1) Santoro et al., 2005 (30) 7 Chronic low back pain and lumbar radiculopathy (lumbar), Thoracic (1), lumbar (6) progressive spinal cord impairment (thoracic) Talacchi at al., 1999 (31) 5 Spastic paraparesis (4 patients), progressive paraplegia (1 patient) Thoracic (5) decompression and hemotoma should be evacuated to prevent with a strong predominance for thoracic lesions. One reported further neurological deficit (1, 2, 9, 26, 28). Recent reports rec- case is a subdural cavernoma (21). We do not have an explana- ommend conservative treatment only in patients with prompt tion for this apparent prevalence. Perhaps some Italian neuro- neurological recovery associated with radiological evidence surgical groups have a specific interest in cavernomas and revealing resolution of the lesion (9, 24). In these cases, subse- search systematically for the histological diagnosis, even in quent serial MRI scans or spinal angiography are needed to cases of spontaneous spinal epidural hematomas or in cases of diagnose cavernomatous lesions or other vascular malforma- progressive myelopathy with an unclear origin. In addition, tions (24). Even in cases of thin, incidental, spinal epidural these cases may be underreported in some other countries. hemorrhages, the eventual existence of these lesions should be Systematic and prospective evaluations, multicenter studies, thoroughly investigated because they may show progression and genetic analysis (19) from this specific population are and promote permanent neurological deficits for the well- needed to reach a final conclusion. known propensity of cavernomas to bleed again after the first hemorrhage (3, 27). CONCLUSIONS There is an inadequate amount of clinical information con- cerning non-acute cases and the presentation of incidental find- Patients who present with clinical and radiological evidence ings of spinal epidural cavernoma. We are not certain how of acute hemorrhage should undergo immediate spinal decom- common or severe myelopathy caused by blood seepage from pression to prevent further neurological deficits. Because cavernomas is, how long it takes to develop, and how common epidural cavernomas are easier to remove than intramedullary spontaneous recovery from small bleeds is. Diagnostic work- cavernomas, the decision to operate is warranted, even in up, including MRI scans, of the entire thoracic and cervical patients in whom these lesions are incidentally found or are spine in case of chronic myelopathy is needed to prevent pit- diagnosed after the imaging work-up of chronic myelopathy. falls such as those seen with our third patient. In cases of Multicenter studies and genetic analysis are needed to under- chronic myelopathy, it is well known that surgery is not cura- stand the high number of cases reported from Italy. tive but can arrest progression (5). Conversely, we think the neurological outcome, including recurrent pain after lesionec- REFERENCES tomy, is better for epidural than for intramedullary cavernomas 1. 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Pure spinal epidural cav- Am J Surg dural neoplasm: Report of two cases with recovery. 57:450–456, ernous hemangiomas are very rare. A review of the English-language 1942. 18. Kim LJ, Klopfenstein JD, Zabramski JM, Sonntag VK, Spetzler RF: Analysis of literature regarding spinal cavernomas performed in 2001 by Appiah pain resolution after surgical resection of intramedullary spinal cord cav- et al. (1) found 157 cases, 80 (51%) of which were extradural. The most ernous malformations. Neurosurgery 58:106–111, 2006. frequent clinical presentation of these lesions is a progressive and com- 19. Labauge P, Laberge S, Brunereau L, Levy C, Tournier-Lasserve E: Hereditary pressive myelopathy (2). Acute symptoms that are caused by sponta- cerebral cavernous angiomas: Clinical and genetic features in 57 French fam- neous hemorrhage in the spinal epidural space from cavernous ilies. Societe Francaise de Neurochirurgie. Lancet 352:1892–1897, 1998. angiomas are a rare entity. In reviewing the literature, this latter pres- 20. Lawton MT, Porter RW, Heiserman JE, Jacobowitz R, Sonntag VK, Dickman entation accounts for 11% of the spinal epidural cavernous heman- CA: Surgical management of spinal epidural hematoma: Relationship gioma cases, which is low in proportion compared with intra-axial between surgical timing and neurological outcome. J Neurosurg 83:1–7, 1995. 21. Mastronardi L, Frondizi D, Guiducci A, Nardi M, Maira G: Conus medullaris cavernous angiomas, which account for 8 to 50% (3). hematomyelia associated with an intradural-extramedullary cavernous Caruso et al. stress the possibility that an acute spinal cord or nerve angioma. Spinal Cord 37:68–70, 1999. root deficit may be related to bleeding of an epidural cavernoma of the 22. Muhonen MG, Piper JG, Moore SA, Menezes AH: Cervical epidural hema- spine. It is important to consider this possible diagnosis, particularly toma secondary to an extradural vascular malformation in an infant: Case when a cervical lesion provokes signs that are similar to subarachnoid report. Neurosurgery 36:585–588, 1995. hemorrhage (Patient 1), or when an acute dorsal syndrome (Patient 3) 23. Miyagi Y, Miyazono M, Kamikaseda K: Spinal epidural vascular malforma- or an acute radiculopathy (Patient 2) may simulate an acute disc her- tion presenting in association with a spontaneously resolved acute epidural niation. Interestingly, the authors underline a number of relevant cases hematoma. Case report. J Neurosurg 88:909–911, 1998. described by Italian authors. 24. Olivero WC, Hanigan WC, McCluney KW: Angiographic demonstration of spinal epidural arteriovenous malformation. Case report. J Neurosurg Giulio Maira 79:119–120, 1993. Rome, Italy 25. Padolecchia R, Acerbi G, Puglioli M, Collavoli PL, Ravelli V, Caciagli P: Epidural spinal cavernous hemangioma. Spine 23:1136–40, 1998. 26. Padovani R, Acciarri N, Giulioni M, Pantieri R, Foschini MP: Cavernous 1. Appiah GA, Knuckey NW, Robbins PD: Extradural spinal cavernous heman- angiomas of the spinal district: Surgical treatment of 11 patients. Eur Spine J gioma: Case report and review of the literature. J Clin Neurosci 8:176–179, 2001. 6:298–303, 1997. 2. Goyal A, Singh AK, Gupta V, Tatke M: Spinal epidural cavernous hemangioma: 27. Pozzati E, Acciarri N, Tognetti F, Marliani F, Giangaspero F: Growth, subse- A case report and review of the literature. Spinal Cord 40:200–202, 2002. quent bleeding, and de novo appearance of cerebral cavernous angiomas. 3. Talacchi A, Spinnato S, Alessandrini F, Iuzzolino P, Bricolo A: Radiologic and Neurosurgery 38:662–670, 1996. surgical aspects of pure spinal epidural cavernous angiomas. Report on 5 28. Rainov NG, Heidecke V, Burkert WL: Spinal epidural hematoma. Report of cases and review of the literature. Surg Neurol 52:198–203, 1999. a case and review of the literature. Neurosurg Rev 18:53–60, 1995. 29. Richardson RR, Cerullo LJ: Spinal epidural cavernous hemangioma. Surg Neurol 12:266-268, 1979 n this report, Caruso et al. present a series of three patients who 30. Santoro A, Piccirilli M, Bristot R, di Norcia V, Salvati M, Delfini R: Extradural Iexperienced the acute onset of pain and neurological deficit after spinal cavernous angiomas: Report of seven cases. Neurosurg Rev 28: hemorrhage of a dural-based cavernous angioma. At 9 to 12 months 313–319, 2005. after emergent surgical treatment, all three patients demonstrated 31. Talacchi A, Spinnato S, Alessandrini F, Iuzzolino P, Bricolo A: Radiologic and surgical aspects of pure spinal epidural cavernous angiomas. Report on 5 durable improvement. This case report reminds the reader that the cases and review of the literature. Surg Neurol 52:198–203, 1999. presence of a spontaneous spinal epidural hematoma should prompt 32. Wyburn-Mason R: Vascular Abnormalities and Tumors of the Spinal Cord and Its emergent surgical treatment and a thorough search for an underlying Membranes. London, Henri Kimpton, 1943, pp 1–5, 49–91. vascular lesion. 33. Zevgaridis D, Buttner A, Weis S, Hamburger C, Reulen HJ: Spinal epidural cavernous hemangiomas. Report of three cases and review of the literature. Christopher E. Wolfla J Neurosurg 88:903–908, 1998. Milwaukee, Wisconsin

COMMENTS aruso et al. present a retrospective series of three patients with Cspinal epidural cavernomas, all of whom presented to the emer- he authors report three cases of spontaneous extramedullary gency room with acute bleeding and were surgically treated. All Thematomas in the spinal canal owing to epidural cavernous patients improved after surgery, although neurological recovery was

E576 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com ACUTE PRESENTATION OF SPINAL EPIDURAL CAVERNOUS ANGIOMAS

incomplete in at least one patient. The longest follow-up period was the cavernoma is asymptomatic or minimally symptomatic. Studies 1 year; the shortest was 9 months. that compare the risks and benefits of conservative management and The authors present a balanced review of the epidural cavernoma lit- surgery for cavernomas in different locations (1) with different clinical erature, especially with regard to management. Cavernomas are low- presentations (2) in a robust, standardized manner are sorely missing. pressure vascular lesions that are distinctly different in structure and The authors make an interesting observation regarding the prepon- histologically and clinically different from more common central nerv- derance of epidural cavernoma cases reported from Italy. Whether or ous system aneurysms and arteriovenous malformations. Unlike these not the authors’ observation represents a true biological process or is a latter two lesions for which the role of surgery is clearly defined, the simple publication bias remains undetermined. role of surgery in cavernomas needs to be further elucidated. Siddharth Kharkar We do not know the risk of bleeding from central nervous system Daniele Rigamonti cavernomas or the factors that determine this risk with certainty. Baltimore, Maryland Interpretation of the available literature is complicated because of rela- tively small sample sizes, limited follow-up periods, and a significant publication bias; the overwhelming majority of reported cases are symp- 1. Deutsch H, Jallo GI, Faktorovich A, Epstein F: Spinal intramedullary caver- tomatic cavernomas that have been surgically managed. If we consider noma: Clinical presentation and surgical outcome. J Neurosurg 93 [Suppl our best estimates of the prevalence of brain cavernomas in the general 1]:65–70, 2000. population (0.4 to 0.5 %, or approximately 1.5 million people, in the 2. Kim LJ, Klopfenstein JD, Zabramski JM, Sonntag VK, Spetzler RF: Analysis of United States) (7, 8) and the prospectively calculated bleeding rates pain resolution after surgical resection of intramedullary spinal cord cav- from symptomatic patients (0.6 to 3.1 % per lesion/yr) (3, 5, 8), patients ernous malformations. Neurosurgery 58:106–111, 2006. presenting with intracranial bleeds from cavernomas should be a fre- 3. Kondziolka D, Lunsford LD, Kestle JR: The natural history of cerebral cav- ernous malformations. J Neurosurg 83:820–824, 1995. quent sight in emergency rooms. Obviously, this is not the case. This 4. McCormick PC, Michelsen WJ, Post KD, Carmel PW, Stein BM: Cavernous thought process inexorably leads to the question of whether or not we malformations of the spinal cord. Neurosurgery 23:459–463, 1988. are overestimating the risk of bleeding from cavernomas. 5. Moriarity JL, Wetzel M, Clatterbuck RE, Javedan S, Sheppard JM, Hoenig- As the authors correctly indicate, the decision to operate is easier to Rigamonti K, Crone NE, Breiter SN, Lee RR, Rigamonti D: The natural history make in cases of epidural cavernomas. As the lesions become more dif- of cavernous malformations: A prospective study of 68 patients. Neurosurgery ficult to resect, such as in intramedullary cavernomas or brainstem 44:1166–1173, 1999. cavernomas, the decision to operate becomes more difficult. Surgery for 6. Ogilvy CS, Louis DN, Ojemann RG: Intramedullary cavernous angiomas of the these lesions is not without risk and the benefit might be incomplete spinal cord: clinical presentation, pathological features, and surgical manage- and transient (1, 2). ment. Neurosurgery 31:219–230, 1992. 7. Otten P, Pizzolato GP, Rilliet B, Berney J: 131 cases of cavernous angioma (cav- Furthermore, spontaneous recovery, although temporary in most ernomas) of the CNS, discovered by retrospective analysis of 24,535 autopsies cases, has been documented after acute bleeding from cavernomas (4, [in French]. Neurochirurgie 35:82–83, 128–131, 1989. 6, 9). This could be possible because the low-pressure nature of caver- 8. Robinson JR, Awad IA, Little JR: Natural history of the cavernous angioma. nomas prevents catastrophic damage in at least some cases. J Neurosurg 75:709–714, 1991. Given this uncertainty, it is a difficult to decide between conservative 9. Zentner J, Hassler W, Gawehn J, Schroth G: Intramedullary cavernous management and surgery for the individual patient, especially when angiomas. Surg Neurol 31:64–68, 1989.

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ADJUNCTIVE RHEOLYTIC THROMBECTOMY FOR CENTRAL VENOUS SINUS THROMBOSIS: TECHNICAL CASE REPORT

Jacobo Kirsch, M.D. OBJECTIVE: Patients with dural sinus thrombosis occasionally present with a malig- Department of Neuroradiology, nant clinical course marked by parenchymal hemorrhage accompanied by either a The Cleveland Clinic Foundation, severe neurological deficit or a persistent deterioration on therapeutic levels of antithrom- Cleveland, Ohio botic medications. This scenario precludes traditional revascularization strategies with Peter A. Rasmussen, M.D. direct fibrinolytic infusion because of the risk of exacerbating the preexisting cerebral Department of Neurosurgery, hemorrhage. In the current series, we describe our experience using the AngioJet (Possis The Cleveland Clinic Foundation, Medical, Minneapolis, MN), a rheolytic mechanical thrombectomy device, in conjunc- Cleveland, Ohio tion with systemic heparinization to achieve rapid sinus revascularization without fib- rinolytic therapy. Thomas J. Masaryk, M.D. METHODS: A retrospective review of a prospectively maintained database identified Departments of Neuroradiology and Neurosurgery, four patients ranging in age from 28 to 67 years (three women, one man) with cerebral The Cleveland Clinic Foundation, venous thrombosis and rapidly deteriorating levels of consciousness who underwent Cleveland, Ohio transfemoral intravenous rheolytic thrombectomy using the AngioJet XMI and/or Xpeedior catheters (Possis Medical). The imaging features, treatment specifications, and disease John Perl II, M.D. outcome were reviewed. Department of Interventional Radiology, Abbott Northwestern Hospital, RESULTS: All four patients underwent successful mechanical thrombectomy as indi- Minneapolis, Minnesota cated by restoration of blood flow through the affected sinuses. Three of the four patients demonstrated normalization of angiographic transit time after thrombectomy. In these David Fiorella, M.D. three patients, rapid neurological improvement ensued. The fourth patient died during Departments of Neuroradiology and the periprocedural period. No procedural complications were encountered. Neurosurgery, The Cleveland Clinic Foundation, CONCLUSION: Systemic heparinization with adjunctive rheolytic thrombectomy (with- Cleveland, Ohio out fibrinolytic therapy) is a safe and effective treatment strategy for selected patients with dural venous sinus thrombosis. Reprint requests: David Fiorella, M.D., KEY WORDS: Prognosis, Thrombectomy, Treatment, Venous sinus thrombosis Department of Neurosurgery, The Cleveland Clinic Foundation, Neurosurgery 60:E577–E578, 2007 DOI: 10.1227/01.NEU.0000255339.26027.68 www.neurosurgery-online.com 9500 Euclid Avenue, S80, Cleveland, OH 44195. Email: fi[email protected] erebral venous thrombosis (CVT) is an rhage, these patients may be treated with a Received, March 10, 2005. uncommon condition that is often chal- direct microcatheter infusion of fibrinolytic Accepted, October 18, 2006. Clenging to diagnose because of its vari- agents into the clot via a transfemoral transve- able clinical presentations and frequently sub- nous approach. However, existing data sug- tle imaging findings (1, 8, 15). If left untreated, gest that the risk-to-benefit profile of this this condition may result in uncontrolled cere- approach is unfavorable in the setting of bral venous hypertension, impaired cerebral intracranial hemorrhage (5). In addition, in perfusion, venous infarction with edema, cere- patients presenting with a precipitous neuro- bral hemorrhage, and death (1, 8, 15). logical deterioration, the time required for a If patients are neurologically stable, antico- fibrinolytic infusion alone to restore adequate agulation is the treatment of choice (1, 3, 8). venous outflow (24–48 h) is often unacceptable However, if patients demonstrate progressive (5). In these two categories of patients, sys- neurological deficits despite heparinization, temic heparinization with adjuvant rheolytic more aggressive treatment measures are thrombectomy represents a potentially supe- required. In the absence of intracranial hemor- rior strategy to achieve sinus recanalization. In

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the current case series, we report our experience using the In all patients, recanalization of the occluded sinus or sinuses AngioJet Rheolytic Thrombectomy System (Possis Medical, was achieved using the AngioJet rheolytic mechanical Minneapolis, MN) to restore venous sinus patency. thrombectomy device. Using mTIMI grades to quantify flow through the dural venous system, we measured all four patients PATIENTS AND METHODS as mTIMI 0 (no perfusion) in the affected sinuses (Table 2) before the procedure. The treated sinuses in all patients were restored This series represents a retrospective review of four consecu- to mTIMI 2 (partial reperfusion) by the end of the procedure. tive patients treated for CVT by mechanical thrombectomy. All Three of the four patients showed marked qualitative improve- patients and/or their families provided informed consent and ment in angiographic transit times after thrombectomy. These were monitored before and after their treatment in the neurolog- three patients improved after therapy and eventually returned ical intensive care unit (NICU). All patients received concomi- to their prethrombosis baseline. One patient (Patient 3) contin- tant intravenous (IV) heparin to achieve therapeutic anticoagu- ued to deteriorate after the procedure and subsequently died. lation (activated partial thromboplastin time, 50–70 s). There were no new cerebral hemorrhages or progressions of All patients underwent cerebral angiography and central existing cerebral hemorrhages after the procedures were per- venography with mechanical thrombectomy using the AngioJet formed. No procedural complications were encountered. Rheolytic Thrombectomy System. We used modified Thrombolysis in Myocardial Infarction (mTIMI) grades to quantify flow through the dural venous system. ILLUSTRATIVE CASES The AngioJet is a coaxial lumen guidewire-directed catheter with a 5-French outer diameter. Thrombectomy is accom- Patient 1 plished with the introduction of a pressurized saline jet stream A 38-year-old woman presented to an outside hospital with a 2-day through the directed orifices in the catheter distal tip. The jets history of worsening headache accompanied by vomiting, seizures, generate a localized low-pressure zone via the Bernoulli effect, and, ultimately, aphasia and an inability to walk. At presentation, com- which mechanically fractionates the thrombus. The saline and puted tomographic scans, magnetic resonance imaging (MRI) scans, and intracranial angiography were initially interpreted as negative. A thrombus are then suctioned back into the exhaust lumen of the magnetic resonance venogram (MRV) was then performed, which catheter and out of the body for disposal minimizing the risk demonstrated CVT of the superior sagittal sinus (SSS) and bilateral for pulmonary embolism. transverse sinuses. At this time, the patient was transferred to our insti- tution for further work-up and treatment. Upon arrival, she was stu- RESULTS porous with left hemiplegia. In addition to dural sinus thrombosis, noninvasive imaging also demonstrated bilateral pulmonary emboli Between November 2001 and July 2002, four patients (one and deep femoral vein thrombosis. man, three women; age range, 28–67 yr; mean age, 41 yr) pre- She was admitted on a heparin infusion and taken to the angiogra- senting to our institution with symptomatic dural venous sinus phy suite the next morning for diagnostic and therapeutic cerebral thrombosis (Table 1) underwent treatment with transvenous angiography, central venography, and mechanical thrombectomy. Angiography was performed after selective catheterization of both rheolytic thrombectomy. In three cases, sinus thrombosis was common carotid arteries. The bilateral angiographic transit time was complicated by parenchymal hemorrhage. All patients were markedly prolonged. Multiple tortuous cortical venous collaterals were fully heparinized on admission. Intervention was initiated identified draining from the frontal and anterior parietal regions into because of progression of symptoms on heparin (n ϭ 1) or a the cavernous sinus and retrograde through the superior ophthalmic malignant neurological presentation (n ϭ 3). No fibrinolytic veins. A deep and prolonged parenchymal blush was observed, consis- agents were used during endovascular intervention. tent with venous hypertension. A sinus venogram was then performed

TABLE 1. Patient presentationa Interval between GCS Indication Deficit Possible Patient Age presentation Presentation atHemorrhage for at associated no. (yr)/sex and presentation intervention follow-up condition treatment (d) 1 38/F 4 HA, SZ, mild aphasia, left 13 Yes Severe neurological None Oral contraceptives, hemiplegia, right hemiparesis deficit Factor V leiden 2 28/F 8 HA, SZ, anomic aphasia 14 Yes Deterioration on None Oral contraceptives antithrombotic therapy 3 30/M 0 LOC 3T Yes Severe neurological deficit Dead Ulcerative colitis 4 67/F 1 Coma 7 No Severe neurological deficit None Diabetic hyperosmolar coma

a GCS, Glasgow Coma Scale; HA, headache; SZ, seizure; LOC, loss of consciousness.

