Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI The appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers -LRB- BRCA-MCs -RRB- on mammography and magnetic resonance imaging -LRB- MRI -RRB- was evaluated . Thus , 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age , tumor size and tumor type matched control group of 29 sporadic breast cancer cases . Detection rates on both modalities were evaluated . Tumors were analyzed on morphology , density -LRB- mammography -RRB- , enhancement pattern and kinetics -LRB- MRI -RRB- . Overall detection was significantly better with MRI than with mammography -LRB- 55/58 vs 44/57 , P = 0.021 -RRB- . On mammography , lesions in the BRCA-MC group were significantly more described as rounded -LRB- 12 / / 19 vs 3/13 , P = 0.036 -RRB- and with sharp margins -LRB- 9/19 vs 1/13 , P = 0.024 -RRB- . On MRI lesions in the BRCA-MC group were significantly more described as rounded -LRB- 16/27 vs 7/28 , P = 0.010 -RRB- , with sharp margins -LRB- 20/27 vs 7/28 , P < 0.001 -RRB- and with rim enhancement -LRB- 7/27 vs 1/28 , P = 0.025 -RRB- . No significant difference was found for enhancement kinetics -LRB- P = 0.667 -RRB- . Malignant lesions in BRCA-MC frequently have morphological characteristics commonly seen in benign lesions , like a rounded shape or sharp margins . This applies for both mammography and MRI . However the possibility of MRI to evaluate the enhancement pattern and kinetics enables the detection of characteristics suggestive for a malignancy . Introduction BRCA1 and BRCA2 are the most well known gene mutations responsible for an increased risk for developing breast cancer . A BRCA1 or BRCA2 mutation carrier -LRB- BRCA-MC -RRB- has approximately a 3 % risk of getting breast cancer before the age of 30 . This risk increases to almost 50 % when she reaches the age of 50 and becomes 50 -- 80 % at the age of 70 -LSB- 1 , 2 -RSB- . To reduce this risk , these women can choose between bilateral prophylactic mastectomy -LSB- 3 -RSB- , oophorectomy -LSB- 4 -RSB- or chemoprevention -LSB- 5 -RSB- . In breast cancer , close surveillance contributes to a more favorable stage of disease at detection and may reduce the rate of death from breast cancer -LSB- 6 , 7 -RSB- . In the surveillance or general screening for breast cancer , mammography still plays a prominent role . However , due to the young age and thus in most cases dense breast tissue , the sensitivity for mammography is moderate . False-negative rates of up to 62 % have been reported for mammography in screening gene mutation carriers -LSB- 8 , 9 -RSB- . A malignant lesion in the breast is mammographically best detected if it presents itself as an ill-defined or spiculated mass , a group of microcalcifications or as an architectural distortion . A smoothly outlined well-defined mass detected on mammography has a chance of less than 1 % of being malignant -LSB- 10 , 11 -RSB- . Tilanus et al. -LSB- 12 -RSB- and Kaas et al. -LSB- 13 , 14 -RSB- have evaluated the mammographic appearance of breast cancer in BRCA-MC . Tilanus and coworkers found the mammographic appearance suspicious for a malignancy in only 38 % of the gene carriers in comparison with 71 % in a control group . `` Prominent pushing margins '' caused by a continuous front of tumor cells not separated by connective tissue were described in the BRCA-MC group as the main reason for a false-negative evaluation of mammograms -LSB- 12 -RSB- . Kaas and coworkers concluded in their study of 31 breast cancer cases in BRCA-MCs that all mammographically detected lesions should be further evaluated by ultrasound and biopsy regardless of their appearance -LSB- 13 -RSB- . Well-defined mammographic tumors correlated in 83 % with histologic circumscribed tumor margins in BRCA1-MCs -LSB- 14 -RSB- . For women with an increased risk for developing breast cancer magnetic resonance imaging -LRB- MRI -RRB- should be included for close surveillance -LSB- 15 , 16 -RSB- . The superior sensitivity of MRI -LRB- 81 % -RRB- for the detection of breast cancer in these women compared with mammography -LRB- 40 % -RRB- has been proven in literature -LSB- 17 -RSB- . However the classification of a lesion detected on MR as benign or malignant still remains a challenge . Morphological and dynamic features are important in breast MRI interpretation . Focal masses with smooth borders are associated with a high negative predictive value for malignancy -LSB- 17 -RSB- . An irregular lesion contour , inhomogeneous enhancement pattern and rim enhancement have been reported as features indicating malignancy -LSB- 18 -RSB- . The dynamic evaluation is often based on the enhancement characteristics 2 -- 7 