Endocrinol Metab 25(4):310-315, December 2010 ORIGINAL ARTICLE 비기능성뇌하수체선종환자에게서뇌하수체기능저하와자기공명영상검사소견과의상관관계 김현민 1 구철룡 1 이은영 1 이우경 1 임정수 1 황세나 1 이미정 1 이승구 4 김선호 2,3,5 이은직 1,2,3 연세대학교의과대학내분비내과 1, 내분비연구소 2, 뇌하수체종양센터 3, 영상의학과 4, 신경외과 5 Correlation between Pituitary Insufficiency and Magnetic Resonance Imaging Finding in Non-Functioning Pituitary Adenomas Hyun Min Kim 1, Cheol Ryong Ku 1, Eun Young Lee 1, Woo Kyung Lee 1, Jung Soo Lim 1, Sena Hwang 1, Mi Jung Lee 1, Seung Ku Lee 4, Sun Ho Kim 2,3,5, Eun Jig Lee 1,2,3 Department of Endocrinology 1, Institute of Endocrine Research 2, Pituitary Tumor Clinic 3, Departments of Radiology 4 and Neurosurgery 5, Yonsei University College of Medicine, Seoul, Korea Background: Non-functioning pituitary adenomas (NFPAs) are characterized by the absence of clinical and biochemical evidence of pituitary hormone hypersecretion, and these tumors constitute approximately one third of all the tumors of the anterior pituitary. Recently, hormonal deficiencies have gradually evolved to become the leading presenting signs and symptoms in patients with NF- PAs. We investigated pituitary hormonal insufficiencies according to the magnetic resonance imaging (MRI) findings in patients with NFPA. Methods: We evaluated the patients who were newly diagnosed with NFPA from 1997 through 2009. Among them, we analyzed 387 patients who were tested for their combined pituitary function and who underwent MRI. The severity of the hypopituitarism was determined by the number of deficient axes of the pituitary hormones. On the MRI study, the maximal diameter of the tumor, Hardy s classification, the thickness of the pituitary gland and the presence of stalk compression were evaluated. Results: The mean age was 46.85 ± 12.93 years (range: 15-86) and 186 patients (48.1%) were male. As assessed on MRI, the tumor diameter was 27.87 ± 9.93 mm, the thickness of the normal pituitary gland was 1.42 ± 2.07 mm and stalk compression was observed in 201 patients (51.9%). Hypopituitarism was observed in 333 patients (86.0%). Deficiency for each pituitary hormone was most severe in the patients with Hardy type IIIA. Hypopituitarism was severe in the older age patients (P = 0.001) and the patients with a bigger tumor size (P < 0.001) and the presence of stalk compression (P < 0.001). However, the patients who had a thicker pituitary gland showed less severe hypopituitarism (P < 0.001). Multivariate analysis showed that age, tumor diameter and the thickness of pituitary gland were important determinants for pituitary deficiency (P = 0.004, P < 0.001, P = 0.022, respectively). Conclusion: The results suggest that the hormonal deficiencies in patient with NFPA were correlated with the MRI findings, and especially the tumor diameter and preservation of the pituitary gland. (Endocrinol Metab 25:310-315, 2010) Key Words: Non-functioning pituitary adenomas, Hypopituitarism, Magnetic resonance imaging 서론 뇌하수체종양은모든원발성뇌종양의 10-20% 를차지하며, 부검을통한조사에서도 25% 에서발견되는상대적으로흔한질환이다 [1]. 