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A TABLE 2. Distribution of thrombosed sinusesa Patient no. Thrombosed sinuses 1 SSS 2 L-TSS L-IJ 3 SSS B-TSS B-IJ ICVs SS 4 SSS L-TSS

a SSS, superior sagittal sinus; L, left; TSS, transverse sigmoid sinus; IJ, internal jugular vein; B, bilateral; ICVs, internal cerebral veins; SS, straight sinus.

before the thrombectomy that demonstrated a multiseptated occlusion in the anterior half of the SSS with a widely patent posterior half B (Fig. 1A). The transverse sinuses were patent bilaterally at this point, in conflict with the preliminary MRV suggestion. After preprocedure images were obtained, an AngioJet XMI catheter was advanced to the level of the coronal suture until resistance was felt. The thrombectomy mechanism was activated and pulled through the thrombosed seg- ment. Post-thrombectomy angiography demonstrated an improved angiographic transit time with disappearance of the aberrant cortical venous collateral drainage into the cavernous sinus. Central venogra- phy demonstrated evacuation of thrombus from the SSS with improved contrast transit throughout the venous sinuses (Fig. 1B). A simultane- ous pulmonary angiogram was performed at the time of the interven- tion, which demonstrated bilateral pulmonary emboli. The patient tol- erated the procedure well and was taken to the NICU on a continued heparin infusion. She was extubated on postprocedure Day 3 and was oriented and following commands. Her motor function continued to improve and she was discharged home on postprocedure Day 9 after conversion to oral Coumadin (DuPont Pharmaceuticals, Wilmington, DE). Laboratory evaluations demonstrated the patient to be heterozygous for Factor V leiden. In addition, at the time of the event, the patient was FIGURE 1. A, central venogram performed through a microcatheter positioned taking oral contraceptives. At the time of the 6-month follow-up exam- within the anterior third of the SSS demonstrating near complete sinus occlu- ination, the patient had made a complete neurological recovery with- sion with a tiny amount of contrast streaming around a large lucent filling out recurrence of symptoms. defect (double arrows) within the anterior aspect of the sinus. There is also ret- rograde cortical venous drainage over the frontal lobes (arrow). B, after rhe- Patient 2 olytic thrombectomy, the thrombus within the anterior sinus was almost com- A 28-year-old woman presented with a 2-day history of headache, pletely evacuated. The anterior sinus filled with contrast, which rapidly flowed which progressed to confusion and speech arrest. She was taken to an antegrade into the transverse-sigmoid system. No cortical venous reflux was outside hospital, where she developed a tonicoclonic seizure. A com- observed after thrombectomy. Right common carotid angiography performed puted tomographic scan demonstrated a small acute parenchymal after thrombectomy also demonstrated a marked improvement in the angio- hemorrhage in the posterior left temporal lobe and marked edema graphic transit time. within the left temporo-occipital lobe. She was then transferred to our institution for further management. Upon arrival, she was confused and somnolent, obeying commands intermittently. An MRI scan and Coumadin, she developed a sudden onset of severe headache. MRV were performed, confirming the diagnosis of thrombosis of the Computed tomographic scans, MRI scans, and MRV were performed left transverse sinus, left sigmoid sinus, and proximal left internal jugu- and demonstrated an increase in the volume of the left temporal lobe lar vein, with venous infarction involving the left temporal and parietal hematoma and the surrounding vasogenic edema (Fig. 2, A and B). lobes, as well as associated hemorrhage involving the medial left tem- The patient was taken to the angiography suite for digital subtraction poral lobe. angiography and mechanical thrombectomy. The patient was admitted to the NICU and placed on IV heparin. On Digital subtraction angiography demonstrated a prolonged her sixth day of hospitalization, and while being converted to parenchymal phase and angiographic transit time. Venous drainage

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ABCD

EFGH

FIGURE 2. A, axial fluid attenuation inversion recovery MRI scan demon- microcatheter positioned within the torcula demonstrating venous drainage strating hemorrhage and edema distributed throughout the left temporal lobe. only through the right transverse-sigmoid system. F, cerebral angiography B, reconstructed maximal intensity projection of the two-dimensional MRV performed through a catheter positioned within the left internal carotid artery source data depicting complete occlusion of the left transverse sigmoid system. after successful rheolytic thrombectomy depicting restored patency of the left Hyperintensity within the region of the left temporal lobe represents ”shine- transverse sigmoid system. With the restoration of venous outflow, the angio- through” from the large T1-weighted hyperintense hematoma. C, venous graphic transit time returned to normal. Fewer large cortical veins persist phase of an angiogram performed from a catheter positioned within the left into the late venous phase when compared with the prethrombectomy internal carotid artery demonstrating complete occlusion of the left angiogram (C). G, central venogram from a microcatheter positioned within transverse-sigmoid system (arrows). Prolonged and intense cortical venous the left mid-transverse sinus confirming sinus patency with a residual filling opacification is evident over the left cerebral hemisphere. D, venogram per- defect within the inferior aspect of the distal transverse sinus and torcula. H, formed through an 8-French guiding sheath positioned within the left inter- axial fluid attenuation inversion recovery image from a 3-month follow-up nal jugular vein demonstrating a large, irregular thrombus extending into the MRI scan demonstrating complete resolution of hemorrhage and edema jugular bulb and distal jugular vein. E, venogram performed through a within the left temporal lobe. was exclusively through the SSS and right transverse-sigmoid system She was converted to oral Coumadin therapy and discharged from (Fig. 2C). Central venography performed before the thrombectomy, the hospital 6 days after the procedure was performed. At the time of demonstrated occlusion of the left transverse-sigmoid system and jugu- her discharge, she was neurologically intact, with the exception of sub- lar vein (Fig. 2, D and E). An AngioJet XMI catheter was advanced to tle cognitive impairment manifest as occasional difficulty with calcula- the level of the torcula, the thrombectomy mechanism was activated, tions and word finding. At the time of the 1-month follow-up examina- and the catheter was pulled through the thrombosed segments of the tion, she had returned to her neurological baseline and was free of transverse-sigmoid system to the internal jugular vein, resulting in seizures. Follow-up MRI scans obtained at 3 months after the proce- partial recanalization. The XMI thrombectomy catheter was exchanged dure demonstrated resolution of right temporal lobe edema and hem- for an AngioJet Xpeedior thrombectomy catheter which was used to orrhage with minimal encephalomalacia (Fig. 2H) complete the thrombectomy of the jugular bulb and sigmoid sinus. Post-thrombectomy angiography demonstrated an improvement in transit time and patency of the transverse-sigmoid systems bilaterally DISCUSSION (Fig. 2F). Central venography confirmed partial recanalization of the Treatment of Sinus Thrombosis left transverse-sigmoid with antegrade flow through to the jugular vein (Fig. 2G). The patient tolerated the procedure well and was taken Anticoagulation with heparin is the treatment of choice for to the NICU for recovery and maintained on a heparin infusion. the vast majority of patients with central venous sinus throm-

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bosis (Fig. 3). In a small, randomized trial comparing IV tion of the AngioJet rheolytic thrombectomy catheter with heparin therapy with placebo, the beneficial effects of heparin direct microcatheter thrombolysis has been used for the treat- were so profound that the study was terminated early. Heparin ment of dural sinus thrombosis, resulting in an accelerated not only improved the odds of achieving a full neurological recanalization of the occluded sinuses and cerebral veins (2, 4, recovery, but also reduced the risk of death (8). A second trial 10, 12). The mechanical evacuation of thrombus from the evaluating the efficacy of low molecular weight heparin sinuses not only decreases the overall clot burden that must demonstrated a trend toward improved outcome and reduced be lysed, but also restores venous flow, overcoming the pro- parenchymal hemorrhage. However, neither end point reached coagulant environment perpetuated by venous stasis. Despite statistical significance (3). Frey et al. (5) reported the successful the practical benefits of this therapeutic strategy, the concomi- restoration of flow in nine out of 12 patients after direct tant usage of fibrinolytic agents raises serious questions intrathrombus infusion of tissue plasminogen activator (tPA) in regarding the safety of this strategy in patients presenting combination with IV heparin. However, in the three patients in with parenchymal hemorrhage. In one report of two cases, the whom flow was not restored, two demonstrated worsening of operators observed an increase in parenchymal hemorrhage parenchymal hemorrhage. Frey et al. (5) concluded that direct and intraventricular hemorrhage despite successful rheolytic tPA infusion may be unsafe in patients with overt parenchymal thrombectomy achieved with adjunctive intra-arterial tPA and hemorrhage on imaging. Thus, in patients presenting with heparin (2). treatable headache alone or patients with stable focal neurolog- In the current series, three of the four patients treated with ical symptoms and hemorrhage, IV heparin represents the best systemic heparinization and adjuvant mechanical rheolytic available first-line therapy. thrombectomy had excellent angiographic and clinical out- Patients with progressive neurological symptoms despite comes. In these patients, the restoration of flow within the dural adequate anticoagulation, those who present with a precipi- venous sinuses produced an immediate improvement in angio- tous neurological deterioration, and those who present with graphic transit time, despite the presence of some residual refractory headache without hemorrhage do not fit into the above treatment algorithm. In this relatively uncommon PRESENTATION subset of CVT patients, a more aggressive strategy of endovascular intervention is warranted to restore sinus patency. In the absence of hemorrhage, these patients Stable Mild Progression of are generally treated with Neurological Severe Neurological transfemoral direct intra- Symptoms Neurological Symptoms thrombus tPA infusion ther- (e.g., Headache) Symptoms on Heparin apy. However, if the presenta- +/– hemorrhage Therapy tion of these patients is complicated by hemorrhage or if the neurological decline is precipitous, tPA infusion therapy becomes a less favor- IV heparin Parenchymal able option because of the risk (peripheral) Hemorrhage of exacerbating the underly- ing hemorrhage as well as the prolonged duration of ther- apy (24–48 h) that is often YES NO required to restore sinus patency. Central IV tPA Rheolytic (1–2mg/hr) + IV heparin The Role of the AngioJet Thrombolysis +/– rheolytic in Central Venous Sinus + IV heparin thrombolysis Thrombosis (if available)

Recently, there have been several case reports in the lit- FIGURE 3. Algorithm for the application of rheolytic thrombectomy in central venous sinus thrombosis. erature in which a combina-

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nonocclusive thrombus within the treated sinuses and cortical 2. Chow K, Gobin YP, Saver J, Kidwell C, Dong P, Viñuela F: Endovascular veins. The flow restoration and concomitant heparinization treatment of dural sinus thrombosis with rheolytic thrombectomy and intra- function not only prevent recurrent thrombosis, but also pro- arterial thrombolysis. Stroke 31:1420–1425, 2000. 3. deBrujin SF, Stam J: Randomized, placebo-controlled trial of anticoagulant mote an environment that allows the inherent physiological fib- treatment with low-molecular-weight heparin for cerebral sinus thrombosis. rinolytic mechanisms to restore full patency to the cortical veins Stroke 30:484–488, 1999. and venous sinuses. 4. Dowd CF, Malek AM, Phatouros CC, Hemphill JC 3rd: Application of a rhe- The patient who failed to improve (Patient 3) had a malig- olytic thrombectomy device in the treatment of dural sinus thrombosis: A new technique. AJNR Am J Neuroradiol 20:568–570, 1999. nant neurological presentation with thrombosis of all of the 5. Frey JL, Muro GJ, McDougall CG, Dean BL, Jahnke HK: Cerebral venous dural venous sinuses as well as the deep venous systems thrombosis: Combined intrathrombus rtPA and intravenous heparin. Stroke (Table 1). In this patient, a large volume of thrombus was dis- 30:489–494, 1999. tributed within the cortical veins and within the deep system 6. Kasirajan K, Gray B, Ouriel K: Percutaneous AngioJet thrombectomy in the and was, thereby, inaccessible to the AngioJet. Despite rheolytic management of extensive deep venous thrombosis. J Vasc Interv Radiol 12:179–185, 2001. evacuation of a large volume of thrombus from the dural 7. Kasirajan K, Gray B, Beavers FP, Clair DG, Greenberg R, Mascha E, Ouriel K: sinuses, the angiographic transit time failed to significantly Rheolytic thrombectomy in the management of acute and subacute limb- improve. In such patients who demonstrate no improvement in threatening ischemia. J Vasc Interv Radiol 12:413–421, 2001. angiographic transit time after rheolytic thrombectomy and are 8. Kimber J: Cerebral venous sinus thrombosis. QJM 95:137–142, 2002. 9. Kuntz RE, Baim DS, Cohen DJ, Popma JJ, Carrozza JP, Sharma S, McCormick clinically deteriorating on IV heparin therapy, the risks of a DJ, Schmidt, DA, Lansky AJ, Ho KK, Dandreo KJ, Setum CM, Ramee SR: A tPA infusion may outweigh the benefits. trial comparing rheolytic thrombectomy with intracoronary urokinase for coronary and vein graft thrombus (The Vein Graft AngioJet Study [VeGAS 2]). Technical Considerations Am J Cardiol 89:326–330, 2002. 10. Opatowsky MJ, Morris PP, Regan JD, Mewborn JD, Wilson JA: Rapid The AngioJet device uses high-velocity saline jets to create a thrombectomy of superior sagittal sinus and transverse sinus thrombosis Bernoulli effect to remove the thrombus. It has been demon- with a rheolytic catheter device. AJNR Am J Neuroradiol 20:414–417, 1999. strated to be minimally traumatic to vascular endothelia. 11. Rinfret S, Katsiyiannis PT, Ho KK, Cohen DJ, Baim DS, Carrozza JP, Laham Additionally, the venous sinuses are surrounded by resistant RJ: Effectiveness of rheolytic coronary thrombectomy with the AngioJet dura mater, which makes the procedure safer. On the other catheter. Am J Cardiol 90:470–476, 2002. 12. Scarrow AM, Williams RL, Jungreis CA, Yonas H, Scarrow MR: Removal of hand, limitations of the use of the catheter include its size and a thrombus from the sigmoid and transverse sinuses with a rheolytic rigidity, which make it difficult to negotiate within the intracra- thrombectomy catheter. AJNR Am J Neuroradiol 20:1467–1469, 1999. nial circulation. 13. Singh M, Tiede DJ, Mathew V, Garratt KN, Lennon RJ, Holmes DR Jr, Rihal Several studies have demonstrated procedural success with CS. Rheolytic thrombectomy with AngioJet in thrombus-containing lesions. Catheter Cardiovasc Interv 56:1–7, 2002. the rheolytic thrombectomy catheter in patients presenting 14. Topaz O, Perin EC, Jesse RL, Mohanty PK, Carr M Jr, Rosenschein U: Power with acute myocardial infarction for thrombus-containing coro- thrombectomy in acute ischemic coronary syndromes. Angiology 54:457–468, nary lesions, extensive deep venous thrombosis, acute limb- 2003. threatening ischemia, and thrombosed grafts in hemodialysis 15. Zhang Z, Long J, LI W: Cerebral venous sinus thrombosis: A clinical study of patients (6, 7, 9, 11, 13, 14). Disadvantages of the AngioJet sys- 23 cases. Chinese Med J (Engl) 113:1043–1045, 2000. tem include the cost of the equipment and the risk of hemoly- Acknowledgments sis and fluid overload (6). This study was previously presented as a poster at the 2003 Joint Annual Meeting of the AANS/CNS Section on Cerebrovascular Surgery and the CONCLUSIONS American Society of Interventional and Therapeutic Neuroradiology.

The current series demonstrates that revascularization of COMMENTS occluded dural venous sinuses with AngioJet rheolytic thrombectomy and IV heparin therapy is an effective treatment he authors used mechanical thrombectomy/thrombolysis catheters for central venous sinus thrombosis in selected patients. The Tto achieve impressive recanalization of thrombosed dural sinuses in adjunctive application of the Angiojet decreases the overall clot four patients. A positive clinical outcome was obtained in three of the burden and restores flow, thereby establishing an environment four patients. that promotes physiological fibrinolytic activity and the Dural sinus thrombosis occurs most commonly in young women reestablishment of cerebral venous patency. This strategy is and is frequently associated with pregnancy, the postpartum period, particularly useful in neurologically unstable CVT patients pre- and the use of oral contraceptives. However, numerous other predis- posing factors exist. Genetic coagulation factor abnormalities, such as senting with intracranial hemorrhage, a scenario in which other Factor V leiden, protein C, protein S, and antithrombin 3, must be endovascular treatments have an adverse risk profile and take excluded. The diagnosis of dural sinus thrombosis continues to be longer to work. missed regularly. An excellent, large case series was previously reported in Neurosurgery (10), and I recommend that the interested REFERENCES reader review it. When diagnosing a patient, one should always remember to examine the missed areas on cranial computed tomo- 1. Bousser MG: Cerebral venous thrombosis: Nothing, heparin, or local throm- graphic or magnetic resonance imaging scans, including the orbits, the bolysis? Stroke 30:481–483, 1999. dural and air sinuses, and the foramen magnum (the edges of the film).