min after the injection of a paramagnetic contrast agent . In this approach , the decrease of signal intensity , often referred to as a type 3 curve or washout , is highly predictive for breast cancer , with a likelihood of malignancy of 87 % -LSB- 19 -RSB- . Until now the appearance of breast malignancies in BRCA-MCs has only been investigated for mammography . In this study we analyzed the MRI characteristics of BRCA-MC-associated tumors compared with sporadic cases of breast cancer . Materials and methods All available -LRB- 35 -RRB- BRCA-MCs with a biopsy-proven malignancy , imaged with MRI for screening -LSB- 9 -RSB- or pre-operative evaluation in the period from July 2000 until November 2006 , were included in the study : 23 BRCA1 carriers and 12 BRCA2 carriers . In order to compare tumor characteristics with sporadic cases of breast cancer an age , tumor type and tumor size matched control group was composed from 206 consecutive sporadic breast cancer cases imaged with MRI in the period from November 2001 until January 2007 . All BRCA-MC cases were age matched within 5 years with sporadic breast cancer cases . Cases were also matched for tumor type -LRB- IDC , ILC or DCIS -RRB- and pathological tumor size . For size matching , the BRCA-MC cases were matched to the closest tumor size in the sporadic cases available , with a limit for the maximum size difference of 0.5 cm for tumors smaller than 1 cm , 1-cm difference for tumors up to 5 cm and 1.5-cm difference for tumors larger than 5 cm . BRCA-MC cases that could not be matched following these criteria were excluded . Mammograms were obtained in the mediolateral oblique and craniocaudal direction on a digital mammographic unit -LRB- Senograph 2000 D or a Senograph DS , GE Healthcare , Wis. , USA -RRB- . Detection , density of the lesion compared with breast tissue , lesion morphology , and size were scored . In the morphologic assessment , lesion type was classified as either a mass , a calcifications or as an architectural distortion . Lesion shape was described as rounded , lobulated or irregular and lesion margins as sharp , vague or spiculated . The size of the tumor was measured by determining the longest axis through the displayed lesion . Spiculae surrounding a solid lesion were interpreted as desmoplastic reaction and not included in the measurement . MRI investigations were performed on a 1.5-Tesla system with a double breast coil -LRB- Magnetom Vision , Sonata or Symphony , Siemens , Erlangen , Germany -RRB- . In the scanning , we used a coronally orientated three-dimensional fast low-angle shot -LRB- FLASH 3D -RRB- with the following parameters : TE 4 ms , TR 8.1 ms , FA 20 ° , FOV 360 mm , TA 96 s , image resolution 1.5 mm × 1.5 mm × 1.5 mm for all patients scanned prior to June 2004 and TE 4 ms , TR 7.5 ms , FA 8 ° , FOV 320 mm , TA 87 s , image resolution 1.3 mm × 1.3 mm × 1.3 mm for all patients scanned after June 2004 . Prior to the MR examination , an intravenous catheter was inserted . All patients were placed in the prone position , with the breasts in the double breast coil and positioned at the isocenter of the magnet . After localizer images were obtained in three directions and a precontrast FLASH 3D series was recorded , 0.1 mmol/kg bodyweight gadolinium chelate -LRB- Magnevist , Schering , Germany or Dotarem , Guerbet , The Netherlands -RRB- was administered using a power injector -LRB- Spectris , Medrad , USA -RRB- at 2.5 ml/s followed by a 15-ml saline flush at the same injection rate . Thereafter , five post contrast FLASH 3D series were recorded . All MRI examinations were retrospectively evaluated on a dedicated breast MRI workstation -LRB- Dynacad , Invivo , USA -RRB- scoring lesion detection , size , morphology and enhancement kinetics . Maximum intensity projections , coronal images and axial reconstructions of both the T1 weighted and subtracted images and time-intensity curves were displayed . The morphologic assessment included lesion shape , margin appearance and enhancement pattern . Lesion shape was classified as being rounded , lobulated or irregular . Margins were described as sharp , vague or spiculated . The enhancement pattern of a lesion was classified as homogeneous , heterogeneous or rim enhanced . Lesion enhancement kinetics were evaluated according to the criteria described by Kuhl et al. -LSB- 19 -RSB- . Type 1 shows persistent enhancement and is highly suggestive for a benign lesion . Type 2 shows a plateau after initial increased enhancement , where the maximum signal intensity is reached approximately 2 -- 3 min after contrast injection and remains constant . This type of curve is seen in both benign and malignant