그중비기능성뇌하수체선종은임상적, 그리고생화학적으로 Received: 25 June 2010, Accepted: 12 September 2010 Corresponding author: Eun Jig Lee Department of Endocrinology, Yonsei University College of Medicine, 262 Seongsan-no, Seodaemun-gu, Seoul 120-752, Korea Tel: +82-2-2228-1983, Fax: +82-2-393-6884, E-mail: ejlee423@yuhs.ac 뇌하수체호르몬의과다분비가없다는특성을지니며 [2,3], 뇌하수체종양중가장흔하여뇌하수체전엽에발생하는모든종양의 1/3 을차지하는것으로알려져있다 [4]. 비기능성뇌하수체선종에서는호르몬의과잉분비로인한증상이드물기때문에조기진단이힘들어주로거대선종이되어주위조직을압박하여증상을일으켜진단이되는경우가많다. 그러나 1980년대이후자기공명영상이나컴퓨터단층촬영과같은영상기술과보다정확하고미세한내분비적검사가발달함에따라조기진단이용이하게되었고, 최근에는진단당시에시야장애와같은압박증상보다는뇌하수체기능저하증
Correlation between Pituitary Insufficiency and MRI Finding in NFPAs 311 을보이는경우가점차많아지고있는추세이다 [5]. 뇌하수체선종환자에게서선종의크기, 형태및연령에따른뇌하수체기능저하증의정도를확인한연구는있었으나 [5], 정상뇌하수체의크기나형태에따른뇌하수체기능부전의정도에대해서는아직알려진바가없다. 따라서본연구에서는비기능성뇌하수체선종을진단받은환자들을대상으로진단당시의자기공명영상소견, 특히종양자체의특성및남아있는뇌하수체의형태에따른뇌하수체기능부전과의연관성을확인하고자하였다. 대상및방법 혹은시상단면에서의장경을측정하였고, modified Hardy s classification에 따라서분류하였다 [7,9] (Fig. 1). 고식적인 Hardy s classification에추가하여, type III를다시 2개의군으로구분하여선종이터어키안상부침범을한경우를 IIIA로분류하였고, 선종이해면정맥동을침범하고내경정맥동맥과접형동침범을한경우를 IIIB로분류하였다 [10-12]. 뇌하수체줄기의편위혹은압박은관상단면에서확인하였을때정중앙에서의편위만존재하는경우를뇌하수체줄기의편위로정의하였고, 뇌하수체줄기의구조를관찰할수없는경우를뇌하수체줄기의압박으로정의하였다 [13] (Fig. 2). 뇌하수체의크기는관상단면혹은시상단면에서의장경으로측정하였다 (Fig. 3). 1. 대상및조사방법 1997년 2월부터 2009년 12월까지연세대학교의과대학세브란스병원에서비기능성뇌하수체선종을진단받은환자들을대상으로후향적의무기록분석을시행하였다. 모든환자들은비기능성뇌하수체선종에대해수술을시행받았다. 수술전에뇌하수체호르몬자극검사를시행하지않은환자를제외하고총 387예의환자를분석대상으로하였으며, 의무기록을통하여성별, 연령, 진단당시임상증상을조사하였다. 본연구는헬싱키선언을준수하여진행하였다. 2. 뇌하수체기능의평가뇌하수체기능을평가하기위해모든환자에게서복합뇌하수체자극호르몬검사를시행하였다. 다음의프로토콜을따랐으며 [6], 적합한저혈당의유도는당뇨의과거력이없는환자에게서는혈당이 40 mg/dl 이하, 당뇨의과거력이있는환자에게서는혈당이기저치보다 50% 이상감소된경우로하였다. 복합뇌하수체자극검사시정상반응의평가는 Table 1을기준으로하였다 [6-8]. 4. 통계및분석모든결과값은평균 ± 표준편차로표시하였고정규분포를따르지않는변수는정중값과범위로표시하였다. 모든통계분석은 SPSS software 17.0 (SPSS Inc., Chicago, IL, USA) 을사용하였다. 연령및자기공명영상에서관찰되는종양의특징에따른뇌하수체기능부전정도의차이에대한통계분석은 one-way ANOVA 를사용하였고, Tukey 의방법으로사후검정을시행하였다. 뇌하수체기능부전에영향을미치는독립적인인자들을알아보기위해다중선형회귀분석을이용하여분석하였다. P값이 0.05 미만일때통계학적으로유의한것으로판정하였다. 3. 자기공명영상검사 뇌하수체종양의크기는두경부자기공명영상을통해관상단면 Fig. 1. Measurement of the tumor size as a maximal diameter in coronal plane. Table 1. Interpretation of combined pituitary function test Test Blood sampling (min) Hormone Normal response Insulin tolerance test (RI, 0.1 U/kg i.v.) TRH stimulation test (500 μg i.v.) LHRH stimulation test (100 μg i.v.) 0, 30, 60, 90, 120 GH Peak GH > 3 ng/ml Cortisol Peak cortisol > 180 ng/ml or increase by 70 ng/ml ACTH Response decision by cortisol response 0, 15, 30, 60, 120 PRL 2 ng/ml < baseline PRL < 15 ng/ml, and peak PRL > 200% of baseline TSH Peak TSH > basal TSH + 5 μiu/ml and free thyroxine in normal range 0, 15, 30, 60, 120 FSH Peak FSH > basal FSH + 2 miu/ml, elevated baseline in postmenopausal women LH Peak LH > basal LH + 10 miu/ml, elevated baseline in postmenopausal women Nadir glucose should be less than 40 mg/dl in nondiabetics or less than 50% of basal level in diabetics for appropriate stress induction. GH, growth hormone; ACTH, adrenocorticotropic hormone; i.v., intravenously; PRL, prolactin; TSH, thyroid-stimulating hormone; TRH, thyrotropin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; LHRH, luteinizing hormone- releasing hormone; RI, regular insulin.