E578 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com RHEOLYTIC THROMBECTOMY FOR CENTRAL VENOUS SINUS THROMBOSIS

In the English-language literature, I found 18 cases of mechanical entral venous sinus thrombosis (CVST) is a rare condition that thrombectomy for dural sinus thrombosis (1, 3, 4, 6, 7, 9, 10). There Ccan present with venous hypertension, venous infarction, are several reported cases in which mechanical thrombectomy was parenchymal hemorrhage, severe neurological deficits, and a malig- performed by inserting the catheter directly into the sinus via a cra- nant course. Anticoagulation with heparin is the standard treatment nial burr hole (2). The female-to-male ratio is more than 3:1; the aver- for most patients with CVST, even those with hemorrhage and mild age age at onset is approximately 38 years. Clinical presentation var- focal neurological deficits. Fibrinolytic agents, such as tissue plas- ied, but there were common symptoms and signs of seizures, minogen activator, can be infused directly into the thrombus; how- including headache, focal neurological deficits, and, in some cases, ever, these agents must be administered slowly and are contraindi- decreased or deteriorating levels of consciousness. Thrombosis of cated with parenchymal hemorrhage. Rheolytic mechanical the superior sagittal sinus was always present, as was thrombosis of thrombectomy with the AngioJet (Possis Medical, Minneapolis, MN) other sinuses, most commonly one or both transverse sinuses, the is an alternative to fibrinolytics in some cases of progressive deterio- sigmoid sinus, and the straight sinus. Remarkably good outcomes ration with hemorrhage or precipitous deterioration. The AngioJet were achieved; 14 of the patients reported in the literature had good avoids fibrinolytics, lowers clot volume, and can restore blood flow in outcomes, two had moderate disability, one had severe disability, the occluded sinus. The favorable clinical results observed by the and there was one death. authors in three of their four patients demonstrates its efficacy; how- The authors present a reasonable algorithm for the treatment of ever, the less favorable case indicates that there is more to treating patients with dural sinus thrombosis. The standard treatment is antico- CVST than simply re-establishing venous flow. The device itself is agulation, the use of which was supported by a Cochrane review (11). large, stiff, and not easily maneuvered; however, it remains a useful Direct infusion of thrombolytic agents or mechanical dissolution of the tool in the management of this difficult disease. thrombi are generally used in the subset of patients who are deteriorat- Michael T. Lawton ing despite anticoagulation; the former is used if there is no intracranial San Francisco, California hemorrhage. Another Cochrane review of thrombolytic drugs for dural sinus thrombosis found no Level 1 evidence to support the use of these drugs and suggested performing a randomized trial, which would be irsch et al. describe their experience using the AngioJet device for a difficult undertaking for such a rare disease (5). Devices are improv- Kmechanical thrombectomy for central venous sinus thrombosis in ing and changing, and new drugs, such as the platelet G2b/3a recep- four patients. There is no question that the outcome can be quite disas- tor inhibitors, are being developed (8). Series of patients should con- trous when this syndrome behaves in a malignant fashion. With the tinue to be reported as they will provide the best evidence for treatment advent of intravenous thrombolytics delivered systemically and of these cases. endovascularly, the hemorrhagic conversion rate seems to be quite problematic. This device obviates the need for additional thrombolyt- R. Loch Macdonald ics but uses systemic heparinization. Unfortunately, this device is rigid Chicago, Illinois and stiff, which is a technical problem that can be resolved. I think this device has significant utility in this regard; the authors’ experience indicates that it is very effective when used to treat CVST. One of the 1. Baker MD, Opatowsky MJ, Wilson JA, Glazier SS, Morris PP: Rheolytic most compelling reasons to use this device is that it obviates the need catheter and thrombolysis of dural venous sinus thrombosis: A case series. for urokinase or 2B3A inhibitors, which carry a significant hemorrhagic Neurosurgery 48:487–494, 2001. complication rate for venous infarction. 2. Chahlavi A, Steinmetz MP, Masaryk TJ, Rasmussen PA: A transcranial approach for direct mechanical thrombectomy of dural sinus thrombosis. Robert H. Rosenwasser Report of two cases. J Neurosurg 101:347–351, 2004. Philadelphia, Pennsylvania 3. Chaloupka JC, Mangla S, Huddle DC: Use of mechanical thrombolysis via microballoon percutaneous transluminal angioplasty for the treatment of acute dural sinus thrombosis: Case presentation and technical report. n a landmark, randomized placebo-controlled study published in Neurosurgery 45:650–657, 1999. IThe Lancet in 1991, Einhaupl et al. (5) demonstrated that heparin 4. Chow K, Gobin YP, Saver J, Kidwell C, Dong P, Viñuela F: Endovascular therapy was greatly superior to placebo for the treatment of CVST. treatment of dural sinus thrombosis with rheolytic thrombectomy and intra- Despite the inclusion of just 20 patients, the statistical benefit was so arterial thrombolysis. Stroke 31:1420–1425, 2000. profound that the trial was stopped early. A retrospective review of 5. Ciccone A, Canhao P, Falcao F, Ferro JM, Sterzi R: Thrombolysis for cerebral vein that data, focusing on heparin therapy in patients with intracerebral and dural sinus thrombosis. Cochrane Database Syst Rev CD003693, 2004. 6. Dowd CF, Malek AM, Phatouros CC, Hemphill JC 3rd: Application of a rhe- hemorrhage, also demonstrated a clear statistical benefit (5). More olytic thrombectomy device in the treatment of dural sinus thrombosis: A recently, de Bruijn et al. (3), using fractionated heparin as a bridge to new technique. AJNR Am J Neuroradiol 20:568–570, 1999. warfarin therapy, were not able to statistically establish a benefit for 7. Opatowsky MJ, Morris PP, Regan JD, Mewborne JD, Wilson JA: Rapid low-molecular weight heparin (nadroparin) but did demonstrate that thrombectomy of superior sagittal sinus and transverse sinus thrombosis intracerebral hemorrhage should not be an exclusion factor. At most with a rheolytic catheter device. AJNR Am J Neuroradiol 20:414–417, 1999. centers that treat CVST, unfractionated heparin remains the first line 8. Qureshi AI, Luft AR, Sharma M, Guterman LR, Hopkins LN: Prevention and treatment of thromboembolic and ischemic complications associated with of treatment in patients with symptomatic CVST, even when hemor- endovascular procedures: Part 1—Pathophysiological and pharmacological rhage occurs. However, the question remains of how to treat those features. Neurosurgery 46:1344–1359, 2000. patients in whom heparin therapy fails. 9. Scarrow AM, Williams RL, Jungreis CA, Yonas H, Scarrow MR: Removal of Kirsh et al. present a series of four patients with CVST who have a thrombus from the sigmoid and transverse sinuses with a rheolytic experienced either precipitous decline while on heparin therapy or AJNR Am J Neuroradiol thrombectomy catheter. 20:1467–1469, 1999. severe neurological deficit unresponsive to heparin therapy and who 10. Soleau SW, Schmidt R, Stevens S, Osborn A, MacDonald JD: Extensive expe- rience with dural sinus thrombosis. Neurosurgery 52:534–544, 2003. underwent systemic heparinization and intrasinus rheolytic therapy. 11. Stam J, De Bruijn SF, DeVeber G: Anticoagulation for cerebral sinus thrombo- Excellent results were achieved in three of the four patients; one sis. Cochrane Database Syst Rev CD002005, 2002. patient who presented with a Glasgow Coma Scale score of 3 died.

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Three of the four patients experienced intracerebral hemorrhage. The 5. Einhaupl KM, Villringer A, Meister W, Mehraein S, Garner C, Pellkofer M, use of a rheolytic catheter for sinus thrombosis was initially reported Haberl RL, Pfister HW, Schmiedek P: Heparin treatment in sinus venous by Dowd et al. (4) in 1999. However, most authors have used the thrombosis. Lancet 338:597–600, 1991. technique in conjunction with thrombolytics (1, 2, 4). Kirsh et al. argue that their technique with heparin alone is safer and should be he authors describe the use of mechanical thrombectomy using the the standard of care. It is likely that there will never be a large enough TAngioJet Rheolytic Thrombectomy System in four patients with number of patients with CVST in whom heparin therapy fails and dural venous sinus thrombosis who presented with either severe neu- ϭ ϭ interventional techniques are required to perform a randomized trial rological deficits (n 3) or deterioration (n 1) despite anticoagula- to determine the safety and efficacy of rheolysis with or without tion. The authors were able to achieve partial reperfusion in all patients thrombolytics. It is easy to find successful cases of rheolysis and with no procedural complications. The results were excellent, with thrombolytics (1, 2, 4). However, if Grade 2 Thrombolysis in three out of four patients showing marked improvement; the fourth Myocardial Infarction flow is established with rheolysis, it is useful to patient continued to deteriorate and subsequently died. know that heparin alone can be efficacious. The authors then describe the role of this device in the treatment of Finally, in the second case presented, the patient developed a severe CVST as follows: 1) for stable patients with no intraparenchymal hem- headache. It is reported that noninvasive imaging demonstrated an orrhage, heparin should be administered; 2) for progressive patients increase in the volume of the left temporal lobe hematoma and the sur- with no intraparenchymal hemorrhage, antithrombolytic therapy rounding vasogenic edema. The patient was taken to the angiography should be administered; and 3) for progressive patients with intra- suite for digital subtraction angiography and mechanical thrombec- parenchymal hemorrhage, mechanical thrombolysis with AngioJet tomy. In most neurosurgical environments, this situation portends going therapy should be administered. to the operating room. Figure 2A demonstrates left uncal herniation sec- The results reported by Kirsch et al. are comparable to those of the ondary to the hematoma and surrounding edema. Remarkably, how- International Study on Cerebral Vein and Dural Sinus Thrombosis (1), ever, this patient had a good outcome. In the setting of sinus thrombo- in which 79% of 624 patients recovered and 8% died after various treat- sis, the venous edema clearly surpassed the hemorrhage. By achieving ments, including anticoagulation in 83% of patients. Given the excellent a Grade 2 thrombolysis in myocardial infarction flow, the authors pre- results of this small study, one could ask the following questions: 1) vented further herniation. In a conscious patient with a headache, this wouldn’t patients with major venous sinus thrombosis, even if they is a more feasible and, most likely, superior strategy than the operative were doing reasonably well, be better off with restoration of sinus removal of the hematoma. However, in a patient with herniation, oper- flow?, 2) wouldn’t heparin be more effective and safer if venous hyper- ative evacuation and postoperative heparin therapy within 24 hours, tension were removed from the equation?, and 3) wouldn’t the rapid with or without rheolysis, may prove to be life saving. restoration of flow be superior to antithrombolytics and also have lower periprocedural hemorrhage risks? Robert D. Ecker If the device is used within a dural sinus, its safety seems to be high. Okinawa, Japan Based on the outcomes described in this report, this technology could L. Nelson Hopkins conceivably be applied as the first-line treatment in patients who Buffalo, New York demonstrate progressive neurological deficits despite heparinization or those presenting with a precipitous neurological deterioration. Conversely, despite how promising the results seem, the small size of 1. Chow K, Gobin YP, Saver J, Kidwell C, Dong P, Viñuela F: Endovascular treat- this series prevents a meaningful statistical analysis and comparison ment of dural sinus thrombosis with rheolytic thrombectomy and intra-arte- with anticoagulation therapy alone. The authors should consider a rial thrombolysis. Stroke 31:1420–1425, 2000. future randomized trial with a larger cohort. 2. Curtin KR, Shaibani A, Resnick SA, Russell EJ, Simuni T: Rheolytic catheter thrombectomy, balloon angioplasty, and direct recombinant tissue plasmino- Rose Du gen activator thrombolysis of dural sinus thrombosis with preexisting hemor- Arthur L. Day rhagic infarctions. AJNR Am J Neuroradiol 25:1807–1811, 2004. Boston, Massachusetts 3. de Bruijn SF, Stam J: Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 30:484–488, 1999. 1. Ferro JM, Canhao P, Stam J, Bousser MG, Barinagarrementeria F; ISCVT 4. Dowd CF, Malek AM, Phatouros CC, Hemphill JC 3rd: Application of a rhe- Investigators: Prognosis of cerebral vein and dural sinus thrombosis: Results olytic thrombectomy device in the treatment of dural sinus thrombosis: A new of the International Study on Cerebral Vein and Dural Sinus Thrombosis technique. AJNR Am J Neuroradiol 20:568–570, 1999. (ISCVT). Stroke 35:664–670, 2004.

E578 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com TECHNICAL CASE REPORTS

HYPERBARIC OXYGEN IN THE TREATMENT OF A RADIOSURGICAL COMPLICATION: TECHNICAL CASE REPORT

Michael Lynn, M.D. OBJECTIVE: Hyperbaric oxygenation is a rarely used method of treatment for steroid- Department of Neurosurgery, refractory radiation-induced edema after stereotactic radiosurgery. We present its suc- University of Florida, cessful implementation for a radiosurgical complication after the treatment of a deep, Gainesville, Florida large arteriovenous malformation. We also review the literature on hyperbaric oxy- William A. Friedman, M.D. genation for radiation-induced complications. Department of Neurosurgery, CLINICAL PRESENTATION: A 25-year-old man underwent radiosurgical treatment University of Florida, for a large arteriovenous malformation. Three years later, substantially smaller remain- Gainesville, Florida ing nidus was retreated. Five months after that treatment, the patient developed edema Reprint requests: around the nidus and hemiparesis. This problem was refractory to high-dose steroids. William A. Friedman, M.D., INTERVENTION: The patient underwent a course of 25 hyperbaric oxygenation treat- P.O. Box 100265, MBI, Department of Neurosurgery, ments. Within 1 month, the edema and hemiparesis had improved, allowing steroids to University of Florida, be tapered. A follow-up examination 1 year later revealed complete thrombosis of the Gainesville, FL 32610. Email: [email protected]fl.edu arteriovenous malformation and minimal neurological deficit. CONCLUSION: This technical case report adds to the few studies in the literature sug- Received, August 14, 2006. gesting that hyperbaric oxygenation therapy, in conjunction with a slow steroid taper, Accepted, November 10, 2006. is a reasonable addition to the treatment armamentarium for radiation-induced cerebral edema associated with clinically evident neurological deficits. KEY WORDS: Arteriovenous malformation, Hyperbaric oxygen, Radiosurgery

Neurosurgery 60:E579, 2007 DOI: 10.1227/01.NEU.0000255343.41206.6F www.neurosurgery-online.com

urgical excision, endovascular embolization, stereotactic for evaluation of an AVM. He presented with intermittent bilat- radiosurgery, or a combination of all three modalities are eral hand tremors, frequent “sinus headaches,” and trouble Swell-established treatment options for cerebral arteriovas- with his memory. The patient did not have a significant med- cular malformations (AVMs) (14). The morbidity of open surgi- ical history, and the results of his neurological examination cal techniques is higher for deep AVMs located in eloquent were entirely normal. Computed tomographic (CT) scans brain. Radiosurgery may be a particularly attractive option for (Fig. 1) and angiography (Fig. 2, A and B) revealed a Spetzler- such lesions (6). Martin Grade IV AVM (17). The nidus was 4 cm in maximal Causes of postradiosurgery deficits have been well docu- diameter and was centered in the deep right hemisphere with mented. After stereotactic radiosurgery, patients are at contin- partial drainage to the right internal cerebral vein. ued risk for hemorrhage and a small percentage experience The patient underwent stereotactic radiosurgery using the radiation-induced brain injury (16). This case report reviews University of Florida radiosurgical system (13). He received a the radiosurgical treatment of a young patient with a large, 1500 cGy dose to the 70% isodose line using eight isocenters. deep AVM complicated by symptomatic radiation-induced The 12-Gy volume treated was 56.5 cm3 and the treatment vol- edema. Resolution of his symptoms followed the introduction ume was 41.8 cm3. Magnetic resonance imaging (MRI) scans of of an infrequently used treatment method, hyperbaric oxygen. the brain revealed an approximate 50% reduction in the size of A review of the literature follows. the AVM at the 1-year follow-up examination; further reduction CASE REPORT was observed after 2 years. An MRI scan performed during the 3-year follow-up evalu- This 25-year-old man was referred to the Department of ation showed residual AVM. The patient underwent radiosur- Neurosurgery at the University of Florida, Gainesville, Florida gical retreatment (5, 7) 39 months after his first treatment

NEUROSURGERY VOLUME 60 | NUMBER 3 | MARCH 2007 | E579 SPECIAL TECHNIQUE APPLICATION

CYBERKNIFE TARGETING THE PTERYGOPALATINE GANGLION FOR THE TREATMENT OF CHRONIC CLUSTER HEADACHES

Shivanand P. Lad, M.D., Ph.D. OBJECTIVE: Cluster headache (CH) is a severe unilateral and periorbital facial pain Department of Neurosurgery, syndrome that is often associated with autonomic symptoms, including ipsilateral Stanford University lacrimation, nasal congestion, conjunctival injection, miosis, ptosis, and eyelid edema. School of Medicine, Stanford, California We evaluated the treatment of medically refractory CH with CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiosurgery targeting the pterygopalatine ganglion. John D. Lipani, M.D., Ph.D. CLINICAL PRESENTATION: A 56-year-old man presented with a 20-year history of med- Department of Neurosurgery, ically refractory CH. His symptoms were described as left-sided, severe, stabbing, burn- Stanford University School of Medicine, ing, and often being associated with tearing and rhinorrhea. These headaches occurred Stanford, California virtually every morning and interfered with sleep, lifestyle, and work performance. INTERVENTION: The patient underwent two pterygopalatine nerve block trials, both Iris C. Gibbs, M.D. of which resulted in the complete relief of headaches for a 24-hour period. Contrast- Department of Radiation Oncology, enhanced computed axial tomography and magnetic resonance imaging scans were Standford University School of Medicine, fused for target identification and treatment planning. The target volume measured Stanford, California 0.296 cm3 and a single fraction of 45.50 Gy was delivered to the 78% isodose line with a maximum dose of 65 Gy. The patient kept a detailed diary of his headaches and was Steven D. Chang, M.D. followed for 12 months after treatment. Department of Neurosurgery, CONCLUSION: Results of CyberKnife targeting of the pterygopalatine ganglion in a Stanford University School of Medicine, patient with medically intractable CHs have revealed a significant decrease in the Stanford, California severity and frequency of headaches after a 12-month follow-up period. In addition, the patient has been able to reduce his medication intake, allowing for a significant John R. Adler, Jr., M.D. decrease in medication-related side effects. Longer follow-up periods and additional Department of Neurosurgery, studies are required to determine the long-term efficacy and late side effects of this Stanford University School of Medicine, treatment strategy. Stanford, California KEY WORDS: Cluster headache, CyberKnife, Neurosurgery, Pterygopalatine, Radiosurgery, Sphenopalatine

Jaimie M. Henderson, M.D. Neurosurgery 60:E580–E581, 2007 DOI: 10.1227/01.NEU.0000255348.33582.DE www.neurosurgery-online.com Department of Neurosurgery, Stanford University School of Medicine, Stanford, California luster headache (CH) is a severe facial (9, 14, 18, 38, 43, 51). The pathophysiology of pain syndrome characterized by unilat- CH is complex and has only recently started to Reprint requests: eral episodic attacks located around the become better understood. When CH is refrac- Shivanand P. Lad, M.D., PhD., C eyes and forehead (9, 14, 18, 38, 43, 51). These tive to medical therapy, alternative treatment Department of Neurosurgery, Stanford University Medical Center, attacks are often accompanied by ipsilateral options have involved trigeminal nerve lesion- 300 Pasteur Drive, autonomic symptoms, including ptosis, mio- ing by surgical sectioning (20, 22, 35), radiofre- Edwards Building, Room R-297, sis, lacrimation, conjunctival injection, rhinor- quency ablation (36, 44, 55), glycerol injections Stanford, CA 94305. rhea, and nasal congestion. These autonomic (11, 19, 42, 46, 58), various nerve blocks, (2, 45, Email: [email protected] phenomena suggest parasympathetic hyperac- 49, 53), and radiosurgery (10, 15, 48). However, tivity and/or sympathetic dysfunction. When these treatment options carry a significant risk Received, June 1, 2006. left untreated, the pain may last from 15 min- of complications that result from trigeminal Accepted, November 7, 2006. utes to 3 hours and can occur from one time denervation. In addition, based on growing every other day to every few hours in a single knowledge and increased understanding of day. The pain has been described as excruciat- CH pathophysiology, the pterygopalatine gan- ing and sometimes results in suicidal thoughts glion (8, 41, 50, 52) and hypothalamic posterior

NEUROSURGERY VOLUME 60 | NUMBER 3 | MARCH 2007 | E580 LAD ET AL.