lesions . In a type 3 curve , the peak enhancement is reached in the early postcontrast phase , and this is followed by a decrease of signal intensity -LRB- wash-out -RRB- . The latter curve is strongly suggestive for a malignant lesion . The dynamic curves were evaluated based on a single voxel or by selecting a region of interest within the lesion , the workstation allowed the readers to use both methods . Because of the possible bias in this retrospective study , a BI-RADS classification -LSB- 20 -RSB- could not be scored objectively and was therefore not included in the evaluation . All studies were evaluated retrospectively by two radiologists in conference and consensus . BRCA-MCs and controls were mixed during the evaluation . Except from the knowledge of a malignancy being present , the radiologists were blinded to any other clinical information . Mammography and MRI images were evaluated in separate sessions . From the histopathology reports , the tumor type , size and mitotic activity index -LRB- MAI -RRB- were recorded . The study was approved by the institutional review board ; since the study was performed retrospectively , informed consent was not required according to the review board . In the statistical evaluation , differences in patient and tumor characteristics between the BRCA-MC and control group were analyzed using an independent sample t-test if variables were continuous and normally distributed . For categorical variables , the Pearson chi-square test was used and we used Fisher 's exact test when any of the expected values was less than five . Pearson 's correlation coefficients were calculated for both mammographic size and MRI size versus pathologic size . All statistical analyses were performed using SPSS statistical software -LRB- version 12.0.1 -RRB- . P values < 0.05 were considered to indicate statistical significance . Results Six BRCA-MC cases could not be matched according to the criteria defined ; these cases were excluded from the study . Four BRCA-MCs were excluded because no match could be found based on patient 's age ; the other two were excluded because no match could be found based on tumor size . The mean age and tumor size of the excluded cases were , respectively , 33 years -LRB- range 27 -- 36 , median 35 , SD 3.4 years -RRB- and 1.4 cm -LRB- range 0.6 -- 2.8 cm , median 1.1 cm , SD 0.8 cm -RRB- . A total of 29 BRCA-MC cases were included for this study . In the BRCA-MC group , five women were symptomatic -LRB- 17 % -RRB- ; 21 women were symptomatic in the control group -LRB- 83 % -RRB- . Mean age in the BRCA-MC group was 42 years -LRB- range 32 -- 68 years , median 40 years , SD 8.0 years -RRB- ; this was 44 -LRB- range 37 -- 64 years , median 43 years , SD 5.6 years -RRB- for the control group . The mean pathological tumor size was 2.0 cm -LRB- range 0.4 -- 7.0 cm , median 1.4 cm , SD 1.5 cm -RRB- in the BRCA-MC group and 2.3 cm -LRB- range 0.6 -- 7.0 cm , median 1.9 cm , SD 1.7 cm -RRB- in the control group . No significant difference was found for patient age -LRB- P = 0.289 -RRB- or maximal pathological tumor size -LRB- P = 0.371 -RRB- . The mean tumor size on mammography was 2.1 cm -LRB- range 0.5 -- 7.0 cm , median 1.5 cm , SD 1.49 cm -RRB- . The mean tumor size on MRI was 2.4 cm -LRB- range 0.6 -- 7.1 cm , median 1.8 cm , SD 1.75 cm -RRB- . There was a significant correlation between imaging measurements and pathological measurements ; 0.664 -LRB- P < 0.001 -RRB- for mammographic measurements and 0.808 -LRB- P < 0.001 -RRB- for MRI measurements . In both the BRCA-MC and control groups , 23 cases were based on invasive ductal carcinoma -LRB- IDC -RRB- , two cases on invasive lobular carcinoma -LRB- ILC -RRB- , one case on ductal carcinoma in situ grade 1 -LRB- DCIS1 -RRB- and three cases on ductal carcinoma in situ grade 2 -LRB- DCIS2 -RRB- . In the BRCA-MC group , a mean MAI of 33.0 -LRB- range 6 -- 100 , median 27 , SD 27.1 -RRB- was found , compared with 17.5 -LRB- range 1 -- 60 , median 14 , SD 15.9 -RRB- in the control group . The difference in MAI between the BRCA-MC and control groups was found to be significant -LRB- P = 0.044 -RRB- . In the control group , one patient refused to undergo mammography because of implants . Overall mammography detected 44 of 57 lesions and MRI detected 55 of 58 lesions . Therefore , the overall detection is significantly better with MRI than with mammography -LRB- P = 0.021 -RRB- . Mammography detected 22 -LRB- 76 % -RRB- lesions in the BRCA-MC group and 22 -LRB- 79 % -RRB- in the control group . No significant difference was found -LRB- P = 0.807 -RRB- . All lesions missed on mammography in the BRCA-MC were IDC . In the control