312 Kim HM, et al. Table 2. Baseline characteristics of 387 patients A C A Fig. 3. Measurement sites of the pituitary gland. (A) Maximal height were measured in coronal plane. (B) Maximal height were measured in sagittal plane. 결과 총 387 예의환자중남성은 186 예 (48.1%), 여성은 201 예였고 (51.9%), 연령은평균 46.85 ± 12.93 세 (15-86 세 ) 였다. 평균추적관찰 기간은 64.38 ± 41.54 개월 (6-148 개월 ) 이었다. 333 예 (86.0%) 의환자에 게서한가지호르몬이상의뇌하수체기능부전이발견되었으며, 성장호르몬결핍이가장흔하였다 (273 명, 70.5%). 성선자극호르몬 결핍은 242 예 (62.5%), 부신피질자극호르몬결핍은 184 예 (47.5%), 갑 상선자극호르몬결핍은 182 예 (47.0%), 프로락틴결핍은 76 예 (19.6%) 에서관찰되었으며, 고프로락틴혈증을가진환자는 188 예 (48.6%) 였 다. 자기공명영상검사에서평균종양의크기는 27.87 ± 9.93 mm (5.35-60.31 mm), 평균뇌하수체크기는 1.42 ± 2.07 mm (0-11.68 mm) 였으며, 뇌하수체줄기의편위는 146 예 (37.7%), 압박은 201 예 (51.9%) 에서관찰되었다. Hardy s classification 에따른분류에서는 B Fig. 2. (A) An example case of normal stalk morphology. (B) An example case of stalk deviation; The stalk attachment of the pituitary gland deviated from the midline to the right side (dotted line). (C) An example case of stalk compression; Normal stalk morphology are not seen. B Characteristics Value No. of patients 387 Mean age (years) 46.85 ± 12.93 (15-86) Male (%) 186 (48.1%) Pituitary function Pituitary insufficiency (%) 333 (86.0%) GH 273 (70.5%) LH/FSH 242 (62.5%) ACTH 184 (47.5%) TSH 182 (47.0%) PRL 76 (19.6%) Hyperprolactinemia 188 (48.6%) MRI findings Tumor diameter (mm) 27.87 ± 9.93 (5.35-60.31) Thickness of pituitary gland (mm) 1.42 ± 2.07 (0-11.68) Presence of stalk compression (%) Normal stalk morphology 40 (10.3%) Stalk deviation 146 (37.7%) Stalk compression 201 (51.9%) Hardy s classification (%) I 21 (5.4%) II 58 (15.0%) IIIA 101 (26.1%) IIIB 153 (39.5%) IV 54 (14.0%) GH, growth hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; PRL, prolactin. Table 3. Pituitary insufficiency in different age groups Age Number of patients Number of deficient hormone < 20 4 1.75 ± 2.06 20 29 44 1.93 ± 1.60 30 39 66 2.33 ± 1.53 40 49 101 2.29 ± 1.46 50 59 107 2.69 ± 1.53 60 69 52 2.73 ± 1.49 70 13 3.85 ± 1.57* *P < 0.05, P values were calculated by one-way ANOVA. type IIIB 가 153 예 (39.5%) 로가장흔하였다 (Table 2). 뇌하수체기능 부전의정도는결핍된뇌하수체호르몬의축의개수로분석하였으 며, 연령이높아질수록뇌하수체기능부전은심해지는소견을보였 다 (P = 0.001) (Table 3). 또한종양의크기가증가할수록뇌하수체 기능부전의정도는악화되는소견을보였으며 (P < 0.001), Hardy s classification 에따라서는 type IIIA 환자에게서기능부전을보이는 호르몬축이 2.88 ± 1.43 개로가장심한부전을보였다 (P < 0.001) (Table 4). 이와는대조적으로뇌하수체조직의크기가클수록, 정상