inferior gray matter (24, 27, 29, 33, 40) have been more recent the superior, posterior portion of the pterygopalatine fossa targets. In this study, we targeted the pterygopalatine (5, 8, 21, 44, 52). Our approach was to target the area of the (sphenopalatine) ganglion using stereotactic radiosurgery, pterygopalatine fossa in its entirety, sufficient to lesion the which we feel provides a less invasive, potentially more effec- ganglion with minimal side effects to surrounding structures. tive, and safer alternative to the traditional refractive CH treat- In our patient, the pterygopalatine fossa comprised a target ment strategies. volume measuring 0.296 cm3 with gross dimensions of 1.2 ϫ 0.9 ϫ 0.6 cm. The pterygopalatine fossa was identified History and its volume was contoured on each successive level at This patient is a 56-year-old man with a 20-year history of which it appeared. It was treated with 45.50 Gy delivered to CHs refractory to medical management. His headaches were the 78% percent isodose line using a 7.5-mm collimator. The described as left-sided, severe, stabbing, burning, and often maximum dose received at any point within the target vol- associated with tearing and rhinorrhea. Interfering with his ume was 65 Gy. Ninety-six percent of the target volume was sleep pattern, the headaches occurred every morning at treated at or above the reference dose with the 63% isodose approximately 4:00 AM. The headaches ranged from 30 min- line representing complete target volume coverage. The abil- utes to 2 hours in duration. In the past 20 years, the longest ity of the CyberKnife (Accuray, Inc., Sunnyvale, CA) to period of time during which the patient reported not having a deliver precision therapy is illustrated in Figure 1. headache was 2 days. His medications included methysergide and, subsequently, verapamil and lithium. Although these CyberKnife Radiosurgery Treatment Delivery additional medications helped reduce the severity of his The patient arrived for his single fraction radiosurgery treat- headaches, the frequency remained the same and the ment (1, 4). He was placed supine on the CyberKnife operating medication-induced side effects of lethargy, nausea, and table and his custom-made facemask and headrest were reap- tremor worsened. Computed tomographic (CT) and magnetic plied to ensure consistent stereotactic positioning. Using a set of resonance imaging (MRI) scans of the brain were unremark- dedicated alignment tools and then an x-ray-based localization able. The patient underwent two pterygopalatine nerve blocks, system, the patient’s head was registered within the coordinate each of which resulted in complete relief of headaches for a system of the CyberKnife. Once the position of the patient was 24-hour period. During this time, attempts to trigger the optimized, radiation delivery began in accordance with the headaches with alcohol were unsuccessful. Because the ptery- treatment plan detailed above. The patient tolerated the proce- gopalatine nerve blocks were successful, in addition to sup- dure well without any adverse reactions. He was given 4 mg of porting evidence found in a small number of previous studies Decadron (Merck & Co., Inc., Whitehouse Station, NJ) before (8, 41, 48, 50, 52), radiosurgical targeting of the pterygopalatine discharge and was asked to keep a detailed record of the fre- ganglion was considered to provide a safe and effective treat- quency and severity of his headaches. ment option. Posttreatment Course Intervention By 2 weeks posttreatment, the patient described a mild decrease in the frequency of his headaches; however, he still CyberKnife Pretreatment Planning Setup reported two significant headaches since his treatment. Within The patient was brought to the CT scanner and placed the first 2 months posttreatment, the patient reported a pain- supine on the treatment table. A custom Aquaplast mask (WFR free period of 16 days. He could not recall a time in the previ- Corp., Wyckoff, NJ) and Accuform headrest (Med-Tec, Dallas, ous 20 years when he did not have a headache for a similar TX) were constructed for the patient to ensure consistent length of time. Because he was headache-free, he discontinued stereotactic positioning throughout the treatment planning all of his CH medications. Unfortunately, he experienced what scans and radiosurgical procedures. A full series of 1.25-mm were most likely rebound headaches from the abrupt removal thick, contrast-enhanced axial CT scans of the head was of his medications. Therefore, he resumed his medications at obtained. The patient then underwent a 2-mm thick, doses that were half of his previously required doses. He then gadolinium-enhanced axial MRI scan of the head. After the described his headaches as mild with a significant reduction in imaging studies were complete, the patient’s intravenous drip both frequency and duration. was discontinued and he was discharged uneventfully. At the 4-, 6-, and 12-month follow-up visits, the patient con- tinued to report stable improvement of his headache symptoms. CyberKnife Treatment Planning He reported more than 50% reduction in both the frequency The full set of CT and MRI scans were fused and analyzed and severity of his symptoms and several week-long durations for target localization. The pterygopalatine ganglion is not of no pain. In addition, the patient has been able to reduce his visible on CT, MRI, or fused scans. However, the pterygopala- medication intake, allowing for a significant decrease in tine fossa is easily identified and can be readily targeted and medication-related side effects. The only reported side effect contoured for radiosurgery treatment planning (5, 8, 21, 44, was a V2 paresthesia at the lateral aspect of his left nostril. This 52). Although individual patient anatomy may vary slightly, occurred approximately 1 month after treatment and was anatomic studies illustrate that the ganglion generally lies in described as a minor annoyance.

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FIGURE 1. CyberKnife treatment planning summary. A contrast-enhanced axial gle fraction. The maximum dose received by any point within the target volume CT and an MRI scan were fused for identification of the pterygopalatine ganglion was 65 Gy. Ninety-six percent of the target volume was treated at or above the ref- target. The target volume encircling the left pterygopalatine fossa measured erence dose with the 63% isodose line representing complete target volume cover- 0.296cm3 with gross dimensions of 1.2 ϫ 0.9 ϫ 0.6 cm. A total peripheral dose of age. The patient’s treatment plan is shown in axial (upper left), coronal (lower 45.5 Gy was delivered to the 78% isodose line using a 7.5-mm collimator in a sin- left), sagittal (upper right) and three-dimensional (lower right) views.

DISCUSSION despite medical management (7). CH attacks may strike up to eight times per day and are characterized by transient, unilat- Clinical Features and Significance eral, severe orbitotemporal pain accompanied by ipsilateral CH is a severe, unilateral, periorbital, facial pain syndrome and autonomic symptoms. These symptoms include ptosis, that is often under diagnosed and suboptimally managed (9, miosis, lacrimation, conjunctival injection, rhinorrhea, and 14, 18, 38, 43, 51). Results of a recent quality of life study sug- nasal congestion, which suggest an etiology of parasympathetic gest that CH significantly impairs a person’s ability to function hyperactivity and/or sympathetic insufficiency (9, 17, 38, 39).

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factors may play a role in the incidence of CH (6, 31, 47, 54). Medical history often reveals a high incidence of head trauma with resulting brain concussion. However, proving a causal relationship between head trauma and CH is difficult (18). Interest- ingly, up to 85% of patients with chronic CH are also chronic cigarette smokers. Despite the possibility that chronic nicotine consump- tion may trigger the syn- drome in some patients (20, 34), cessation of smoking has, unfortunately, not proven to be effective in alleviating the symptoms of CH.

Pathophysiology Although the syndrome FIGURE 2. Schematic model showing putative pathways thought to be involved in CH. 1, pain afferents from the trigem- has been well defined from a inal nerve synapse on the trigeminocervical complex (TNC), which project to the thalamus and lead to activation of pain clinical view point, its patho- transmission. Reflex activation of parasympathetic outflow via the hypothalamus to the superior salivatory nucleus (SSN) physiology has not been well and through the pterygopalatine (sphenopalatine) ganglion (PPT) leads to the parasympathetic symptoms ipsilateral to understood until recently. the pain. 2, a sympathetic nerve defect, possibly by vascular changes in the cavernous sinus is thought to be responsible There are three major clinical for the partial Horner’s syndrome. 3, recent functional MRI and positron emission tomography studies suggest that the features that provide clues to posterior hypothalamic gray matter modulates by phase-shifting in the suprachiasmatic nuclei, which is an important key CH pathophysiology: 1) pain site in triggering pain and controlling the cycling aspects of the disorder. GG, geniculate ganglion; ICA, internal is localized to the ophthalmic carotid artery; SCG, superior cervical ganglion; SCN, suprachiasmatic nucleus. division of the trigeminal nerve with maximum pain Epidemiology, Genetics, and Risk Factors centered around the eye and forehead, 2) ipsilateral autonomic CH has an overall prevalence rate of 0.1 to 0.4% and an inci- features reflect parasympathetic hyperactivity and/or sympa- dence of 2.5 to 9.8% cases per 100,000 per year. In addition, CH thetic hypoactivity, and 3) the episodic and seasonal predilec- has a 6:1 male predominance, a mean age of onset of 30 years, tion of attacks indicate a dysfunctional central pacemaker, per- haps located within the suprachiasmatic nucleus of the and a seasonal predilection for spring and fall (9, 14, 39, 47). hypothalamus (Fig. 2) (9, 14, 18, 38, 43, 51). Chronic CH may arise de novo (primary chronic CH) or evolve The pterygopalatine ganglion is suspended from the V2 from episodic CH (secondary chronic CH). Chronic CH affects branch of the trigeminal nerve within the pterygopalatine 20% of all CH patients and is defined by attacks that last longer fossa. The ganglion receives parasympathetic input originating than 1 year without remissions or with remissions lasting less from the superior salivatory nucleus in the brainstem. than 1 month. The episodic form of CH is most common, affect- Parasympathetic fibers from the superior salivatory nucleus ing 80% of all CH patients. Episodic CH is characterized by two travel in the nervus intermedius, a component of the facial or more CHs separated by more than 1 month of remission, nerve, to the greater superficial petrosal nerve. These fibers are with remissions lasting months to years. Ten percent of joined by sympathetic fibers from the carotid plexus (deep pet- ϫ ∼ episodic CH patients (10 80 8%) develop secondary chronic rosal nerve) to form the vidian nerve of the pterygoid canal CH, with attacks that can persist for years (9, 14, 39, 47, 56). before entering the pterygopalatine ganglion. The pregan- Before 1990, CH was not generally thought to be an inherited glionic parasympathetic fibers synapse in the pterygopalatine disorder. However, recent reports have revealed an increased ganglion while the sympathetic fibers pass straight through. incidence of CH in monozygotic twins and a familial occur- Finally, the postganglionic parasympathetic fibers and the sym- rence in 7% of families. This results in a 14-fold increased risk pathetic fibers travel in branches of the trigeminal nerve to the of CH in first-degree relatives and a twofold increased risk for lacrimal gland for lacrimation and mucosa of the nose and second-degree relatives. These reports demonstrate that genetic mouth for secretion. Many observers think that the Horner’s

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TABLE 1. Historical surgical approaches for cluster headachesa Surgical approach Outcome Series (ref. no.) Complications of TN lesions TN sectioning Approximately 85% effective Jarrar et al., 2003 (20) and Transient: hyperacusis, tinnitus, with significant morbidities Kirkpatrick et al., 1993 (22) jaw deviation, difficulty TN radiofrequency rhizotomy Approximately 70% effective Onofrio and Campbell, 1986 (44) chewing, and ice-pick pain with 20% recurrence Permanent: facial anesthesia, TN glycerol rhizotomy Approximately 80% effective Pieper et al., 2000 (46) hypoesthesia, corneal with 40% recurrence anesthesia, anesthesia Gamma knife radiosurgery Ͼ50% effective with limited conflicting Donnet et al., 2005 (10) dolorosa to the TN results on morbidity and recurrence and Ford et al., 1998 (15)

a TN, trigeminal nerve. syndrome associated with CH occurs as the result of distention success. Furthermore, complications of trigeminal nerve dam- of the wall of the internal carotid artery in the carotid canal, age can be quite debilitating and, therefore, alternative thera- thus compressing the sympathetic plexus that invests the peutic strategies are required. carotid wall (5, 11–13, 17, 21, 38, 57). Other proposed surgical targets include the vagus and occip- The intimate relationship of the parasympathetic fibers, sym- ital nerves. Vagal nerve stimulation was studied in a trial with pathetic fibers, and trigeminal nerve indicate that irritation six CH patients, two of whom experienced dramatic improve- within the pterygopalatine ganglion may play a role in this ment with restoration of their ability to work and two others disease by mediating autonomic dysfunction and pain trans- who had improvement with their headaches (37). Occipital mission. However, the exact mechanism responsible for trigger- nerve blocks have been proposed to target the trigemino- ing these symptoms still remains unclear. For example, another cervical complex and have been used for CH with cervico- area of interest is the hypothalamus, which is thought to be occipital spreading as an abortive therapy (10, 15, 48). Most involved in mediating the episodic nature of the attacks seen in recently, hypothalamic deep brain stimulation has been shown CH (14, 29). Visual input from the retina travel to the suprachi- to be of benefit in relieving CH with good long-term follow-up asmatic nucleus in the hypothalamus and fibers from the hypo- results (24, 29, 33, 40, 59). thalamus travel in the dorsal longitudinal fasciculus to the brainstem where relay fibers in the reticular formation can Rationale for Targeting the Pterygopalatine Ganglion influence the superior salivatory nucleus. The question as to The classic association of autonomic dysfunction in CH is whether or not CH is centrally mediated or triggered by likely mediated by synapse activity within the pterygopala- peripheral relay mechanisms remains unanswered. tine ganglion. It is also thought that the Horner’s syndrome seen in CH is owing to sympathetic fibers that pass through Surgical and Radiosurgical Treatments for Refractory CH this ganglion. Because the pterygopalatine ganglion is sus- A number of surgical procedures have been used to treat pended from the maxillary nerve, one might expect CH pain refractory cases of CH. Many of these procedures have focused to follow a predominantly V2 distribution rather than V1. on the trigeminal nerve in an attempt to interrupt the transmis- One explanation for this might involve the existence of aber- sion of pain signals. The various treatment strategies, summa- rant trigeminal sensory transmission. Previous studies have rized in Table 1, include trigeminal nerve sectioning, glycerol shown that targeting the pterygopalatine ganglion can allevi- rhizotomy, radiofrequency rhizotomy, and gamma knife radio- ate the symptoms of CH while avoiding significant trigeminal surgery. Results reveal that severe damage to the trigeminal nerve dysfunction (8, 41, 50, 52). nerve, such as that caused by sectioning, alleviates pain while Sanders and Zuurmond (52) reported on a series of sacrificing nerve function (20, 22, 35). Percutaneous retrogasser- 66 patients with refractory CHs who were treated with ian glycerol rhizolysis (PRGR) (11, 19, 42, 46, 58) or percuta- radiofrequency blockade of the pterygopalatine ganglion. neous radiofrequency retrogasserian rhizotomy (PRFR) (36, 44, Of the patients presented, 56% reported complete relief of 55) produces mild to moderate injury to the nerve and offers symptoms, 26% reported partial pain relief, and 18% better preservation of nerve function. However, these proce- reported no pain relief. No long-term side effects were dures are also associated with a high rate of recurrence. Like reported (52). In addition, Devoghel (8) reported on the use trigeminal neuralgia, a 70 to 85 Gy dose of gamma knife radio- of alcohol injections to the sphenopalatine ganglion and surgery to the trigeminal nerve root entry zone has revealed observed an 85% rate of pain relief and parasympathetic dis- mixed results (10, 15, 48). Although CH pain is transmitted turbances in more than 120 patients with a follow-up dura- through the trigeminal nerve, it is unlikely that the pathophys- tion between 6 months and 4 years (8). iology of CH is solely owing to pathology within the nerve In another study, Pollock and Kondziolka (48) presented a itself. Consequently, targeting this nerve has resulted in limited case report in which stereotactic radiosurgery was used to

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treat sphenopalatine neuralgia (SN). Although distinguished parasympathetic hyperactivity, and hypothalamic overactivity. from CH, SN is characterized by similar clinical symptoms. Recent functional MRI and positron emission tomographic SN seems to be caused by irritation of the ganglion by infec- studies suggest that a key site in deep brain stimulation (DBS) tion and is associated with longer pain duration, inflamed for controlling the cyclical aspects of CH lies in the posterior nasal mucosa on the involved side, female predominance inferior hypothalamic gray matter region, modulated by phase- (2:1), and deformity or scarring (48). In their case report, a shifting in the suprachiasmatic nuclei. This has led to the intro- 70-year-old woman with a 15-year history of left SN under- duction of the posterior inferior hypothalamic gray matter as a went three lidocaine blocks of the pterygopalatine ganglion possible therapeutic target for DBS (3, 16, 23–26, 29, 30). Leone with good relief. This was followed by radiosurgery targeting et al. (24, 27–29) recently reported on a series of 16 patients the pterygopalatine ganglion with median and maximum with intractable chronic CH. Attacks reappear when the stim- radiation doses of 45 and 90 Gy, respectively. The patient was ulator is switched off and disappear when it is turned on again. pain-free for 8 months, but reported a 50% recurrence at Notably, it took several days or weeks between turning the 17 months. At this point, she was treated again with a maxi- stimulator on or off for change of the clinical picture indicating mum dose of 80 Gy to the ganglion target and remained pain- a possible delayed reprogramming effect. Of the 16 patients, 13 free with no associated morbidity at the time of her 7-month were persistently pain-free or almost pain-free, and the other follow-up examination (48). three were improved (24, 27–29). Like all surgical interventions, As discussed by Lim et al. (32), the median and maximum DBS is not without its own inherent risks, especially in the radiation doses used were 65.5 and 78 Gy, respectively, and hypothalamus, which include potential TIAs, brainstem hem- the median target volume measured 0.085 cm3 (range, orrhages, etc. However, several studies have shown good long- 0.04–0.8 cm3) for patients with trigeminal neuralgia who are term follow-up results and DBS represents a promising new treated with CyberKnife radiosurgery in a single session. therapy that will serve as an additional treatment approach to The segment of the nerve encompassed by the 79% isodose offer patients experiencing medically intractable, chronic CH. line averaged 7.2 mm in length (range, 5–12 mm) (32). The pterygopalatine ganglion is a significantly larger target volume (∼6X) compared with the typical 7 mm cisternal seg- CONCLUSION ment of nerve targeted in the trigeminal nerve, which used a The present study suggests that stereotactic radiosurgery tar- 3 target volume measuring 0.296 cm in our patient. Because the geting the pterygopalatine ganglion rather than the trigeminal optimal effective dose to the pterygopalatine ganglion for CH nerve may be an effective treatment option for patients experi- has yet to be determined, we devised a radiation dose plan encing chronic CH. With more than 1 year of follow-up evalua- based on our collective clinical experience and potential vol- tion, our patient continues to report stable improvement of his ume effects. Thus, we chose a dose of approximately 30% less headache symptoms with greater than 50% reduction in both the (median, 45.5 Gy; maximum, 60 Gy) than what is typically used frequency and severity of his symptoms and several week-long for trigeminal neuralgia and a similar peripheral dose as that stretches without any headaches at all. In addition, the patient reported by Pollock and Kondziolka (48). Given our goal of has been able to reduce his medication intake, allowing for a sig- conformal coverage of the entire ganglion and the inherent nificant decrease in medication-related side effects. More infor- homogeneity of CyberKnife radiosurgery, we chose not to mation is required concerning long-term efficacy, side effects, approach a higher maximum dose to minimize potential collat- and dosage planning when treating this debilitating disease. eral damage. Initial, conservative median and maximum doses of 45.5 and 60 Gy, respectively, were selected with the rationale Disclosure that additional treatments could be delivered at a later date John R. Adler, Jr., M.D., is a shareholder in and consultant for Accuray, Inc., the based on the patient’s treatment response. The maximum dose manufacturer of the CyberKnife Radiosurgical System. to the ipsilateral optic nerve was 1.19 Gy and the maximum dose to the chiasm was 2.15 Gy. These doses are well below the tolerance dose for these structures. There was minimal radiation REFERENCES to the eye itself, making the risk of xerophthalmia very low. 1. Adler JR Jr, Chang SD, Murphy MJ, Doty J, Geis P, Hancock SL: The Because of damage to postganglionic fibers innervating the Cyberknife: A frameless robotic system for radiosurgery. Stereotact Funct lacrimal gland, we recognized the potential risk of xeroph- Neurosurg 69:124–128, 1997. thalmia resulting from sphenopalatine ganglion irradiation. 2. 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Cephalalgia 58. Waltz TA, Dalessio DJ, Ott KH, Copeland B, Abbott G: Trigeminal cistern 24:934–937, 2004. glycerol injections for facial pain. Headache 25:354–357, 1985. 31. Leone M, Russell MB, Rigamonti A, Attanasio A, Grazzi L, D’Amico D, Usai 59. Wang SJ, Lirng JF, Fuh JL, Chen JJ: Reduction in hypothalamic 1H-MRS S, Bussone G: Increased familial risk of cluster headache. Neurology metabolite ratios in patients with cluster headache. J Neurol Neurosurg 56:1233–1236, 2001. Psychiatry 77:622–625, 2006.