group , five cases of IDC and one case of ILC were missed . Mammographic lesion characteristics are presented in Table 1 . Lesions in the BRCA-MC group were significantly more described as rounded -LRB- 12 / / 19 vs 3/13 , P = 0.036 -RRB- and were more often described to have sharp margins -LRB- 9/19 vs 1/13 , P = 0.024 -RRB- . Lesions in the control group were significantly more described as irregular -LRB- 10/13 vs 6/19 , P = 0.029 -RRB- . From the six BRCA-MCs that were excluded , only three lesions were detected on mammography . In two cases a mass was detected and in one case calcifications . Both these masses were described as rounded with sharp margins . Table 1Mammographic lesion characteristics for both groups BRCA-MC groupControl groupP valueLesions detectedn = 22n = 22Lesion typeMass19130 .042 Arch . distortion140 .345 Calcification250 .216 Lesion densityaHyperdense810 .050 Isodense11120 .050 Lesion morphologyaRounded1230 .036 Lobulated1 -- 1.000 Irregular6100 .029 Lesion marginsaSharp910 .024 Vague880 .473 Spiculated240 .194 aLesion density , morphology and margins of mass-like lesions only On MRI , 27 lesions -LRB- 93 % -RRB- were detected in the BRCA-MC group , 28 -LRB- 97 % -RRB- in the control group . No significant difference was found -LRB- P = 0.553 -RRB- . The lesions missed in the BRCA-MC group were both cases of DCIS , one case of DCIS1 , seen on mammography as an architectural distortion , and one case on DCIS2 , seen on mammography as a mass . The lesion missed in the control group was based on DCIS2 , seen on mammography as calcifications . Their was no significant difference found for the detection of breast cancer between mammography and MRI within the BRCA-MC -LRB- P = 0.18 -RRB- or the control group -LRB- P = 0.13 -RRB- . Morphological and dynamic MR characteristics are presented in Table 2 . Lesions in the BRCA-MC group were significantly more often described as rounded -LRB- 16/27 vs 7/28 , P = 0.010 -RRB- , with sharp margins -LRB- 20/27 vs 7/28 , P < 0.001 -RRB- and to show rim enhancement -LRB- 7/27 vs 1/28 , P = 0.025 -RRB- . Lesions in the control group were significantly more often described as irregular -LRB- 18/28 vs 8/27 , P = 0.010 -RRB- , with vague margins -LRB- 15/28 vs 6/27 , P = 0.017 -RRB- and with a heterogeneous enhancement pattern -LRB- 22/28 vs 12/27 , P = 0.009 -RRB- . No significant difference between the two groups was found for enhancement kinetics -LRB- P = 0.667 -RRB- . From the six BRCA-MCs that were excluded , five were detected on MRI . Four of these lesions were described as rounded , one as irregular . The delineation was described as sharp in four and as vague in one of these cases . The enhancement pattern was described as homogeneous in two , heterogeneous in one and as rim-enhancement in two of these cases . All five cases showed a type 3 curve . Table 2MRI lesion characteristics for both groups BRCA-MC groupControl groupP valueLesions detectedn = 27n = 28Lesion morphologyRounded1670 .010 Lobulated331 .000 Irregular8180 .010 Lesion marginsSharp207 < 0.001 Vague6150 .017 Spiculated160 .049 Enhancement patternHomogeneous850 .304 Heterogeneous12220 .009 Rim710 .025 Enhancement kineticsType 1121.000 Type 2460.525 Type 322200.380 Discussion In this study , the overall false-negative rate for mammography was significantly higher compared with MRI . Although it is expected that the sensitivity for MRI in both the control group and the BRCA-MC is higher compared with mammography , no significant difference was found in this study within the two groups . This is probably due to the relatively small numbers of cases in this study . Kaas et al. -LSB- 13 -RSB- described in their mammographic study on BRCA1 and BRCA2 mutation carriers a sensitivity of 64 % for the detection of a tumor in the original reports . In this study , 76 % of the lesions were visible on mammography . Since this was a retrospective study and the radiologist was aware of the fact that a tumor was present at the time of the evaluation , no conclusion can be drawn from the difference in detection between both studies . On mammography , the mass like lesions detected in the BRCA-MC group were significantly more often described as rounded . Also , lesions were found to differ in margin appearance ; tumor margins in the BRCA-MC group were significantly more often described as sharp . A smooth , nonspiculated mass has previously been described by Tilanus et al. -LSB- 12 -RSB- as a reason for a false-negative mammographic evaluation in BRCA-MC . Thus , although Sickles et al. -LSB- 21 -RSB- described that nonpalpable , circumscribed , noncalcified breast masses -LRB- probably benign -RRB- should be