Correlation between Pituitary Insufficiency and MRI Finding in NFPAs 313 Table 4. Pituitary Insufficiency depending on Tumor Size and Hardy s Classification Number of patients Table 5. Pituitary insufficiency depending on pituitary gland thickness and stalk morphology 뇌하수체줄기의형태가잘유지될수록뇌하수체기능부전은양호 한것으로나타났다 ( 각각 P < 0.001, P < 0.001) (Table 5). 뇌하수체 기능부전과관련되어있는독립적인인자를확인하기위해다중선 형회귀분석을시행하였으며, 그결과연령이높을수록 (P = 0.004), 종양의크기가클수록 (P < 0.001) 뇌하수체기능부전은심해지며, 남아있는뇌하수체의크기가클수록 (P = 0.022) 뇌하수체기능부 전은양호한것을알수있었으나, 상관계수는각각 0.016, 0.045, -0.108 로상관정도는낮았다 (Table 6). 고찰 Number of patients Number of deficient hormone Thickness of 5 mm 29 1.21 ± 1.55 pituitary gland < 5 mm 120 2.11 ± 1.57* Not seen 238 2.81 ± 1.45* Presence of stalk Normal stalk 40 1.18 ± 1.41 compression Stalk deviation 146 2.29 ± 1.59* Stalk compression 201 2.87 ± 1.38* *P < 0.001, P values were calculated by one-way ANOVA. Number of deficient hormone Tumor size < 10 mm 9 0.44 ± 0.52 10-20 mm 72 1.35 ± 1.42 20-30 mm 154 2.51 ± 1.53** 30-40 mm 101 3.03 ± 1.29** 40-50 mm 42 3.12 ± 1.23** 50 mm 9 3.56 ± 1.33** Hardy s I 21 1.19 ± 1.60 classification II 58 1.74 ± 1.58 IIIA 101 2.88 ± 1.43** IIIB 153 2.65 ± 1.51** IV 54 2.48 ± 1.35* *P < 0.05, **P < 0.001, P values were calculated by one-way ANOVA. 비기능성뇌하수체선종에서발생하는뇌하수체기능부전은뇌 하수체줄기문맥혈관의압박, 종양으로인한정상조직의압박, 터 키안내압력의증가에의해발생하는것으로알려져있다 [14]. 특히 뇌하수체는뇌하수체줄기를통해문맥혈관의혈액공급은물론 자극이나억제의신호전달이이루어지기때문에, 뇌하수체줄기의 기계적인압박은고프로락틴혈증과다른호르몬의기능부전을유 발한다 [15,16]. 이전연구결과와마찬가지로본연구에서도비기능 Table 6. Multiple linear regression for variables independently associated with impaired pituitary function Variable 성뇌하수체선종환자의 86.0% 에서한가지이상의뇌하수체기능 부전이발견되었으며, 빈도는성장호르몬의결핍이가장흔했고, 성 선자극호르몬 부신피질자극호르몬 갑상선자극호르몬 프로락틴 의순이었다 [17,18]. 성장호르몬결핍이있는환자의 75.9% 에서성선자극호르몬결핍 이동반되었으며, 59.8% 에서부신피질자극호르몬결핍도동반되었 으나, 성장호르몬결핍이없는환자의 30.7% 에서도성선자극호르몬 결핍이관찰되었다, 하지만, 후향적단면연구의한계로비기능성뇌 하수체선종환자에게서뇌하수체기능부전이나타나는시간적순 서를예측할수는없었다. 그러나성장호르몬이기능부전에가장 민감한호르몬이라는점과, 특히이것이비기능성뇌하수체선종환 자의 70% 이상에게서관찰된다는점을확인하였다 [19]. 본연구에서는, 자기공명영상검사상에서발견되는뇌하수체줄기 의압박및편위여부와남아있는뇌하수체의정도가뇌하수체기 능에보다직접적인효과를미치는것을확인하였다. Hardy s classification type III 의환자들을선종의주된침범방향에따라 IIIA 와 IIIB 로재분류하였을때, 터키안상부침범을한 IIIA 에서는 101 예의 환자중 65.3% 의환자에게서뇌하수체줄기압박이관찰되었고, 정 상뇌하수체줄기형태가남아있는경우는 1 예로매우드물었다. 