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Acknowledgments (9%), transient palatal hypesthesia (14%), and V2 hypesthesia (6%), indi- We thank Simon Kimm, M.D., for his help with producing Figure 2. None of cating that invasive ablation of the SPG is not a benign procedure. the authors received financial support for the generation of this article. Unfortunately, preoperative use of diagnostic, local anesthetic, SPG blockade to predict the outcome of permanent lesioning was not men- tioned. Notwithstanding, the results of this series suggest that ablation COMMENTS of the SPG may be a useful procedure, particularly for patients with intractable episodic CH. Although the numbers are small, this series he surgical options for patients with intractable cluster headache also suggests that a previous destructive procedure on the trigeminal T(CH) are quite varied, largely because of our poor understanding system may be a negative prognostic indicator. concerning the pathophysiology of this disorder. In the past, I have Devoghel (1) reported the results of alcohol infiltration of the SPG for tried to target the trigeminal nerve using radiosurgery. This has only 120 patients with with CH. With a follow-up period of 6 months to 4 had little apparent benefit as a less invasive alternative to a posterior years, pain relief and parasympathetic disturbances were reported in fossa exploration with either decompression or partial sectioning of the more than 85% of patients who were treated with this technique. trigeminal nerve together with sectioning of the nervus intermedius. It seems that the SPG may play an important role in the genesis and Radiosurgical targeting of the pterygopalatine ganglion may provide a CH, although this role is unclear. Therefore, targeting the SPG for treat- safe method to relieve this disabling headache disorder and preserve ment of refractory CH seems to have some appeal. Radiosurgical tar- facial sensation. However, further investigation of this technique is geting of the SPG for CH represents a potentially attractive alternative necessary to determine its long-term safety and effectiveness. to radiofrequency ablation, given the potential complications of inva- Bruce E. Pollock sive procedures that target the SPG. Although radiosurgery is noninva- Rochester, Minnesota sive and may avoid many risks associated with ablative, percutaneous procedures performed on the SPG or trigeminal nerve, we should he authors present the first case report of CH treated by stereotactic remember that radiosurgery is still an irreversible, ablative procedure. Tradiosurgical targeting of the sphenopalatine ganglion (SPG). Moreover, the radiobiological effect of high-dose radiation on the SPG Unfortunately, the literature regarding the effectiveness of blockade remains largely unknown. Consequently, further studies seem neces- and/or lesioning of the SPG for various pain conditions, particularly for sary before radiosurgery is adopted as a standard acceptable treatment CH, is sparse. Sanders and Zuurmond (2) reported the results of percu- for refractory CH. Given the relatively small number of patients with taneous radiofrequency lesioning of the SPG through 114 procedures in refractory CH, this may prove to be difficult. 66 patients with either episodic (n ϭ 56) or chronic (n ϭ 10) CH. Richard K. Osenbach Complete pain relief, denoted by no pain and complete cessation of Durham, North Carolina medications, or partial pain relief, denoted by a reduction of CH attacks and a less than 50% reduction in medication use, was achieved in 82% of all patients. Complete or partial pain relief occurred in 86% of 1. Devoghel JC: Cluster headache and sphenopalatine block. Acta Anaesthesiol patients with episodic CH versus 60% of patients with chronic CH. Belg 32:101–107, 1981. Only one out of eight patients who underwent a previous destructive 2. Sanders M, Zuurmond WW: Efficacy of sphenopalatine ganglion blockade in procedure on the trigeminal system experienced even partial pain relief. 66 patients suffering from cluster headache: A 12- to 70-month follow-up eval- Reported complications included epistaxis (12%), cheek hematoma uation. J Neurosurg 87:876–880, 1997.

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Suboptimal Sphenoid and Sellar Exposure: A Consistent Finding in Patients Treated with Repeat Transsphenoidal Surgery for Residual Endocrine-inactive Macroadenomas To the Editor: We read with great interest the article by Mattozo et al. (3) entitled “Suboptimal Sphenoid and Sellar Exposure: A Con- sistent Finding in Patients Treated with Repeat Transsphen- oidal Surgery for Residual Endocrine-inactive Macroade- nomas.” In their article, the authors retrospectively analyze a consecutive series of 30 patients who underwent microscopic endonasal transsphenoidal reoperation for residual or recurrent endocrine-inactive macroadenomas to determine possible fac- tors influencing suboptimal tumor removal during first sur- gery. Three patients underwent operation 6 to 9 years earlier by the senior author (DFK) at the beginning of his experience in transsphenoidal surgery; the remaining patients underwent operation elsewhere and not in “. . . well-recognized pituitary tumor centers.” The article by Mattozo et al. raises very interesting concerns about features that may contribute to incomplete removal of FIGURE C1. Sellar computed tomographic scan (bone window) performed 12 pituitary tumors at the first instance. The primary concern, months after the transsphenoidal removal of a GH-secreting macroadenoma according to the authors’ observations, may be an insufficient using the “open sella” technique, i.e., without sellar floor reconstruction. Note opening of the bony structures (i.e., sphenoid wall and sella the complete spontaneous reossification of the sellar floor. turcica). Their belief is based on the observation that, in most reoperation cases of residual tumor, they found inadequate ation were completely solved in the few cases in which the bone removal with small bony holes either at the sphenoidal bone regeneration was so substantial that the sphenoid anterior keel, the sellar floor, or both, requiring further bone removal wall seemed completely unbroken (i.e., without any reconstruc- (small or large according to their surgical schedules). tion at the end of the previous approach) or the sphenoid sinus Inadequate surgical exposure is a common problem in neuro- was completely ossified (Fig. C1). surgical practice. For instance, as outlined by authors, it was We obviously refer to patients on whom we performed the already advocated by Laws et al. (2) as a factor limiting tumor first operation. Such occurrence is more frequent, but not exclu- removal during transsphenoidal approaches to pituitary ade- sive, in growth hormone-secreting adenomas. In two recent nomas. In these instances, as well as in reducing postoperative cases of wide macroadenomas (one growth hormone -secreting, complications, surgical experience (i.e., number of transsphe- the other not) that were removed incompletely, in which the noidal approaches performed) plays a pivotal role (1). Never- sella and sphenoid were deliberately left open in view of a sec- theless, we would like to make some comments. ond surgical approach, we had serious problems reaching the It is clear that, in the authors’ opinion, the openings in bone pituitary fossa at the time of reoperation because a very hard structures they found at the time of reoperation were the same and diffuse reossification occurred within a few months, with as those left at the end of the first surgical approach. We think surgical findings at the time of reoperation can be misleading, spontaneous reconstruction of the sphenoid wall and sellar especially when the time elapsed since the earlier surgery is floor (and complete ossification of the sinusal cavity in one). In quite long (range, 1–169 months). Indeed, it is our experience both patients, the records of the first operation confirmed the that, in some cases, spontaneous reossification, especially at large opening we left at the end of the surgical approach. Such the sellar floor, may occur even if no reconstruction was per- cases were so impressive to us that we now perform a very formed with bone or cartilage fragments at the end of the first accurate preoperative evaluation of bony structure by means of operation (4). Reossification of the bony structures encroached computed tomographic scanning in all cases of reoperation. during the first transsphenoidal approach may sometimes be so According to these findings, we are not sure that the size of the lively and fast that the residual breaches in the sphenoid and bone opening we find at reoperation is absolutely indicative of the sella seem surprisingly small. The doubts that the small an insufficient sphenoid and sellar exposure. The same remark openings in bony structures observed at the time of reoperation may be made for openings in the sellar dura. We completely were owing to insufficient bony removal during the first oper- agree with the suggestions of Mattozo et al. about the impor-

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tance of an adequate exposure of sellar structures for improv- Secondly, in cases with a suboptimal opening of the sphenoid ing the extension of pituitary tumor removal. They are to be keel and sella (90% of our cohort), these two bony openings were commended for having raised a very interesting feature of typically in a linear trajectory from the nasal cavity, as demon- transsphenoidal surgery. strated in Figure 3 of our article. In several cases, there was an obvious defect in the tumor that indicated a continuation of this Gianluigi Zona same trajectory from the sphenoid and sellar bony openings. Renato Spaziante Third, in four patients with a suboptimal opening of the sphenoid Genova, Italy sinus, the midline sphenoid keel was still intact with its normal anatomical configuration. In other words, the previous sphe- noidotomy was clearly confined to one side of the sphenoid and 1. Ciric I, Ragin A, Baumgartner C, Pierce D: Complications of transsphenoidal surgery: Results of a national survey, review of the literature, and personal did not cross the midline. It is unlikely that new bone growth experience. Neurosurgery 40:225–237, 1997. would exactly replicate the virgin sphenoid keel anatomy. Finally, 2. Laws ER Jr, Fode NC, Redmond MJ: Transsphenoidal surgery following the opening observed in the sellar floor was typically associated unsuccessful prior therapy. An assessment of benefits and risks in 158 with vigorous scar tissue and adhesions of the same shape in the patients. J Neurosurg 63:823–829, 1985. 3. Mattozo CA, Dusick JR, Esposito F, Mora H, Cohan P, Malkasian D, Kelly DF: dura underlying it. Likewise, the dura surrounding the identified Suboptimal sphenoid and sellar exposure: a consistent finding in patients previous opening appeared to be “virgin” dura without evidence treated with repeat transsphenoidal surgery for residual endocrine-inactive of scar tissue or hemosiderin staining. macroadenomas. Neurosurgery 58:857–865, 2006. For these reasons, we think that, although some of our patients 4. Spaziante R, de Divitiis E, Cappabianca P, Zona G: Repair of the sella turcica may have had new bone growth between their first and second after transsphenoidal surgery, in Schmidek HH, Roberts DW (eds): Schmidek and Sweet’s Operative Neurosurgical Techniques. Indications, Methods and Results. operations that caused us to underestimate the size of the previ- Philadelphia, W.B. Saunders, 2005, ed 5, vol 1, pp 390–408. ous sphenoid and sellar openings, in the majority of cases, the openings were likely relatively stable over time. These relatively

10.1227/01.NEU.0000255362.40313.04 small bony openings likely contributed to the subtotal tumor removal seen in this cohort. Nonetheless, the remarks by Drs. Zona and Spaziante draw attention to an important confounding In Reply: factor that we did not adequately address in our report. We appreciate the thoughtful comments from Drs. Zona and Carlos A. Mattozo Spaziante regarding our article on suboptimal exposure in Joshua R. Dusick transsphenoidal surgery. The authors raise a valid point in that, Hugo Mora although suboptimal exposure may contribute to incomplete Dennis Malkasian tumor removal in some cases, they suggest that our findings may Daniel F. Kelly have been biased by the fact that sellar floor and sphenoid keel Los Angeles, California bone regrowth can occur after surgery, especially if reoperation is Felice Esposito delayed by a significant period of time. The authors provide Naples, Italy examples of cases in which they have reoperated on their patients and observed dramatic, even complete, regrowth of bone in the area of the previous sellar opening. 1. Mattozo CA, Dusick JR, Esposito F, Mora H, Cohan P, Malkasian D, Kelly DF: We acknowledge that new bone growth may have occurred Suboptimal sphenoid and sellar exposure: a consistent finding in patients in some of the patients presented in our report. In our study, treated with repeat transsphenoidal surgery for residual endocrine-inactive the median time to reoperation after previous surgery was 25 macroadenomas. Neurosurgery 58:857–865, 2006. 2. Paige KT, Vega SJ, Kelly CP, Bartlett SP, Zakai E, Jawad AF, Stouffer N, months (range, 1–169 mo); only six patients underwent reoper- Whitaker LA: Age-dependent closure of bony defects after frontal orbital ation within 6 months of their original surgery. However, there advancement. Plast Reconstr Surg 118:977–984, 2006. are several points that we believe support our observations 3. Sarnat BG: Gross growth and regrowth of sutures: Reflections on some per- and hypothesis in the great majority of cases. sonal research. J Craniofac Surg 14:438–444, 2003. First, Drs. Zona and Spaziante point out that, in their experi- ence, new bone growth was noted in patients with acromegaly 10.1227/01.NEU.0000255363.17442.25 and patients with endocrine-inactive adenomas. Our study included no patients with acromegaly. Additionally, our patients with endocrine-inactive adenomas had a mean age of 50 years, Outcome of Oculomotor Nerve Palsy from Posterior and there were no patients younger than 15 years. Previous Communicating Artery Aneurysms: Comparison of studies indicate that the likelihood of new craniofacial bone Clipping and Coiling growth after surgical intervention decreases with increasing age To the Editor: (2, 3). Thus, although we certainly acknowledge that regrowth We read with interest the article by Chen et al. (2), who ana- may have occurred in some cases, we think this process likely lyzed 13 patients with posterior communicating artery played a relatively minor role in our patient cohort, which was, aneurysms and third nerve palsy. They compared the outcome on average, older and included no patients with acromegaly. of endovascular coiling versus surgical clipping. The result of

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their analysis favors surgical clipping over endovascular coil- Posterior Communicating Artery Aneurysms: Comparison of ing. Half of their patients presented with subarachnoid hemor- Clipping and Coiling” (1). We did not elaborate on possible rhage; the other half presented with only mass effect. mechanisms underlying oculomotor nerve palsy (ONP) for two We notice that the most important aspect that has significant reasons. First, the study was retrospective, and the available bearing on the outcome, i.e., the etiopathogenic mechanism of data were insufficient to perform such an analysis. Second, the the third nerve palsy was not analyzed in this timely study. purpose of the study was to compare the efficacy of surgical There are four different mechanisms that can be postulated in and endovascular treatment based only on the manifestation of cases of aneurysmal third nerve palsy: 1) the direct “pressure ONP caused by a posterior communicating artery (PComA) effect” of the aneurysm upon the nerve, 2) the “pulsating/ aneurysm. throbbing” effect of the aneurysm, 3) the “irritating” effect of We agree that there are several possible mechanisms (i.e., direct the subarachnoid blood in patients with ruptured aneurysms, compression, pulsating/throbbing effect, or an “irritating” effect). and 4) a “combination” of one or more of the above. We think However, only direct compression has been observed intraoper- that the final outcome is as much a function of the pathogenic atively by previous authors and us. A PComA aneurysm need not mechanism of the third nerve palsy as of the treatment modal- be large to compress the oculomotor nerve given the proximity ity selected. In our experience, surgical clipping and, thereby, between the PComA and the oculomotor nerve (2). The most decompression of the nerve is a preferable method of treat- important factor is the direction in which the aneurysm projects ment if the size and site of the aneurysm indicate that the nerve in relationship to the oculomotor nerve. Inferiorly and laterally is simply mechanically compressed. On the contrary, if the projecting aneurysms more likely compress the nerve (2). effect is thought to be solely owing to irritation by subarach- Angiography often shows a notch at the inferior and lateral part noid blood with a small aneurysm not in direct apposition with of a PComA aneurysm dome (Fig. C2). Presumably, the notch the nerve, endovascular intervention should ideally produce indicates the site of oculomotor compression. Intuitively, this type comparable results to that of surgery. Perhaps the major of ONP will likely benefit by surgical clipping of the aneurysm. dilemma regarding decision-making arises in cases in which In contrast, the presence of densely packed coils could, in theory, the third nerve palsy is thought to be purely owing to the “pul- be detrimental to the nerve by causing further compression. In satility” effect alone. In theory, if this is an isolated cause, our series, ONP resolved in two patients in the coiling group. endovascular obliteration of the aneurysm should produce sat- However, it was less often seen in the patients with coiling com- isfactory results. However, in the absence of robust supportive pared with patients who underwent surgical treatment (1). In data, we prefer to err on the surgical side for such cases and patients who recover after coil embolization, ONP has been have not been disappointed so far. Although our own observa- attributed to the pulsating, throbbing, or irritation effect of the tions are entirely in agreement with the authors’ conclusions in aneurysm. Our data, however, were unable to determine the general, unless the pathogenic mechanism responsible for the mechanisms. Perhaps, it is impossible to identify the mechanisms oculomotor nerve palsy is taken into consideration, we doubt of ONP with current technology. if a multicenter study such as that suggested by the authors will produce meaningful results. Nassir Mansour AB Kishor A. Choudhari Belfast, United Kingdom

1. Birchall D, Khangure MS, McAuliffe W: Resolution of third nerve paresis after endovascular management of aneurysms of the posterior communicat- ing artery. AJNR Am J Neuroradiol 20:411–413, 1999. 2. Chen PR, Amin-Hanjani S, Albuquerque FC, McDougall C, Zabramski J, Spetzler RF: Outcome of oculomotor nerve palsy from posterior communicat- ing artery aneurysms: Comparison of clipping and coiling. Neurosurgery 58:1040–1046, 2006. 3. Giombini S, Ferraresi S, Pluchino F: Reversal of oculomotor disorders after C intracranial aneurysm surgery. Acta Neurochir (Wien) 112:19–24, 1991. FIGURE C2. Two-dimensional 4. Hyland HH, Barnett HJ: The pathogenesis of cranial nerve palsies associated anteroposterior and lateral (A), and with intracranial aneurysms. Proc R Soc Med 47:141–146, 1954. three-dimensional lateral (B) views of three cerebral angiograms from 10.1227/01.NEU.0000255364.17442.EB three cases of ONP. The common fea- ture is the inferolateral “notch” on the aneurysm dome, presumably In Reply: indicating direct compression on the We appreciate Dr. Choudhari’s Letter to Editor regarding ipsilateral oculomotor nerve. our article, “Outcome of Oculomotor Nerve Palsy from

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We are glad that the authors’ experience concurs with our results. We agree that it will be ideal in choosing treatment TABLE 1. The result of the population studya modalities for different subgroups of patients if the mechanism Genotype frequency Allele frequency of ONP in the presence of a PComA or other aneurysms can be identified and analyzed. Although it is unlikely that all mech- G/G G/C C/C G C anisms will be elucidated, a well-designed randomized multi- Control 31 18 3 80 24 center trial might identify the best treatment modalities. (n = 52) 60% 35% 6% 77% 23% P. Roc Chen Total MMD 27 21 0 71 21 Sepi Amin-Hanjani (n = 48) 56% 44% 0% 74% 22% Felipe C. Albuquerque FMMD 6 1 0 13 1 Cameron G. McDougall (n = 7) 86% 14% 0% 93% 7% Joseph M. Zabramski Non-FMMD 21 20 0 62 20 Robert F. Spetzler (n = 41) 51% 49% 0% 76% 24% Phoenix, Arizona a MMD, moyamoya disease; FMMD, familial moyamoya disease.