managed with periodic mammographic surveillance regardless of lesion size and patient age , and Sardanelli et al. -LSB- 22 -RSB- published that both the well-defined margins and the rounded shape are more often associated with benign lesions , these findings are not applicable to the BRCA-MCs studied in this or other studies on this subject . Tilanus et al. -LSB- 12 -RSB- stated that any mammographic mass in BRCA-MCs must be regarded with suspicion . A similar conclusion was published by Kaas et al. -LSB- 13 -RSB- . An additional evaluation using ultrasound and biopsy of all lesions detected in BRCA-MC is mandatory , regardless of their morphological appearance . In their study of 28 BRCA-MCs , Hamilton et al. -LSB- 23 -RSB- also described the appearance of breast tumors on ultrasound . On ultrasound , 53 % of the tumors were classified as either benign or indeterminate , making a biopsy of any detected mass inevitable . We are also of the opinion that any solid lesion detected in BRCA-MCs should be evaluated by a biopsy . In the screening of women with an increased risk for developing breast cancer , more tumors are detected by MRI compared with mammography -LSB- 8 , 9 -RSB- . In this study , all lesions missed on MRI were cases of DCIS . MRI is known to have a lower sensitivity in detecting DCIS compared with invasive carcinomas -LSB- 24 -RSB- , especially in low-grade DCIS . The low or intermediate contrast uptake that is often observed in pure DCIS and the absence of a type 3 curve can result in a false-negative evaluation -LSB- 24 -RSB- . Kriege et al. -LSB- 9 -RSB- found in the screening of 1,909 women with an increased risk for developing breast cancer , including 358 carriers of germ-line mutations , that MRI missed five cases of DCIS that were detected on mammography , with six noninvasive tumors detected in total in the study . However , Kuhl et al. -LSB- 25 -RSB- reported MRI to be more sensitive for DCIS compared with mammography in a prospective study of women with an increased risk for developing breast cancer . Although MRI proved to be more sensitive for the detection of DCIS compared with mammography , not all cases of DCIS were detected by either modality . Therefore , at this point both modalities are still needed in the screening of women with an increased risk for developing breast cancer . Similar to mammography , on MRI a significantly higher number of lesions were described as rounded and with sharp margins in the BRCA-MC group . Furthermore , the number of lesions with ` rim-enhancement ' was found to be significantly higher in the BRCA-MC group . The presence of this enhancement pattern has been associated with malignant lesions -LSB- 26 , 27 -RSB- . Because MRI enables the radiologist to evaluate the enhancement pattern of the lesion , where mammography does not , these lesions will become more suspectedly malignant , even though other morphologic features are more often seen in benign lesions . The association of rim-enhancement -LRB- Fig. 1 -RRB- with central necrosis or insufficient microvessel growth can be an indicator for the growth rate of tumors . Jimenez and coworkers have described centrally necrotizing carcinomas to have an accelerated clinical course and early systemic metastasis -LSB- 28 -RSB- . An accelerated growth rate can be associated with a high MAI . In this study , the MAI was found to be significantly different between both groups . This is in agreement with Tilanus et al. -LSB- 12 -RSB- , who also found the mitotic count to be significantly higher in tumors found in gene mutation carriers . The higher rate of sharp tumor margins and rim-enhancement may thus be explained by the more aggressive nature of tumors in BRCA-MCs . Several authors have implied that , due to the rapid growth rate of tumors in gene mutation carriers , the screening frequency should be adjusted -LSB- 13 , 29 -RSB- . Komenaka et al. -LSB- 29 -RSB- suggest a higher screening frequency in carriers because of the high number of interval cancers found in their group . Half of these interval malignancies were already positive for lymph-node involvement . The 13 carriers in their study were screened with mammography . Mammography in carriers is not sensitive , particularly because the women are young and thus more often have dense breasts -LSB- 30 , 31 -RSB- . The use of MRI in screening has already been a step forward since MRI can detect smaller tumors , often occult for mammography , that are less likely to have progressed into lymph-node involvement -LSB- 9 -RSB- . Fig. 1a An MLO mammogram from the right breast of a 42-year-old BRCA1-mutation carrier . b A coronal subtraction MR image of the same breast . An 