이 와비교하여 IIIB 에서는 153 예의환자중 60.7% 에서뇌하수체줄기 압박이있었고, 5 예의환자에게서정상적인형태의뇌하수체줄기를 관찰할수있었으며, 뇌하수체기능부전정도는 IIIA 에서더중증으 로나타났다. 이렇게같은 Hardy s classification type 의환자에게서 발견되는기능부전의차이는종양크기및침습정도보다는뇌하수 체형태및양적인보존이뇌하수체기능에중요한영향을미친다는 점을시사한다. Number of deficient hormone Coefficient P-value Age (years) 0.016 0.004 Tumor size (mm) 0.045 < 0.001 Thickness of pituitary gland (mm) -0.108 0.022 Presence of stalk compression 0.167 0.288 Hardy s classification -0.118 0.149 188 예 (48.8%) 의환자에게서고프로락틴혈증이관찰되었으며, 이 는기존의 Karavitaki 등 [20] 의연구에서나타난 38.5% 와비슷한결 과를보였다. 또한고프로락틴혈증의정도도비교적경하여, Bevan 등 [21] 이제시한비기능성뇌하수체선종을시사하는기준치인 3,000 mu/l (150 ng/ml) 를초과하는경우는소수였다 (7 예, 3.82%) [21]. 비기능성뇌하수체선종환자에서종양으로인한뇌하수체줄 기의압박으로고프로락틴혈증이나타나는것이주된기전으로알 려져있으나 [22], 본연구에서는자기공명영상검사상에서관찰되는
314 Kim HM, et al. 뇌하수체줄기의편위혹은압박이고프로락틴혈증의발생에영향을미치는독립적인인자는아닌것으로나타났다. 터키안내압력의증가로인하여문맥혈관의압박으로시상하부-뇌하수체의신경전달과정에문제를일으키는것이나, 혈액공급의부족으로뇌하수체에허혈을야기하는것이다른기전으로제시되고있다 [16]. 후향적자료분석에의한결과라는점과단면연구를통해진단당시의자기공명영상소견과뇌하수체기능부전과의관계만을확인할수있다는점은본연구의한계점이다. 그러나본연구는종양의크기나 Hardy s classification 등종양자체의특성뿐아니라남아있는뇌하수체의크기나정상적인뇌하수체의줄기의형태가직접적으로뇌하수체기능부전에영향을미친다는결과를보여주었다. 추가적으로, 수술을고려할수있는비기능성뇌하수체선종환자에게서진단시자기공명영상에서관찰되는종양의특성과뇌하수체의크기및줄기의형태가그당시의뇌하수체기능부전뿐아니라수술후뇌하수체기능회복과어떠한연관성이있는지확인하고, 궁극적으로는비기능성뇌하수체선종환자에게서적합한수술의시점을결정하는데도움을줄수있는지를알아보는후속연구가필요할것으로생각된다. 요약배경 : 비기능성뇌하수체선종은뇌하수체종양중가장흔하며, 최근에는진단당시에시야장애와같은압박증상보다는뇌하수체기능저하증을보이는경우가점차많아지고있다. 본연구에서는비기능성뇌하수체선종을진단받은환자들을대상으로진단당시의자기공명영상소견, 특히종양자체의특성및남아있는뇌하수체의형태에따른뇌하수체기능부전과의연관성을확인하고자하였다. 방법 : 1997년 2월부터 2009년 12월까지연세대학교의과대학세브란스병원에서비기능성뇌하수체선종을진단받은환자들을대상으로후향적의무기록분석을시행하였으며, 수술전의뇌하수체호르몬자극검사결과와자기공명영상에서종양의장경, Hardy s classification, 뇌하수체의크기, 뇌하수체줄기의편위및압박을조사하였다. 결과 : 총 387예의환자가분석에포함되었다. 평균연령은 46.85 ± 12.93 세 (15-86 세 ) 였고, 남성이 186예 (48.1%) 였다. 자기공명영상상에서평균종양의크기는 27.87 ± 9.93 mm (5.35-60.31 mm), 평균뇌하수체크기는 1.42 ± 2.07 mm (0-11.68 mm) 였으며, 뇌하수체줄기압박은 201예 (51.9%) 에서관찰되었다. 한가지이상의뇌하수체기능부전은 333예 (86.0%) 에서발견되었으며, 성장호르몬결핍이가장흔하였다 (274 예, 70.5%). 뇌하수체기능부전의정도는 Hardy s classification type IIIA 환자에게서가장심하였으며, 결핍호르몬의수는연령이증가할수록 (P = 0.001), 종양의크기가커질수록 (P < 0.001) 증가하였으며, 뇌하수체의크기가클수록 (P < 0.001), 뇌하수 체줄기가정상형태일수록 (P < 0.001) 감소하는소견을보였다. 다 중선형회귀분석결과연령, 종양의크기및뇌하수체의크기가뇌 하수체기능부전의중요한결정인자인것으로나타났다 ( 각각 P = 0.004, P < 0.001, P = 0.022). 결론 : 비기능성뇌하수체선종환자에게서뇌하수체기능부전은 자기공명영상소견과관련되어있었으며, 특히종양및뇌하수체의 크기와깊은연관성을보였다. 