1. Chen PR, Amin-Hanjani S, Albuquerque FC, McDougall CG, Zabramski JM, Spetzler RF: Outcome of oculomotor nerve palsy from posterior communicat- loproteinase 2 according to the method published by Hirano ing artery aneurysms: Comparison of clipping and coiling. Neurosurgery et al. (1), and the frequency of the G and C alleles at position 58:1040–1046, 2006. -418 was calculated. Our results are summarized in Table C1. 2. O’Shaughnessy BA, Getch CC, Bendok BR, Batjer HH: Surgical management of unruptured posterior carotid artery wall aneurysms. Neurosurg Focus Interestingly, the frequency in the Japanese population devi- 15:E9, 2003. ates from that of the Korean population. The frequencies of this SNP in the Japanese normal controls and Japanese

10.1227/01.NEU.0000255365.25066.CD patients with MMD were almost the same; there was no sig- nificant difference between them. Kang et al. reported that nine out of 11 patients with FMMD (82%) showed a heterozy- Single Nucleotide Polymorphisms of Tissue Inhibitor of gous genotype, namely the G/C heterozygous genotype at Metalloproteinase Genes in Familial Moyamoya Disease position -418. However, our results revealed only one FMMD To the Editor: patient (14%) with the G/C heterozygous genotype; the other Kang et al.’s (3) article, “Single Nucleotide Polymorphisms of six demonstrated the G/G homozygous genotype. From this Tissue Inhibitor of Metalloproteinase Genes in Familial Moya- current evidence, we are unable to apply Kang et al.’s conclu- moya Disease,” was intriguing because, until now, there has sion to the Japanese population (3). not been positive data of the population study using single Marco T. Paez nucleotide polymorphism (SNP) analysis for moyamoya dis- Toshiyuki Yamamoto ease (MMD). Kang et al. showed significantly higher frequency Tokyo, Japan of a G/C heterozygous genotype in the tissue inhibitor of met- alloproteinase 2 promoter region at the -418 position in familial

MMD (FMMD). 1. Hirano K, Sakamoto T, Uchida Y, Morishima Y, Masuyama K, Ishii Y, Nomura MMD is a cerebrovascular disorder with an unknown etiol- A, Ohtsuka M, Sekizawa K: Tissue inhibitor of metalloproteinases-2 gene ogy. This disease is found mostly among the people of East polymorphisms in chronic obstructive pulmonary disease. Eur Respir J Asia, especially the Japanese and Koreans. The clinical back- 18:748–752, 2001. ground of MMD is speculated to be common in these two 2. Ikezaki K, Han DH, Kawano T, Kinukawa N, Fukui M: A clinical comparison of definite moyamoya disease between South Korea and Japan. Stroke populations (2). We have continuously studied the genetics of 28:2513–2517, 1997. MMD and have published some articles with our results (5, 3. Kang HS, Kim SK, Cho BK, Kim YY, Hwang YS, Wang KC: Single nucleotide 6). Therefore, we were interested in analyzing the genotype polymorphisms of tissue inhibitor of metalloproteinase genes in familial moy- frequency of the same SNP in Japanese MMD patients soon amoya disease. Neurosurgery 58:1074–1080, 2006. 4. Maki Y, Enomoto T: Moyamoya disease. Childs Nerv Syst 4:204–212, 1988. after the publication of the article by Kang et al. (3). The sub- 5. Yamamoto T, Akasaka Y, Ohtani K, Hayashi T, Kashiwagi S, Ichiyama T, jects consisted of 52 and 48 samples from normal Japanese Nishikawa M, Kato M, Maegaki Y, Oka A, Ohno K: Molecular screening for individuals and Japanese MMD patients, respectively. Of 48 moyamoya disease by use of expressed sequence tag on chromosome 3p [in Japanese MMD patients, seven had FMMD and 41 were non- Japanese]. No To Hattatsu 37:20–25, 2005. FMMD patients. MMD patients were diagnosed based on cri- 6. Yamamoto T, Akasaka Y, Ohtani K, Hayashi T, Kashiwagi S, Ichiyama T, Nishikawa M, Kato M, Maegaki Y, Oka A, Ohno K: No association between teria published elsewhere (4). All patients were diagnosed moyamoya disease and polymorphism of IGF2R [in Japanese]. No To with MMD before adolescence. Genomic deoxyribonucleic Hattatsu 37:15–19, 2005. acid from peripheral blood was used. In FMMD cases, only propositi were involved in this study. We analyzed the 10.1227/01.NEU.0000255366.19228.8D sequences of the promoter region of tissue inhibitor of metal-

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FIGURE C3. Diagrams illustrating the direct sequencing result of polymerase show heterozygous genotype at this position; the other two patients (Patients chain reaction products generated including the part of position -418 (arrows) 5 and 10) do not. in the TIMP2 promoter among 11 familial MMD patients. Nine patients

In Reply: entation, response to revascularization surgery, and outcome We appreciate the interest in our article (1) shown by Paez between FMMD and nonfamilial MMD patients, although the and Yamamoto. In our study, there was a significant differ- genetic bases of the two groups might differ. Speculated com- ence of the G/C heterozygous genotype at position -418 of the mon clinical features of MMD between the Korean and tissue inhibitor of metalloproteinase 2 promoter region among Japanese populations would not ensure the same results of FMMD patients, nonfamilial MMD patients, and normal con- single nucleotide polymorphism studies. We attach part of trols. However, the study in the Japanese population, by Paez our sequencing data of 11 FMMD patients as supporting and Yamamoto, which was composed of seven FMMD material for our study (Fig. C3). patients and 41 nonfamilial MMD patients, showed different Hyun-Seung Kang results. Seung-Ki Kim There would be some possible explanations for this differ- Kyu-Chang Wang ence. The significance of our study may be limited by the Seoul, South Korea small number of patients evaluated (11 FMMD cases and 50 nonfamilial MMD cases), as we stated in our article. Although we will not devaluate the study conducted by Paez and 1 . Kang HS, Kim SK, Cho BK, Kim YY, Hwang YS, Wang KC: Single nucleotide Yamamoto, the significance of our study would be better eval- polymorphisms of tissue inhibitor of metalloproteinase genes in familial moy- amoya disease. Neurosurgery 58:1074–1080, 2006. uated by studies including more numerous cases. Various loci 2. Ikeda H, Sasaki T, Yoshimoto T, Fukui M, Arinami T: Mapping of a familial related to FMMD have been reported, supporting a multifac- moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet torial inheritance pattern (2–5). Therefore, the other FMMD 64:533–537, 1999. patients who did not show the genotype might have sequence 3. Inoue TK, Ikezaki K, Sasazuki T, Matsushima T, Fukui M: Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 15:179–182, 2000. variation at other loci. Moreover, the difference between the 4. Sakurai K, Horiuchi Y, Ikeda H, Ikezaki K, Yoshimoto T, Fukui M, Arinami T: two studies might reflect the ethnic difference between the A novel susceptibility locus for moyamoya disease on chromosome 8q23. J populations. We do not see any differences in the clinical pres- Hum Genet 49:278–281, 2004.

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5. Yamauchi T, Tada M, Houkin K, Tanaka T, Nakamura Y, Kuroda S, Abe H, inal neuralgia is not the compression of the whole trigeminal Inoue T, Ikezaki K, Matsushima T, Fukui M: Linkage of familial moyamoya nerve, but rather the compression of some rootlets, also disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. stretching the central-peripheral myelin zone in the brain- Stroke 31:930–935, 2000. stem. The compressed rootlets, which cause the symptoms of trigeminal neuralgia, are sensorial ones. 10.1227/01.NEU.0000255367.19228.C4 Ibrahim M. Ziyal Tunçalp Özgen Microanatomy of the Central Myelin-peripheral Ankara, Turkey Myelin Transition Zone of the Trigeminal Nerve We read Peker et al.’s (1) article, “Microanatomy of the Central Myelin-peripheral Myelin Transition Zone of the 1. Peker S, Kurtkaya Ö, Üzün I˙, Pamir MN: Microanatomy of the central myelin- Trigeminal Nerve,” with interest. The authors suggest that the peripheral myelin transition zone of the trigeminal nerve. Neurosurgery root entry zone (REZ) and myelin transitional zone (TZ) are 59:354–359, 2006. 2. Sjögvist O: Studies on pain conduction in the trigeminal nerve. A contribution distinct structures. Their measurement revealed that the central to the surgical treatment of facial pain. Acta Psychiatrica et neurologicasup- myelin occupied only the initial one-fourth of the trigeminal plementum XVII. Mercators Tryckeri, Helsingfors, 1938. nerve length. That the REZ and TZ are different anatomical 3. Ziyal IM, Sekhar LN, Özgen T, Söylemezog˘lu F, Alper M, Bes¸er M: The entities was also documented in our recent study (3). On the trigeminal nerve and ganglion: An anatomical, histological, and radiological other hand, the authors speculate that they observed very study addressing the transtrigeminal approach. Surg Neurol 61:564–574, 2004. sharp delineation of the thick, homogenous central myelin from the fasciculated peripheral myelin. We do not agree with the authors on this point. The trigeminal nerve should not be 10.1227/01.NEU.0000255368.26852.AA accepted as a single nerve root. The trigeminal nerve has linear, connecting, and crossing rootlets (3). Some rootlets are larger (motor rootlets), and In Reply: there are anastomotic connections between the cutaneous We thank Drs. Ziyal and Özgen for their Letter to the (sensory) and the muscle (motor) rootlets, as well as between Editor regarding our article, “Microanatomy of the Central the sensory rootlets, with a few aberrant rootlets (3). Myelin-peripheral Myelin Transition Zone of the Trigeminal Although the rootlets form the trigeminal ganglion, the so- Nerve” (1). We are aware of their article, which is also called gasserian ganglion, this dense semilunar network has referred to in our study. In our study, we examined 100 a plexiform architecture rather than a ganglion. During our trigeminal nerves obtained from cadavers. The results of our study, we observed that the fibers of the motor rootlets had study correspond with the largest anatomical study in the a diameter ranging from 8 to 11 µ. From the pons to the gan- literature. In the study by Ziyal et al. (2), the authors glion, the epineurium became thicker, and the root flattened histopathologically examined only six trigeminal nerves. In to an ovaloid shape. The diameter of the sensory fiber one of the figures accompanying their study, the shape of the groups were less than 4 µ. The calibers of the motor fibers transitional zone seems to mimic a Scandinavian fiord. were constant, but the fiber calibers of the sensory roots However, the shape of the transitional zone in the other diminished from the brainstem towards the periphery. In specimen they show is sharp. We do agree with the authors 1938, Sjögvist first reported that the trigeminal nerve has that, of the treatment options for trigeminal neuralgia, between 40 and 50 rootlets before entering the brainstem (2). microvascular decompression shows a high rate of cure. We also observed that the trigeminal nerve was leaving the However, we are not sure how this surgery helps to relieve pons in a group of approximately 45 to 55 bundles (rootlet) the symptoms of this disease. (3). The rootlets were entering the brainstem at various Selçuk Peker depths. Each rootlet was changing from central myelin to M. Necmettin Pamir peripheral myelin in different levels of the brainstem; i.e., Istanbul, Turkey the distance between the REZ and the TZ should be different for each rootlet. In our study, we demonstrated that the interphase of the central and peripheral nervous system is composed of small cones. These cones are formed by the 1. Peker S, Kurtkaya Ö, Üzün I˙, Pamir MN: Microanatomy of the central myelin- extension of glial fibrillary acidic protein expressing glial peripheral myelin transition zone of the trigeminal nerve. Neurosurgery cells into the root (3). At the origin of the nerve in the brain- 59:354–359, 2006. 2. Ziyal IM, Sekhar LN, Özgen T, Söylemezog˘lu F, Alper M, Bes¸er M: The trigem- stem, i.e., the area between the REZ and the TZ, the exten- inal nerve and ganglion: An anatomical, histological, and radiological study sion of glial fibrillary acidic protein formed large and small addressing the transtrigeminal approach. Surg Neurol 61:564–574, 2004. bundles. Consequently, this network of several rootlets con- stitutes an irregular central-peripheral myelin border zone 10.1227/01.NEU.0000255370.11605.43 similar to the fiords of Scandinavia. What occurs in trigem-

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Intramedullary Endometriosis of the Conus venous metastases from deeply invasive endometriosis or ade- Medullaris: Case Report nomyosis. In 1951, Faulconer (6) demonstrated varied locations To the Editor: of müllerian grooves, i.e., dorsolateral, lateral, ventrolateral, We read with great interest the article by Agrawal et al. (1) and ventral, on the cranial end of the genital ridge in human embryos. We postulate that the intraspinal endometriosis in entitled, “Intramedullary Endometriosis of the Conus Medul- this patient is a heterotopic organoid müllerian rest, develop- laris: Case Report.” In particular, we wish to comment on the mentally misplaced embryonic müllerian tissue from müllerian pathogenesis of intramedullary endometriosis of the conus grooves described by Faulconer. Of interest, a case of spinal medullaris in this 40-year-old woman, progressively sympto- intradural müllerianosis has been published recently (2), which matic below the L1 level since the age of 28 years. Symptoms is not dissimilar to that of Agrawal et al., except for the pres- and signs worsened for 2 days at the onset of the menstrual ence of all three müllerian tissues: endocervicosis, endosalpin- cycle, ostensibly associated with periodic intraspinal bleeding. giosis, and endometriosis. We postulate that this rare case The authors describe a mass in the spinal canal involving the described by Agrawal et al. is a specific example of a choris- conus cauda region, which was densely adhesive with the toma, endometrial tissue within the spinal cord, and that a conus and cauda equina and was not separable from the cord müllerian rest offers a more powerful explanatory hypothesis tissue and nerve roots. The mass consisted of firm, fleshy, and than venous metastases from nonexistent pelvic endometriosis. relatively avascular tissue, with necrosis and old hemorrhage. In summary, we postulate that this case of intraspinal Figure 2A in the article represents a histological section demon- endometriosis is truly müllerianosis (4), an organoid lesion, a strating endometrial glands with surrounding stroma choristoma, a müllerian anlage misplaced during embryonic entrapped in the mesenchymal tissue. Of special significance to development. We further postulate that this organoid müllerian the discussion of pathogenesis, the uterus and genital organs rest, in the same manner as eutopic endometrium, was subject were normal; specifically, there was no evidence of pelvic to apoptosis as an endometrium regulator, and was not subject endometriosis found at the time of a bilateral oophorectomy to apoptotic-programmed cell death (7). Finally, we suggest subsequent to laminectomy. In 1940, Oscar Batson (3) described that the intraspinal organoid lesion described by Agrawal et al. the vertebral venous network. Injecting radiopaque brilliant behaves more like eutopic endometrium than ectopic water color substances into the dorsal veins in the penises of endometrium. In other words, we postulate that the male cadavers, Batson demonstrated a pattern that seemed to intramedullary endometriosis of the conus medullaris be an exact replica of the pattern made by the early spread of described is in reality intramedullary müllerianosis of the carcinoma of the prostate, with extensive filling of the vertebral conus medullaris. veins and the bypassing of the caval veins. This specimen fur- nished a composite picture of the metastatic pattern of Ronald E. Batt advanced cases of carcinomatosis with primary origin in the John Yeh prostate. Further experiments in anesthetized monkeys con- Buffalo, New York firmed these observations. Richard A. Smith In all of Batson’s experiments, increased intra-abdominal Attleboro, Massachusetts pressure blocked flow into the caval venous system and facili- Dan C. Martin tated flow into the vertebral venous system. His experiments Germantown, Tennessee indicated that, under conditions of increased abdominal pres- Charles Chapron sure and during the Valsalva maneuver, blood is actually Paris, France (actively) squeezed out of the intra-abdominal veins into the vertebral vein system. Batson reported that vertebral veins have many and rich communications with the veins in the 1. Agrawal A, Shetty BJ, Makannavar JH, Shetty L, Shetty J, Shetty V: spinal canal, the veins around the spinal column, and those Intramedullary endometriosis of the conus medullaris: Case report. within the bones of the column. Neurosurgery 59:E428, 2006. Agrawal et al. (1) postulate that intraspinal endometriosis 2. Barresi V, Cerasoli S, Vitarelli E, Donati R: Spinal intradural mullerianosis: A case report. Histol Histopathol 21:1111–1114, 2006. probably results from the reverse transport of endometriotic tis- 3. Batson OV: The function of the vertebral veins and their role in the spread of sue via the vertebral venous system described by Batson. We metastases. Ann Surg 112:138–149, 1940. cannot support the authors’ position. The history, physical, and 4. Batt RE, Smith RA, Buck GM, Severino MF, Naples JD: Mullerianosis. Prog operative findings do not support that hypothesis. Not only Clin Biol Res 323:413–426, 1990. 5. Chapron C, Chopin N, Borghese B, Foulot H, Dousset B, Vacher-Lavenu MC, was there no evidence of pelvic endometriosis, there was also Vieira M, Hasan W, Bricou A: Deeply infiltrating endometriosis: Pathogenetic no evidence of deeply invasive endometriosis (5) and no evi- implications of the anatomical distribution. Hum Reprod 21:1839–1845, 2006. dence of aggressive deeply infiltrating adenomyosis (8) from 6. Faulconer RJ: Observations on the origins of müllerian groove in human which endometriotic venous metastases might originate. embryos. Contrib Embryol 229:161–164, 1951. 7. Goumenou AG, Matalliotakis IM, Tzardi M, Fragouli YG, Mahutte NG, Arici The one and the only endometriotic lesion was located in the A: Apoptosis and differential expression of apoptosis-related proteins in spinal cord. Endometriosis of the spinal cord is a rare lesion; it endometriotic glandular and stromal cells. J Soc Gynecol Investig 11:318– would occur much more commonly if its pathogenesis was via 322, 2004.

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8. Leyendecker G, Herbertz M, Kunz G, Mall G: Endometriosis results from the 7. Soderberg CH, Dahlquist EH: Catamenial pneumothorax. Surgery dislocation of basal endometrium. Hum Reprod 17:2725–2736, 2002. 79:236–239, 1976. 8. Tsunezuka Y, Oda M, Moriyama H, Ohshima M, Kurumaya H: Thoracoscopic findings and surgical management of catamenial hemopneumothorax. Ann 10.1227/01.NEU.0000255369.03981.0A Thorac Cardiovasc Surg 12:197–199, 2006.

In Reply: 10.1227/01.NEU.0000255371.11605.0A Despite decades of research, the pathogenesis of endometrio- sis remains poorly understood (8). It has been proposed that different types of endometriotic lesions are likely to have dis- Factors Associated with Survival and Neurological crete etiologies (5). It is not necessary that ectopic endometrial Outcome after Cardiopulmonary Resuscitation of tissues originate from primary endometrial tissue (8) and Neurosurgical Intensive Care Unit Patients endometriosis is also reported in posthysterectomy patients To the Editor: (7). Endometriosis appears in patients without endometrial tis- We read with great interest Yi et al.’s (2) article analyzing the sue, including those with Turner syndrome or uterine hypoplasia, outcome of neurosurgical patients who experienced cardiopul- or in the male bladder, prostate, and testis. This means ectopic monary arrest while admitted to their neurosurgical intensive endometria tissue may be from coelomic metaplasia rather than care unit. We would like to bring a study we published 2 years primary endometrial tissue (8). However, the most widely earlier with a similar objective, which was not included in their accepted theory proposes retrograde menstruation, implantation, discussion, to the attention of the authors (1). Because the and proliferation and differentiation of endometrial tissue, as authors only compared their findings with those of studies in well as invasion of the underlying tissue (6). As suggested by Batt non-neurosurgical populations, we think it is pertinent to make et al. in their Letter to the Editor, an alternative theory is that a comparison with our results. endometriosis results from metaplasia of müllerian-type epithe- We studied a smaller population but found comparable rates lium, by which cellular modification owing to epigenetic or of successful resuscitation (61 versus 49% in the study by Yi genetic alterations results in transformation of a specific müller- et al.) and survival until hospital discharge (18% in both series). ian tissue type into endometrial tissue (3). Müllerianosis is a term As Yi et al. reported, we also found that a longer duration of used to indicate lesions composed of an admixture of two or resuscitation efforts was associated with a worse chance of three types of müllerian-derivation glands in heterotopic sites recovery. However, in our population, we also noted that car- and at histological examination lesions in müllerianosis are com- diac arrest after a declining clinical course was uniformly pre- posed of endocervical, endometrial and tubal glands within a dictive of fatal outcome. Thus, deteriorating neurological status smooth muscle nodule (2, 4). We cannot totally disagree with the preceding cardiac arrest should be considered a strong marker authors; however, because our patient had only endometrial tis- of poor prognosis in critically ill neurosurgical patients who sue, it is difficult to justify term intramedullary müllerianosis of require cardiopulmonary resuscitation. We think this particular the conus medullaris in our case (1). finding has important practical implications and should be com- Amit Agrawal municated to family members when discussing the value of Dharan, Nepal cardiopulmonary resuscitation. Bellore J.P. Shetty Eelco F.M. Wijdicks Jagadeesh H. Makannavar Alejandro A. Rabinstein Lathika Shetty Rochester, Minnesota Jayaprakash Shetty Vikram Shetty Mangalore, India 1. Rabinstein AA, McClelland RL, Wijdicks EF, Manno EM, Atkinson JL: Cardiopulmonary resuscitation in critically ill neurologic-neurosurgical patients. Mayo Clin Proc 79:1391–1395, 2004. 1. Agrawal A, Shetty BJ, Makannavar JH, Shetty L, Shetty J, Shetty V: Intra- 2. Yi HJ, Kim YS, Ko Y, Oh SJ, Kim KM, Oh SH: Factors associated with survival medullary endometriosis of the conus medullaris: Case report. Neurosurgery and neurological outcome after cardiopulmonary resuscitation of neurosur- 59:E428, 2006. gical intensive care unit patients. Neurosurgery 59:838–845, 2006. 2. Barresi V, Cerasoli S, Vitarelli E, Donati R: Spinal intradural mullerianosis: A case report. Histol Histopathol 21:1111–1114, 2006. 10.1227/01.NEU.0000255372.49722.6C 3. Fujii S: Secondary Müllerian system and endometriosis. Am J Obstet Gynecol 165:219–225,1991. 4. Lim S, Kim JY, Park K, Kim BR, Ahn G: Mullerianosis of the mesosalpinx: A case report. Int J Gynecol Pathol 22:209–212, 2003. In Reply: 5. Nisolle M, Donnez J: Peritoneal endometriosis, ovarian endometriosis, and We are very grateful for the keen advice of Drs. Wijdicks and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 68:585–596, 1997. Rabinstein. As they acknowledge, our article dealt exclusively 6. Sampson J: The development of the implantation theory for the origin of with neurosurgical patients who had been admitted to the neu- peritoneal endometriosis. Am J Obstet Gynecol 40:549–556, 1940. rosurgical intensive care unit (3). When compared with the arti-

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cle by Rabinstein et al. (1), patients with inoperable neurologi- brain injury [single or multiple]). In this retrospective study of cal disorders (Alzheimer’s disease, multiple sclerosis, amyo- 705 consecutive patients, the extracerebral or systemic dysfunc- trophic lateral sclerosis, and other causes of dementia) and tion exerts more striking influences on the final outcome than patients who are already comatose or collapsed upon cardiac we expected. However, certain factors (e.g., natural healing arrest were not included in this study. Although not equipped process or alteration after resuscitation) are deemed responsi- with cerebral monitoring (electroencephalography, electrphys- ble for this discrepancy in the mostly improved outcome after iology, transcranial Doppler, angiography, etc.), we tried to the initial ictus, regardless of the underlying disease. We hope determine the genuine impact of cerebral lesions and other inter- to publish this study in the near future. vening systemic illness on the ultimate outcome after cardiopul- monary resuscitation. This is the actual reason why we excluded Hyeong-Joong Yi such “critically ill” patients; therefore, the primary reason for Seoul, South Korea discrepancy or omission is for the reason pointed out. The most important highlight in this study was to elucidate medical futil- ity by demonstrating the real outcome and to provide rational 1. Rabinstein AA, McClelland RL, Wijdicks EF, Manno EM, Atkinson JL: background in discussing the value of resuscitation with imme- Cardiopulmonary resuscitation in critically ill neurologic-neurosurgical diate family members or surrogates. patients. Mayo Clin Proc 79:1391–1395, 2004. We recently conducted another mortality and outcome vali- 2. Schuiling WJ, de Weerd AW, Dennesen PJ, Algra A, Rinkel GJ: The simplified dation study using the well-known acute physiology and acute physiology score to predict outcome in patients with subarachnoid hemorrhage. Neurosurgery 57:230–236, 2005. chronic health evaluation II and the simplified acute physiol- 3. Yi HJ, Kim YS, Ko Y, Oh SJ, Kim KM, Oh SH: Factors associated with survival ogy score II in all neurosurgical patients and two specific sub- and neurological outcome after cardiopulmonary resuscitation of neurosur- sets of patients (subarachnoid hemorrhage versus traumatic gical intensive care unit patients. Neurosurgery 59:838–845, 2006.