11-mm sharply delineated rounded lesion is present on the mammogram projecting over the upper quadrants -LRB- arrow -RRB- . On MRI , the same lesion was detected -LRB- arrow -RRB- with rim-enhancement . The rim-enhancement makes this lesion morphologically suspect malignant . Ultrasound guided core biopsy proved this lesion to be an invasive duct carcinoma Rounded , homogeneous enhancing lesions found on MRI are in general not considered suspicious . A homogeneous enhancement pattern , found in nine BRCA-MCs , does not contribute to the malignant nature of these lesions . Therefore , enhancement kinetics are of value . In this study , the dynamic analysis showed in both the BRCA-MC and the control groups a type 3 curve in , respectively , 82 % and 71 % of the cases . As described by Kuhl et al. -LSB- 19 -RSB- , a type 3 enhancement curve is highly indicative for malignancy . Using this characteristic , even rounded , sharply delineated , homogeneous enhancing lesions become suspect malignant -LRB- Fig. 2 -RRB- . Fig. 2a A coronal subtraction MR image from the right breast of a 49-year-old BRCA1-mutation carrier . Lateral located in the right breast , a sharply delineated rounded , homogeneous enhancing lesion is visible with a longest diameter of 9 mm -LRB- arrow -RRB- . b The relative enhancement versus time curve . The type 3 curve seen for this lesion was the only characteristic indicating a possible malignancy . Pathology proved this lesion to be an invasive duct carcinoma Despite all the findings discussed in this study , it remains questionable if the characterization of a lesion detected on either mammography or MRI in BRCA-MCs is even necessary . As the chance for these women to develop breast cancer is significantly increased , almost any detected lesion will in practice be classified as suspect malignant until proven otherwise . Sardanelli et al. -LSB- 17 -RSB- found a positive predictive value for MR in women with an increased risk of only 53 % due to a high number of false positives . As stated previously for mammographically detected lesions , additional evaluation by core biopsy is the only definitive classification for lesions detected in this group of women . In the case of MRI screening in high risk women , short-term follow-up , target ultrasound or MRI-guided biopsies are therefore often indicated -LSB- 32 -RSB- . What the best strategy in this group of women will be , also in terms of cost effectiveness , needs to be further studied . We conclude that in BRCA-MC malignant lesions frequently have morphological characteristics that are commonly seen in benign lesions , like a rounded morphology or a sharp delineation . This applies for both mammography and MRI . However , the possibility of MRI to evaluate the enhancement pattern and enhancement kinetics of lesions enables the radiologist to detect characteristics suggestive for a malignancy .

B O O O B O B O O O O B O O O O O O B O B O O O O O O B O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O B O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O B O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O B O O O B O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O B O O O O O O O O O O O O O O O B O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O B O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O B O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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Intraoperative monitoring study of ipsilateral motor evoked potentials in scoliosis surgery Ipsilateral motor evoked potentials -LRB- MEPs -RRB- in spinal cord surgery intraoperative monitoring is not well studied . We show that ipsilateral MEPs have significantly larger amplitudes and were elicited with lower stimulation intensities than contralateral MEPs . The possible underlying mechanisms are discussed based on current knowledge of corticospinal pathways . Ipsilateral MEPs may provide additional information on the integrity of descending motor tracts during spinal surgery monitoring . Introduction Intraoperative monitoring -LRB- IOM -RRB- of the motor pathways is a routine procedure for ensuring integrity of corticospinal tracts during scoliosis surgery . In combination with somatosensory evoked potentials , motor evoked potential -LRB- MEP -RRB- monitoring is widely utilized in operations with significant risks of spinal cord damage -LSB- 2 , 14 -RSB- . MEPs are most effectively obtained with multi-pulse cortical electrical stimulation during IOM -LSB- 3 -RSB- . However , anesthetic agents , which cause suppression of cortical and spinal motor neuron excitability , affect them -LSB- 4 , 5 -RSB- . While most IOM protocols