참고문헌 1. Asa SL, Ezzat S: The pathogenesis of pituitary tumours. Nat Rev Cancer 2:836-849, 2002 2. Cheol Ryong Ku, Eun Jig Lee: Treatment and prognosis of non-functioning pituitary adenomas. Asia-Pacific Journal of Endocrinology, E-pub, 2010 3. Cury ML, Fernandes JC, Machado HR, Elias LL, Moreira AC, Castro M: Non-functioning pituitary adenomas: clinical feature, laboratorial and imaging assessment, therapeutic management and outcome. Arq Bras Endocrinol Metabol 53:31-39, 2009 4. Milker-Zabel S, Debus J, Thilmann C, Schlegel W, Wannenmacher M: Fractionated stereotactically guided radiotherapy and radiosurgery in the treatment of functional and nonfunctional adenomas of the pituitary gland. Int J Radiat Oncol Biol Phys 50:1279-1286, 2001 5. Nomikos P, Ladar C, Fahlbusch R, Buchfelder M: Impact of primary surgery on pituitary function in patients with non-functioning pituitary adenomas -- a study on 721 patients. Acta Neurochir (Wien) 146:27-35, 2004 6. Lee EJ, Ahn JY, Noh T, Kim SH, Kim TS, Kim SH: Tumor tissue identification in the pseudocapsule of pituitary adenoma: should the pseudocapsule be removed for total resection of pituitary adenoma? Neurosurgery 64:62-69, 2009 7. Melmed S, Kleinberg D: Anterior pituitary. In: Kronenberg H, Williams RH eds. Williams textbook of endocrinology. 11th ed. pp240-242, Philadelphia, Elsevier Saunders, 2008 8. Melmed S, Jameson JL: Disorders of the anterior pituitary and hypothalamus. In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J eds. Harrison s principles of internal medicine. 17th ed. pp2195-2216, New York, McGraw-Hill Medical, 2008 9. Mohr G, Hardy J, Comtois R, Beauregard H: Surgical management of giant pituitary adenomas. Can J Neurol Sci 17:62-66, 1990 10. Lee SC, Senior BA: Endoscopic skull base surgery. Clin Exp Otorhinolaryngol 1:53-62, 2008 11. Kassam AB, Gardner PA, Snyderman CH, Carrau RL, Mintz AH, Prevedello DM: Expanded endonasal approach, a fully endoscopic transnasal approach for the resection of midline suprasellar craniopharyngiomas: a new classification based on the infundibulum. J Neurosurg 108:715-728, 2008 12. Kassam AB, Prevedello DM, Thomas A, Gardner P, Mintz A, Snyderman C, Carrau R: Endoscopic endonasal pituitary transposition for a transdorsum sellae approach to the interpeduncular cistern. Neurosurgery 62:57-72, 2008
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