NEUROSURGERY VOLUME 60 | NUMBER 3 | MARCH 2007 | E582 SUBMIT LISTINGS TO Joel D. MacDonald, M.D. University of Utah CALENDAR OF EVENTS Department of Neurosurgery 30 North 1900 East, 3B-409 SOM Salt Lake City, UT 84132-2303 Full contact information is available online only TEL: 801/581-6908 Listings for this section need to be submitted at least 3 months in advance. Please include a telephone number and/or a fax number. FAX: 801/581-4138 EMAIL: [email protected]

INTERNATIONAL / GENERAL NEUROSURGERY

MARCH 26–30, 2007 Hands-on Workshop in “Endoscope-assisted Mainz, Germany CONTACT: Mrs. Sandra Hoelle Keyhole Microneurosurgery” TEL: 49/7461-95-1132 FAX: 49/7461-95-2050 EMAIL: [email protected] WEB SITE: www.aesculap-neuro.com APRIL 14–19, 2007 American Association of Neurological Washington, DC CONTACT: Patty Anderson, Director of Meetings Surgeons 2007 Annual Meeting TEL: 847/378-0500 EMAIL: [email protected] WEB SITE: www.AANS.org JUNE 21–23, 2007 12th EMN Annual Meeting–Euroacademia Fiuggi, Italy CONTACT: Cristina Tartaglia Multidisciplinaria Neurotraumatologica TEL: +39 051 765357 FAX: +39 051 765195 EMAIL: [email protected] WEB SITE: www.csrcongressi.com JUNE 24–27, 2007 56th Congress Nazionale SINch Joint Meeting Rome, Italy E-MAIL: [email protected] with Congress of Neurological Surgeons WEB SITE: csrcongressi.com JUNE 28–30, 2007 3rd International Meeting Updates Arezzo, Italy CONTACT: Cristina Tartaglia in Neuro-oncology TEL: +39 051 765357 FAX: +39 051 765195 EMAIL: [email protected] WEB SITE: www.csrcongressi.com JULY 2–6, 2007 Hands-on Workshop in “Endoscope-assisted Tuttlingen, Germany CONTACT: Mrs. Sandra Hoelle Keyhole Microneurosurgery” TEL: 49/7461-95-1132 FAX: 49/7461-95-2050 EMAIL: [email protected] WEB SITE: wwwaesculap-neuro.com SEPTEMBER 3–7, 2007 Hands-on Workshop in “Endoscope-assisted Mainz, Germany CONTACT: Mrs. Sandra Hoelle Keyhole Microneurosurgery” TEL: 49/7461-95-1132 FAX: 49/7461-95-2050 EMAIL: [email protected] WEB SITE: www.aesculap-neuro.com DECEMBER 18–22, 2007 12th AACNS/13th WFNS Interim Meeting Nagoya, Japan CONTACT: Tetsuo Kanno EMAIL: [email protected] WEB SITE: www.aacns07.umin.ne.jp

NATIONAL AND REGIONAL MEETINGS

MARCH 2, 2007 Interurban Neurosurgical Society Chicago, IL CONTACT: Marlene Rakowski TEL: 715/542-3201 EMAIL: [email protected] MARCH 9–11, 2007 7th South Cone Society of Neurological Gramado, Brazil CONTACT: Apio Antunes, M.D., Ph.D. Surgeons Meeting TEL: 55/51 3311 8969 FAX: 55/51 3311 8969 WEB SITE: www.plenariumcongressos.com.br/ congressos/neurocirurgiadoconesul/ MARCH 14–17, 2007 Southern Neurosurgical Society, 58th Sea Island, GA CONTACT: Anil Nanda, M.D. Annual Meeting: Finesse, Finances, and TEL: 318/675-6404 Floods WEB SITE: www.southernneurosurgery.org JUNE 16–20, 2007 Rocky Mountain Neurosurgical Society Jackson, WY CONTACT: Joel D. MacDonald, M.D. TEL: 801/581-6908 FAX: 801/581-4385 EMAIL: [email protected] WEB SITE: www.rmns.org JUNE 26–29, 2007 Society of University Neurosurgeons London, England CONTACT: Neil Kitchen, M.D., F.R.C.S. (SUN) Annual Meeting TEL: 020/7837 3611, x3152 FAX: 020/7676 2045 EMAIL: [email protected] WEB SITE: www.uclh.nhs.uk

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JULY 1–3, 2007 5th Sardinian Neurosurgical Meeting: Alghero, Italy WEB SITE: www.sinch2007-neurosurgery. Vascular Surgery Spine Surgery csrcongress.com JULY 27–28, 2007 Pennsylvania Neurosurgical Society Hershey, PA CONTACT: Jessica Judy, Meeting Manager Annual Scientific Meeting TEL: 717/558-7850, x1463 FAX: 717/558-7841 EMAIL: [email protected] JULY 29–AUGUST 1, 2007 13th Annual Montana Leibrok Whitefish, MT CONTACT: Cindy Poulsen, Program Assistant Neurosurgery Symposium TEL: 406/329-5733 FAX: 406/329-2775 EMAIL: [email protected] WEB SITE: www.umt.edu/mnif/symposium.htm AUGUST 2–4, 2007 Neurosurgery Update 2007 in the Napa, CA CONTACT: University of California, San Francisco Wine Country TEL: 415/476-4251 EMAIL: [email protected] WEB SITE: www.cme.ucsf.edu SPINE / PERIPHERAL NERVE

MARCH 1–3, 2007 6th Annual Symposium on Current Las Vegas, NV CONTACT: Barbara Stokes, CME Coordinator Concepts in Spinal Disorders TEL: 310/423-2935 FAX: 310/423-0309 EMAIL: [email protected] WEB SITE: www.csmc.edu/cme MARCH 7–10, 2007 23rd Annual Meeting of the AANS/CNS Phoenix, AZ CONTACT: John Hurlbert, M.D. Section on Disorders of the Spine and TEL: 847/240-2500 Peripheral Nerves FAX: 847/240-0804 EMAIL: [email protected] WEB SITE: www.spinesection.org MARCH 9–11, 2007 Principles and Treatment of Spinal Atlanta, GA CONTACT: AO North America Disorders for Residents and Fellows TEL: 800/769-1391 Course FAX: 610/695-2420 WEB SITE: www.aona.org MARCH 28–31, 2007 Preservation of Motion in the Spine Florida Keys, FL TEL: 888/577-4635 EMAIL: cmemrf@floridaortho.com WEB SITE: www.currentsolutions.info APRIL 28–29, 2007 Challenges and Complications in San Francisco, CA CONTACT: AO North America Complex Spine Surgery Symposium TEL: 800/769-1391 FAX: 610/695-2420 WEB SITE: www.aona.org APRIL 30–MAY 3, 2007 4th Low Back Pain Symposium Bodrum, Turkey TEL: 32/14-346028 FAX: 32/14-346028 EMAIL: [email protected] WEB SITE: www.vitalmedbodrum.com MAY 1–4, 2007 Spine Arthroplasty Society’s 7th Annual Berlin, Germany CONTACT: Pascale M. Davis Meeting TEL: 33/6 18 41 69 89 EMAIL: [email protected] WEB SITE: www.sas7berlin.com/clear.gif MAY 4–5, 2007 19th Annual International Bethesda Spine Bethesda, MD CONTACT: Gene S. Evans, Program Coordinator Workshop: Cervical Course TEL: 757/496-5742 FAX: 757/496-4983 EMAIL: [email protected] WEB SITE: www.bethesdaspine.com MAY 4–10, 2007 Uniformed Services University of the Health Bethesda, MD CONTACT: Gene Evans Sciences and Walter Reed and National TEL: 757/496-5742 Naval Medical Centers 19th Annual International WEB SITE: www.bethesdaspine.com Bethesda Spine & PeripheralNerve Workshop MAY 6–7, 2007 19th Annual International Bethesda Spine Bethesda, MD CONTACT: Gene S. Evans, Program Coordinator Workshop: Thoracolumbar Course TEL: 757/496-5742 FAX: 757/496-4983 EMAIL: [email protected] WEB SITE: www.bethesdaspine.com

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MAY 9–10, 2007 19th Annual International Bethesda Spine Bethesda, MD CONTACT: Gene S. Evans, Program Coordinator Workshop: Peripheral Nerve Course TEL: 757/496-5742 FAX: 757/496-4983 EMAIL: [email protected] WEB SITE: www.bethesdaspine.com MAY 19–20, 2007 Controversies in Spine Trauma Symposium Naples, FL CONTACT: AO North America TEL: 800/769-1391 FAX: 610/695-2420 WEB SITE: www.aona.org MAY 30–JUNE 1, 2007 23rd Annual Meeting of the Cervical Spine Leuven, Belgium CONTACT: Jan Goffin, M.D., Ph.D. Research Society-European Section FAX: 32 16 34 42 85 EMAIL: [email protected] WEB SITE: www.csrs-leuven2007.be JUNE 2–3, 2007 Spine Deformity Symposium Coronado, CA CONTACT: AO North America TEL: 800/769-1391 FAX: 610/695-2420 WEB SITE: www.aona.org JUNE 2–3, 2007 Degenerative Spine Symposium Coronado, CA CONTACT: AO North America “Principles and Emerging Technologies” TEL: 800/769-1391 FAX: 610/695-2420 WEB SITE: www.aona.org JUNE 27–30, 2007 Joint 46th Annual Scientific Meeting of the Reykjavik, Iceland CONTACT: Sigrun Knutsdottir Intetyrnational Spinal Cord Society and Tenth TEL: 354/543-9104 Congress of the Nordic Spinal Cord Society EMAIL: [email protected] WEB SITE: www.sci-reykjavik2007.org JULY 7–8, 2007 Challenges and Advances: Distraction Toronto, Canada WEB SITE: www.aona.org Osteogenesis JULY 11–14, 2007 14th International Meeting on Advanced Paradise Island CONTACT: Jill E. Smith, Medical Meetings Spinal Technologies (IMAST) (Nassau) Bahamas Assistant TEL: 630/681 1040 FAX: 630/682 5811 EMAIL: [email protected] WEB SITE: www.imastonline.org JULY 18–24, 2007 Cleveland Spine Review: Hands-on Course Cleveland, OH CONTACT: Martha Tobin TEL: 800/223-2273, Ext. 53449 EMAIL: [email protected] WEB SITE: www.clevelandclinic.org/ neurosicence/professionals.cme AUGUST 2–5, 2007 Advanced Concepts in the Management Ontario, Canada CONTACT: AO North America of Spinal Disorders TEL: 800/769-1391 FAX: 610/695-2420 WEB SITE: www.aona.org SEPTEMBER 27–29, 2007 Spine Tumor Symposium Vancouver, Canada CONTACT: AO North America TEL: 800/769-1391 FAX: 610/695-2420 WEB SITE: www.aona.org NOVEMBER 2–4, 2007 Principles and Treatment of Spinal Las Vegas, NV CONTACT: AO North America Disorders for Residents and Fellows TEL: 800/769-1391 Course FAX: 610/695-2420 WEB SITE: www.aona.org STEREOTACTIC / FUNCTIONAL

MARCH 12–16, 2007 Principles and Practice of Gamma Pittsburgh, PA CONTACT: Charlene Baker Knife Radiosurgery TEL: 412/647-7744 EMAIL: [email protected] WEB SITE: www.neurosurgery.pitt.edu APRIL 24–25, 2007 UCLA Shaped Beam Radiosurgery Los Angeles, CA CONTACT: UCLA Stereotactic Radiosurgery Tutorial Course (Basic) TEL: 310/267-5217 FAX: 310/794-1848 EMAIL: [email protected] WEB SITE: http: //neurosurgery.ucla.edu/ conferences

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MAY 14–18, 2007 Principles and Practice of Gamma Pittsburgh, PA CONTACT: Charlene Baker Knife Radiosurgery TEL: 412/647-7744 EMAIL: [email protected] WEB SITE: www.neurosurgery.pitt.edu MAY 16–18, 2007 2nd Anatolian Course of Interventional Ankara, Turkey CONTACT: Prof. Dr. Saruhan Cekirge Neuroradiology TEL: 90/312 305 11 88 FAX: 90/312 311 21 45 EMAIL: [email protected] WEB SITE: www.acinr.org JUNE 12–13, 2007 UCLA Shaped Beam Radiosurgery Los Angeles, CA TEL: 310/267-5217 Tutorial Course (Basic) FAX: 310/794-1848 EMAIL: [email protected] WEB SITE: http: //neurosurgery.ucla.edu/ conferences JUNE 23–27, 2007 ISRS: International Stereotactic San Francisco, CA CONTACT: ISRS Headquarters Secretariat Radiosurgery Society TEL: 32/2 779 59 59 FAX: 32/2 779 59 60 EMAIL: [email protected] WEB SITE: www.ISRS2007.org JULY 9–13, 2007 Principles and Practice of Gamma Pittsburgh, PA CONTACT: Charlene Baker Knife Radiosurgery TEL: 412/647-7744 WEB SITE: www.neurosurgery.pitt.edu SEPTEMBER 24–28, 2007 Principles and Practice of Gamma Pittsburgh, PA CONTACT: Charlene Baker Knife Radiosurgery TEL: 412/647-7744 EMAIL: [email protected] WEB SITE: www.neurosurgery.pitt.edu NOVEMBER 12–16, 2007 Principles and Practice of Gamma Pittsburgh, PA CONTACT: Charlene Baker Knife Radiosurgery TEL: 412/647-7744 EMAIL: [email protected] WEB SITE: www.neurosurgery.pitt.edu TUMOR

MARCH 2, 2007 3rd Annual Pituitary Update Conference Cleveland, OH CONTACT: Martha Tobin TEL: 800/223-2273, Ext. 53449 EMAIL: [email protected] WEB SITE: www.clevelandclinic.org/ neuroscience/professionals/cme MARCH 2–4, 2007 Hands-on Cadaver Workshop: Microsurgical St. Louis, MO CONTACT: Practical Anatomy & Surgical Approaches to Intrinsic Brain Tumors Education TEL: 314/977-7400 FAX: 314/977-7345 EMAIL: [email protected] WEB SITE: http: //pa.slu.edu APRIL 13–14, 2007 AANS/CNS Section on Tumors Seventh Washington, DC CONTACT: Paula Nedza Biennial Symposium TEL: 847/378-0500 EMAIL: [email protected] WEB SITE: www.AANS.org CEREBROVASCULAR

MARCH 5–9, 2007 Microsurgery of Aneurysms: St. Louis, MO CONTACT: Practical Anatomy and Surgical Recent Advances Education TEL: 314/535-4000 FAX: 314/535-8214 WEB SITE: http: //pawslab.slu.edu JULY 30–AUGUST 3, 2007 4th Annual ASITN Course & Workshops Dana Point, CA CONTACT: ASITN WEB SITE: www.asitn.org

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PEDIATRICS MAY 3–4, 2007 Workshop on Endoscopic Treatment of San Antonio, TX Contact: Melissa D. Dockal, Assistant to Craniosynostosis the Chair Tel: 210/567-5626 Fax: 210/567-6066 Email: [email protected] Web Site: http: //neurousrgery.uthscsa.edu TRAUMA / CRITICAL CARE

MARCH 24–25, 2007 Principles of Operative Treatment of Syracuse, NY CONTACT: AO North American Craniomaxillofacial Trauma and TEL: 800/769-1391 Reconstruction FAX: 610-695-2420 WEB SITE: www.aona.org APRIL 21–22, 2007 Principles of Operative Treatment of Cleveland, OH CONTACT: AO North American Craniomaxillofacial Trauma and TEL: 800/769-1391 Reconstruction FAX: 610/695-2420 WEB SITE: www.aona.org MAY 24–26, 2007 2nd Biennial International Vocational Vancouver, Canada TEL: 604/875 1775 Outcomes in Traumatic Brain Injury FAX: 604/682 1521 Conference EMAIL: [email protected] WEB SITE: www.tbicvancouver.com MAY 29, 2007 Surgical Management of Maxillofacial Jasper, Canada CONTACT: AO North America Trauma Canadian Association of Oral TEL: 800/769-1391 and Maxillofacial Surgeons (CAOMS) FAX: 610/695-2420 WEB SITE: www.aona.org AUGUST 4–5, 2007 Principles of Operative Treatment of Kansas City, MO CONTACT: AO North America Craniomaxillofacial Trauma and TEL: 800/769-1391 Reconstruction FAX: 610/695-2420 WEB SITE: www.aona.org AUGUST 18–19, 2007 Principles of Operative Treatment of Minneapolis, MN CONTACT: AO North America Craniomaxillofacial Trauma and TEL: 800/769-1391 Reconstruction FAX: 610/695-2420 WEB SITE: www.aona.org SEPTEMBER 21–23, 2007 International Conference on Recent Tianjin, China CONTACT: Kui Lui, M.D., Ph.D. Advances in Neurotraumatology TEL: 86/22-23359875 FAX: 86/22-23359858 EMAIL: [email protected] OCTOBER 6–7, 2007 Principles of Operative Treatment of Charlotte, NC CONTACT: AO North America Craniomaxillofacial Trauma and TEL: 800/769-1391 Reconstruction FAX: 610/695-2420 WEB SITE: www.aona.org OCTOBER 20–21, 2007 Principles of Operative Treatment of Dallas, TX CONTACT: AO North America Craniomaxillofacial Trauma and TEL: 800/769-1391 Reconstruction FAX: 610/695-2420 WEB SITE: www.aona.org NOVEMBER 3–4, 2007 Principles of Operative Treatment of Miami, FL CONTACT: AO North America Craniomaxillofacial Trauma and TEL: 800/769-1391 Reconstruction FAX: 610/695-2420 WEB SITE: www.aona.org DECEMBER 1–2, 2007 Principles of Operative Treatment of New Jersey or CONTACT: AO North America Craniomaxillofacial Trauma and New York (TBD) TEL: 800/769-1391 Reconstruction FAX: 610/695-2420 WEB SITE: www.aona.org