involving MEPs utilize total intravenous anesthesia -LRB- TIVA -RRB- , we have previously reported success with desflurane as a halogenated inhalational anesthetic agent -LSB- 15 -RSB- . In IOM , MEPs are elicited mostly with contralateral cortical electrical stimulation . Ipsilateral MEP responses have not been adequately studied in this context . Our paper describes observations of ipsilateral and contralateral MEPs with bilateral recordings , in conjunction with TIVA or desflurane during IOM of scoliosis surgery . Methods We studied nine patients -LRB- mean age 16.2 years ; range 14 -- 17 years ; 1 male -RRB- over a 6-month period in a prospective manner . The local ethical committee has approved the study protocol . All patients did not have medical conditions contraindicating transcranial electrical stimulation . Apart from scoliosis , they were healthy and had normal neurological examinations . Multi-pulse transcranial electrical stimulation was performed using two constant-current stimulators connected in parallel configuration from a Dantec Keypoint EMG machine -LRB- Dantec , Skovlunde , Denmark -RRB- . A train of five square wave stimuli 0.5 ms in duration was delivered at 4 ms -LRB- 250 Hz -RRB- interstimulus intervals . Stimulating electrodes consisted of 9 mm gold-plated disc electrodes at C3C4 -LRB- International 10 -- 20 system -RRB- affixed with collodion . Stimulation output was increased from 50 mA in steps of 5 mA until a reproducible MEP was elicited . The intensity was then increased and fixed at 10 % above this threshold intensity to obtain a supramaximal MEP response . Each stimulator was capable of delivering a maximum output of 100 mA -LRB- 200 mA in total -RRB- . MEP recordings were obtained with 13 mm disposable subdermal needles -LRB- Technomed Europe , Beek , Netherlands -RRB- in the tibialis anterior -LRB- TA -RRB- bilaterally . Filter settings were set at 10 Hz and 2 kHz . Input impedance of stimulating and recording electrodes were maintained below 5 kΩ . For induction of anesthesia , sodium thiopentone at 4 mg/kg and fentanyl at 2 mcg/kg was administered ; 0.8 mg/kg of intravenous atracurium was used to facilitate endotracheal intubation . No further doses of neuromuscular blocking agents were used subsequently . In the desflurane group , anesthesia was maintained using 60 % nitrous oxide in oxygen . Desflurane was introduced through a calibrated vaporizer up to an end-tidal concentration of 2.1 -- 4.3 % , with a mean concentration of 3.4 % -LRB- approximately 0.5 maximum alveolar concentration -RRB- . This was measured using an Ohmeda respiratory gas monitor 5250 -LRB- BOC Group , Louisville , USA -RRB- . Closed circuit mechanical ventilation was adjusted to maintain end-tidal carbon dioxide levels between 32 and 35 mmHg . In the TIVA group , anesthesia was maintained using the regime of 10 mg/kg of propofol for the first 10 min , 8 mg/kg for the next 10 min and 5 mg/kg for the subsequent length of operation ; 50 % air in oxygen was administered . In both groups , morphine was titrated as required for pain relief . Monitoring included electrocardiography , pulse oximetry , capnography and direct radial artery pressures . All patients were kept nornothermic with a warming blanket . Normotensive anesthesia was maintained throughout the operation . After approximately 45 min post-induction , a train of four-twitch assessment was performed using a nerve stimulator -LRB- Fischer Paykel NS242 , UK -RRB- . Cortical stimulation was commenced only when the amplitude of the fourth was visibly similar to the first . An interval of 3 -- 5 min was allowed between two trains of cortical stimulation . This alternated with monitoring of somatosensory evoked potentials from posterior tibial nerve stimulation . We measured two parameters : MEP amplitude , onset latency and initial stimulation intensity . Peak to peak amplitudes -LRB- between two largest peaks opposite in polarity -RRB- and onset latency was utilized for all MEP responses recorded bilaterally . Hence , ipsilateral MEPs refer to MEPs recorded from the TA on the same side as cortical stimulation . Within each patient , ten consecutive supramaximal MEPs obtained before insertion of pedicle screws used as a baseline were averaged to obtain the first two parameters . The initial stimulation intensity was defined as the minimal intensity required to obtain five consistent visible MEP responses at a vertical gain of 20 μV per division . During insertion of pedicle screws and instrumentation , a 50 % reduction of MEP amplitude or 10 % prolongation of latency was brought to the surgeon 's attention . Statistical analyses using Student 's t-tests