CRANIAL BASE

MAY 2–6, 2007 Eighth Congress of the European Skull Prague, Czech Republic CONTACT: Prof. Vladimir Benes, M.D., Ph.D. Base Society: Multimodality Management TEL: 420/973 202 951 FAX: 420/973 202 963 EMAIL: [email protected] WEB SITE: www.esbs2007.com

NEUROSURGERY VOLUME 60 | NUMBER 3 | MARCH 2007 | E585 CALENDAR OF EVENTS

MINIMALLY INVASIVE NEUROSURGERY

MARCH 26–30, 2007 Hands-on Workshop in “Endoscope- Mainz, Germany CONTACT: Ms. Sandra Hoelle Assisted Keyhole Microneurosurgery” TEL: 49/7461 95 1132 FAX: 49/7461 95 2050 EMAIL: [email protected] WEB SITE: www.aesculap-neuro.com MAY 9–12, 2007 Neuroendoscopy 2007 Paris, France CONTACT: NEUROENDOSCOPY 2007/MCI FRANCE TEL: 01 53 85 82 53 FAX: 01 53 85 82 83 EMAIL: [email protected] WEB SITE: www.neuroendoscopy2007.com JUNE 27–30, 2007 ISCAS—11th Annual Conference of the Berlin, Germany CONTACT: Ms. Franziska Schweikert International Society for Computer Aided TEL: +49/7742 922 434 Surgery FAX: +49/7742 922 438 EMAIL: offi[email protected] WEB SITE: http: //www.cars-int.org JULY 2–6, 2007 Hands-on Workshop in “Endoscope- Tuttlingen, Germany CONTACT: Ms. Sandra Hoelle Assisted Keyhole Microneurosurgery” TEL: 49/7461 95 1132 FAX: 49/7461 95 2050 EMAIL: [email protected] WEB SITE: www.aesculap-neuro.com SEPTEMBER 3–7, 2007 Hands-on Workshop in “Endoscope- Mainz, Germany CONTACT: Ms. Sandra Hoelle Assisted Keyhole Microneurosurgery” TEL: 49/7461 95 1132 FAX: 49/7461 95 2050 EMAIL: [email protected] WEB SITE: www.aesculap-neuro.com SPECIAL TOPICS

MARCH 8–11, 2007 Neuro-oncology 2007: Current Concepts Oahu, HI CONTACT: The Cleveland Clinic Educational Foundation TEL: 800/223-2273, Ext. 53449 FAX: 216/445-9406 EMAIL: [email protected] WEB SITE: www.clevelandclinicmeded.com/ neurooncology2007 MARCH 16–18, 2007 7th Meeting of the Conosur Society of Gramado, Brazil CONTACT: Apio Antunes, M.D., Ph.D. Neurological Surgeons TEL: 55/51-3222-5760 FAX: 55/51-3222-5760 EMAIL: [email protected] WEB SITE: www.plenariumcongressos.com.br MARCH 17–20, 2007 International Symposium on Cognitive Tübingen, Germany TEL: 49/70712980325 Neurosurgery FAX: 49/7071294549 EMAIL: [email protected] WEB SITE: www.iscns.org MARCH 30–APRIL 1, 2007 Challenges and Advances: State of the Art Baltimore, MD CONTACT: AO North American Reconstruction in Microsurgery TEL: 800/769-1391 FAX: 610/695-2420 WEB SITE: www.aona.org APRIL 28–29, 2007 Fundamentals of Orbital and Mid-facial Rosemont, IL CONTACT: AO North America Reconstruction TEL: 800/769-1391 FAX: 610/695-2420 WEB SITE: www.aona.org MAY 6–JUNE 8, 2007 The Society of Neurological Surgeons San Francisco, CA WEB SITE: www.societyns.org Annual Meeting (Senior Society) MAY 20–22, 2007 Neurosurgery Review by Case Houston, TX CONTACT: Vanessa Garlisch Management: Oral Board Preparation TEL: 847/378-0600 EMAIL: [email protected] WEB SITE: www.AANS.org

E585 | VOLUME 60 | NUMBER 3 | MARCH 2007 www.neurosurgery-online.com CALENDAR OF EVENTS

MAY 22–26, 2007 ABNS Oral Board Examination Houston, TX CONTACT: ABNS TEL: 715/441-6015 FAX: 715/794-0207 EMAIL: [email protected] WEB SITE: www.abns.org MAY 27–29, 2007 ABNS Oral Board Examination Houston, TX TEL: 715/441 6015 FAX: 715/794 0207 EMAIL: [email protected] WEB SITE: www.abns.org JUNE 4–8, 2007 Gamma Knife Radiosurgery Training Program Cleveland, OH CONTACT: Rosemary Vernick TEL: 216/444-7591 FAX: 216/445-9999 WEB SITE: www.clevelandclinicmeded.com JUNE 9–14, 2007 ASNR 45th Annual Meeting & NER Chicago, IL CONTACT: ASNR 45th Annual Meeting Foundation Symposium 2007 TEL: 630/574-0220 FAX: 630/574-1740 EMAIL: [email protected] WEB SITE: www.asnr.org/2007 JUNE 15–16, 2007 5th Annual ASITN Practicum Chicago, IL CONTACT: ASITN TEL: 703/691-2272 WEB SITE: www.asitn.org JUNE 27–30, 2007 11th Annual Conference of the Berlin, Germany CONTACT: CARS Conference Office International Society for Computer TEL: 49/7742922434 Aided Surgery FAX: 49/7742922438 EMAIL: offi[email protected] WEB SITE: www.cars-int.org JUNE 27–30, 2007 Computer Assisted Radiology & Berlin, Germany TEL: 49/7742922434 Surgery—21st International Congress FAX: 49/7742922438 & Exhibition EMAIL: offi[email protected] WEB SITE: www.cars-int.org JULY 7–8, 2007 Challenges and Advances: Distraction Toronto, Canada CONTACT: AO North America Osteogenesis TEL: 800/769-1391 FAX: 610/695-2420 WEB SITE: www.aona.org JULY 11–14, 2007 14th IMAST Paradise Island, CONTACT: IMAST Meeting Planning Office Bahamas TEL: 630/681-1040 FAX: 630/682-5811 WEB SITE: www.imastonline.com SEPTEMBER 5–8, 2007 The British Scoliosis Society in Conjunction Edinburgh, Scotland CONTACT: Scoliosis Research Society with the Scoliosis Research Society TEL: 414/289-9107 42nd Annual Meeting FAX: 414/276-3349 EMAIL: [email protected] WEB SITE: www.srs.org SEPTEMBER 5–8, 2007 SRS 42nd Annual Meeting & One-day Edinburgh, Scotland CONTACT: Michael John McMaster Course WEB SITE: www.srs.org/meetings OCTOBER 10–13, 2007 American Academy for Cerebral Palsy Vancouver, Canada CONTACT: American Academy for Cerebral Palsy and Developmental Medicine & Developmental Medicine TEL: 414/918-3014 FAX: 414/276-2146 EMAIL: [email protected] WEB SITE: www.aacpdm.org NOVEMBER 4-6, 2007 Neurosurgery Review by Case Houston, TX CONTACT: Vanessa Garlisch Management: Oral Board Preparation TEL: 847/378-0500 EMAIL: [email protected] WEB SITE: www.AANS.org

NEUROSURGERY VOLUME 60 | NUMBER 3 | MARCH 2007 | E586 THIS MONTH IN NEUROSURGERY

MARCH 2007 Podcasts available at www.neurosurgery-online.com EDITOR’S CHOICES

FEATURED ON THE WEB GAMMA KNIFE RADIOSURGERY IN THE MANAGEMENT 460 490 546 555 OF MALIGNANT MELANOMA BRAIN METASTASES This study reviews the outcome of patients who REBUILDING LOST HEARING (OU) and Casady High School were instrumented underwent gamma knife radiosurgery for the BY CELL TRANSPLANTATION with the head Impact Telemetry System, which management of melanoma brain metastases. A total of The concept of hearing restoration, while enticing, enabled real-time monitoring and recording of 244 patients were treated for 754 tumors. The global has been marked by a distinct pessimism. The linear magnitude, rotational magnitude, and survival after radiosurgery was 5.3 months. Improved peripheral auditory nervous system has complex duration of the head impact. The recordings survival was achieved in cases of single metastases, KPS anatomy, and hearing loss has long been thought showed that college players sustained high level of 90% or more, and controlled systemic disease. to be irreversible because it involves permanent impacts more frequently than high school players, Sustained local control was seen in 86.2% of tumors after loss of sensory hair cells and neurons. Recent and skill position players sustained high level radiosurgery. Tumor volume and hemorrhagic changes in progress in molecular and cellular biology brings a impacts more frequently than linemen. Studies the tumor were the most important factors affecting local renewed optimism to the field and provides such as these will ultimately improve the clinical control. Symptomatic complication rates associated with opportunities for novel treatments based on gene understanding of mechanisms of concussion and radiosurgery were low. This study confirms the safety and therapy and cell transplantation. In this paper, the increase safety for football players. [p. 490] efficacy of gamma knife radiosurgery for the management authors focus on cell transplantation, paying of melanoma brain metastases. [p. 471] particular attention to the auditory nerve and the MINIMALLY INVASIVE LUMBAR SPINAL cerebellopontine angle side rather than the DECOMPRESSION FOR THE ELDERLY: EVALUATION AND TREATMENT OF PATIENTS WITH cochlea. The auditory nerve is crucially placed PROSPECTIVE OUTCOMES OF 57 and provides a safe and effective route for the PATIENTS AGED 75 YEARS OR OLDER SUSPECTED NORMAL PRESSURE HYDROCEPHALUS ON delivery of donor cells. [p. 417] Degenerative lumbar spinal disease is a major LONG-TERM ANTICOAGULATION THERAPY cause of morbidity among the elderly. Minimally Long-term anticoagulation therapy is often considered to EMBOLIZATION PRIOR TO RADIOSURGERY invasive surgical techniques that have recently be a contraindication to shunt surgery in elderly patients REDUCES THE OBLITERATION RATE OF been developed to treat lumbar spinal disease are with normal pressure hydrocephalus (NPH). This study ARTERIOVENOUS MALFORMATIONS particularly appealing in elderly patients evaluates risk of shunt surgery in NPH patients on This study examines the effect of prior endovas- considered to be poor surgical candidates due to warfarin. In total, 25 patients were evaluated for cular embolization on the rate of obliteration of age or comorbidities. This study examines the possible shunt surgery with a protocol of CSF pressure brain arteriovenous malformations (AVM) after outcomes of 57 patients aged 75 years or older monitoring and controlled CSF drainage via spinal radiosurgery. Between 1989 and 2000, 61 who underwent minimally invasive lumbar spine catheter. Of the 15 patients who underwent shunt patients with prior embolization were treated with decompression surgery. Significant improvements surgery, 87% showed significant improvement in at LINAC radiosurgery. Of these, 47 patients were were observed in back pain, leg pain, and least one symptom at mean follow-up of 8.2 months. identified to have matched controls in terms of physical function with few complications. The Only one patient developed a subdural hematoma, and AVM volume, location, and marginal dose, results suggest that elderly patients can be there were no thromboembolic complications while off forming two study groups A and B. The median considered candidates for minimally invasive warfarin during the perioperative period. This study follow-up was 44 months. The study found that lumbar spine surgery. [p. 503] concludes that elderly patients on warfarin can be obliteration rates after radiosurgery were signifi- safely evaluated and treated for NPH. [p. 497] cantly lower in the group treated with prior em- QUANTUM DOTS ARE PHAGOCYTIZED BY bolization compared to the matched controls. The MACROPHAGES AND COLOCALIZE WITH LITIGATION OF MISSED CERVICAL SPINE authors conclude that they can no longer support EXPERIMENTAL GLIOMAS INJURIES IN PATIENTS PRESENTING WITH the practice of planned pre-radiosurgery emboli- A method for rapid, accurate distinction of tumor BLUNT TRAUMATIC INJURY zation in patients with the AVM characteristics tissue from normal brain tissue has the potential to This study provides data on the causes and costs of similar to those included in the study. [p. 443] improve outcomes in the surgical management of litigation of missed cervical spine injury in patients brain tumors. Nanoparticles are often identified presenting with blunt trauma. In addition, the authors STEREOTACTIC RADIOSURGERY FOR VESTIBULAR by the body as foreign materials and sequestered have analyzed the causes of missed injuries and SCHWANNOMAS IN PATIENTS WITH NEURO- by the reticuloendothelial system, including the resultant outcomes of litigation, with the goal of FIBROMATOSIS TYPE II: AN ANALYSIS OF resident tissue macrophages and microglia which determining whether “under-imaging” contributed TUMOR CONTROL, COMPLICATIONS, AND colocalize with brain tumors. Quantum dots are a significantly to the occurrence of missed injuries and HEARING PRESERVATION RATES type of optical nanocrystal with favorable resultant litigation. To this end, the authors have This article reports a single institutional experi- characteristics for in vivo use, such as lack of developed a simple classification scheme for errors ence with gamma knife radiosurgery for the known toxicity and resistance to photobleaching. in diagnosis that will be useful to other researchers management of vestibular schwannomas associ- This study shows that when delivered in nano- in this area. The study adds medicolegal support for ated with neurofibromatosis type II. In total, 74 molar doses in a rat model of experimental the judicious use of imaging studies to clear cervical tumors were treated in 62 patients with a median glioma, these particles are visible within brain spines and concludes that exposure to liability follow-up of 53 months. The local control rate tumors, but not in normal tissues. This optical makes a low threshold for CT a reasonable was 87.5% for all tumors, and tumor volume was labeling of tumors may augment the surgical alternative. [p. 516] predictive of local control. The serviceable hearing biopsy and resection of brain tumors. [p. 524] preservation rate was 52.6%, and the risk of per- EVOLUTION OF THE HUMAN BRAIN: CHANGING manent facial, trigeminal, and vestibular dysfunc- TREATMENT OF TRAUMATIC BRAIN INJURY WITH A BRAIN SIZE AND THE FOSSIL RECORD tion were 7.7%, 3.8%, and 3.8%, respectively. COMBINATION THERAPY OF MARROW STROMAL Research concerning the evolution of the human Radiation dose was the most significant predictive CELLS (MSCS) AND ATORVASTATIN IN RATS brain is rooted in the desire to equate intelligence factor for both hearing preservation and the oc- Bone marrow stromal cells (MSCs) and statins and behavior with certain structures and currence of complications. There were no cases have individually shown promise in repairing measurements of the brain. This field requires a of malignant degeneration in irradiated tumors or tissue damage from a variety of disorders, in- multidisciplinary approach to thoroughly new radiation-induced tumors. This study con- cluding traumatic brain injury (TBI), stroke, and examine the factors and effects of genetics, firms the safety and efficacy of stereotactic radio- myocardial ischemia. After demonstrating the behavior, anatomy, and physiology on the surgery as primary management of vestibular benefits with monotherapies of MSCs and development of the human brain. In this article, schwannomas in neurofibromatosis type II statins, the authors designed a novel study to the authors examine some of the major theories patients. [p. 460] examine the efficacy of combination therapy concerning how brains, human and otherwise, with MSCs and atorvastatin in a rat model of increased in size throughout evolution. They IN VIVO STUDY OF HEAD IMPACTS IN TBI. The study found that combination therapy compare the changes in overall brain size in FOOTBALL: A COMPARISON OF NCAA with MSCs and atorvastatin has a superior hominids as illustrated by the fossil record DIVISION I VERSUS HIGH SCHOOL IMPACTS effect on the reduction of neurological deficits and examine instances of behavioral This study compares the frequency and mag- compared to the monotherapies. This demon- changes in our early ancestors that correlate nitude of head impact between NCAA Division I strates that these treatments are complementary with these changes. This article gives an and high school American football players. The and allows for decreased dosages of individual introduction to one of the central tenets of helmets of players at the University of Oklahoma agents. [p. 546] this field of study. [p. 555]

CHARLES Y. LIU, M.D., PH.D., CONTRIBUTOR N5 Coming in the April Issue of... EUROSURGER N OFFICIAL JOURNAL OF THE CONGRESS OF NEUROLOGICAL SURGEONSY APRIL 2007 VOLUME 60 NUMBER 4

SPECIAL EXPERIMENTAL STUDY CLINICOPATHOLOGICAL STUDIES Magnetic Resonance Imaging-guided Focused Ultrasound for Thermal Clinical Significance of ABCA2, a Possible Molecular Marker Ablation in the Brain: A Feasibility Study in a Swine Model for Oligodendroglioma Ram/Cohen Soichi Solitary Fibrous Tumors of the Central Nervous System: CLINICAL STUDIES Clinicopathological and Therapeutic Considerations of 18 Cases Metellus Potential of Ferumoxytol Nanoparticle Magnetic Resonance Imaging, Perfusion, and Angiography in Central Nervous System Malignancy EXPERIMENTAL STUDIES Neuwelt Prolonged Target Deprivation Reduces the Capacity of Injured Treatment Options for Third Ventricular Colloid Cysts: Motoneurons to Regenerate Comparison of Open Microsurgical versus Endoscopic Resection Gordon/Furey/Midha Spetzler/Horn An Experimental Model of Ventral Root Repair Showing the Beneficial Response of C-reactive Protein after Craniotomy for Effect of Transplanting Olfactory Ensheathing Cells Microsurgery of Intracranial Tumors Choi/Li Mirzayan/Samii Augmentation of Cerebral Blood Flow and Reversal of Endovascular Coil Embolization of Ruptured and Unruptured Endothelin-1-induced Vasospasm: A Comparison of Intracarotid Posterior Circulation Aneurysms: Review of a 10-year Experience Nicardipine and Verapamil Veznedaroglu/Pandey/Rosenwasser Joshi/Lavine The Effects of Diffuseness and Deep Perforating Artery Supply Establishment of an In Vivo Meningioma Model with Human on Outcomes after Microsurgical Resection of Brain Telomerase Reverse Transcriptase Arteriovenous Malformations Carroll/Black Lawton/Du/Lawton Cognitive Outcome after Aneurysmal Subarachnoid Hemorrhage: LEGACIES Time-course of Recovery and Relationship to Clinical, Radiological, and Management Parameters The Significance of the Rete Mirabile in Vesalius’ Work: Foss An Example of the Dangers of Inductive Inference in Medicine Bataille Predictors of Cerebral Infarction in Patients with Aneurysmal Subarachnoid Hemorrhage E. Latunde Odeku: The First African-American Neurosurgeon Macdonald/Ferguson Trained in the United States McClelland A Polymorphism in the Tumor Necrosis Factor-α Gene is Associated with Aneurysmal Subarachnoid Hemorrhage CASE REPORTS Fontanella Detection of Caspase-3, Neuron-specific Enolase and High-sensitivity Symptomatic Mass Effect of a Hypertrophied Pericranial Flap after C-reactive Protein Levels in both the Cerebrospinal Fluid and Serum Repair of a Dural Defect: Case Report of Patients after Aneurysmal Subarachnoid Hemorrhage Than Tanriverdi/Kacira Chronic Subdural Hematoma Associated with Subdural Influence of Nerve Radiation Dose in the Incidence of Trigeminal Rhabdomyosarcoma: Case Report Dysfunction after Trigeminal Neuralgia Radiosurgery Nejat/Keshavarzi Massager/Levivier Superior Sagittal Sinus Thrombosis Owing to Calvarial Tuberculosis: Early Hypodensity on Computed Tomography of the Brain in Case Report Accidental Pediatric Head Injury Sundaram Steinbok Neuromuscular Choristoma of the Oculomotor Nerve: Case Report A Novel Approach to the Diagnosis and Management of Kawamoto Meralgia Paresthetica Lymphangioma of the Clivus: Case Report O’Neill/Nouraei Kaya Extracranial Nasopharyngeal Craniopharyngioma: Case Report SPECIAL TECHNICAL REPORT Heth/Shuman Middle Cerebral Artery Stenting for Acute Ischemic Stroke after Symptomatic Chiari Type I Malformation after Radiation Therapy Unsuccessful Merci Retrieval in an Infant: Case Report Hopkins/Sauvageau/Levy Souweidane/Hoffman

Entire Journal content and NEUROSURGERY Podcasts available online at www.neurosurgery-online.com