were obtained with Microsoft SPSS for Windows Version 10.1 . Statistical significance was considered at P < 0.05 . Results There were no complaints of headache , seizures or skin burns postoperatively ; all patients had normal neurological examination . MEPs were successfully obtained from all patients with TA recordings bilaterally . There were four patients in the TIVA group and five in the desflurane group . Mean ages for desflurane -LRB- 16.2 -RRB- and TIVA -LRB- 15.7 -RRB- groups were not significantly different -LRB- P = 0.6 -RRB- . None of the patients had MEP amplitude or latency changes exceeding our set limits so as to require immediate surgical attention during and after pedicel screw insertion and spinal instrumentation . The ipsilateral MEP amplitudes -LRB- standard deviation -RRB- were significantly larger than contralateral MEP amplitudes -LSB- 68.9 -LRB- 27.1 -RRB- vs. 52.5 -LRB- 15.7 -RRB- μV , P < 0.01 , paired t-test -RSB- . The initial stimulation intensity to obtain ipsilateral MEPs was significantly lower than for contralateral MEPs -LSB- 66.9 -LRB- 12.3 -RRB- vs. 74.4 -LRB- 10.1 -RRB- mA , P < 0.05 , paired t-test -RSB- . However , there were no significant latency differences for ipsilateral and contralateral MEPs -LSB- 32.0 -LRB- 2.1 -RRB- vs. 31.5 -LRB- 2.0 -RRB- ms , P = 0.3 , paired t-test -RRB- . There was no significant difference between use of TIVA or desflurane anesthesia for MEP amplitudes obtained , with ipsilateral -LRB- P = 0.06 , unpaired t-test -RRB- and contralateral -LRB- P = 0.09 , unpaired t-test -RRB- stimulation . Additionally , there was also no significant difference between right and left sided MEP amplitudes , either with ipsilateral -LRB- P = 0.9 , paired t-test -RRB- or contralateral -LRB- P = 0.7 , paired t-test -RRB- stimulation . We consecutively studied an additional 17 subjects monitored for scoliosis surgery using an identical protocol -LRB- 1 men , mean age 16.1 years , range 14 -- 22 -RRB- . All had the TIVA anesthetic regimen . With right cortex stimulation , mean initial stimulation intensity to obtain ipsilateral MEPs -LSB- 39.7 -LRB- 9.9 -RRB- mA -RSB- was significantly lower than to obtain contralateral MEPs -LSB- 47.1 -LRB- 11.3 -RRB- mA , paired t-test , P < 0.0005 -RSB- . With left cortex stimulation , similar findings were obtained -LSB- 40.6 -LRB- 10.7 -RRB- vs. 50.3 -LRB- 11.8 -RRB- mA , paired t-test , P < 0.0005 -RSB- . With right cortex stimulation , mean ipsilateral MEP amplitudes -LSB- 107.1 -LRB- 35.7 -RRB- μV -RSB- were significantly larger than mean contralateral MEP amplitudes -LSB- 90 -LRB- 37.1 -RRB- μV , paired t-test , P = 0.01 -RSB- . With left cortex stimulation , similar findings were again observed -LSB- 112.1 -LRB- 37 -RRB- vs. 82.3 -LRB- 30.9 -RRB- μV , paired t-test , P = 0.0004 -RSB- . With right cortex stimulation , mean ipsilateral MEP latencies -LSB- 30.2 -LRB- 2.4 -RRB- ms -RSB- were not significantly different from mean contralateral MEP latencies -LSB- 30 -LRB- 2.3 -RRB- ms , paired t-test , P = 0.3 -RRB- . With left cortex stimulation , similar findings were again observed -LSB- 30 -LRB- 2.1 -RRB- vs. 30.4 -LRB- 2.3 -RRB- ms , paired t-test , P = 0.2 -RSB- . Examples of MEPs obtained with both ipsilateral and contralateral stimulation are shown in schematically in Fig. 1 and 2 . Fig. 1Schematic diagram showing right cortical stimulation , resulting in ipsilaterally and transcallosally conducted corticospinal impulses activating the spinal cord anterior horn cell . The right ipsilateral MEP recording is from the TA . Summation of ipsilaterally conducted and transcallosally generated descending impulses may thus result in larger ipsilateral MEPs from right cortical stimulationFig . 2Actual consecutive MEPs obtained from a patient , showing larger amplitude responses with ipsilateral stimulation . Both recordings were made from the TA at 70 % stimulation intensity Discussion The present study showed that ipsilateral MEPs have significantly larger amplitudes and were elicited with significantly lower stimulation intensities than contralateral MEPs . However , onset MEP latencies were not significantly different . The origin of ipsilateral MEPs in humans is not well understood . In animal studies , cat corticospinal neurons have been shown to evoke ipsilateral actions via ipsilaterally descending reticulospinal tracts , as well as via contralaterally descending reticulospinal neurons , both by synapsing spinal interneurons -LSB- 9 -RSB- . Tracer studies in rhesus monkeys have quantified ipsilateral corticospinal fibers as approximately 9 -- 12 % of the total descending corticospinal projections -LSB- 14 -RSB- . Thus , current evidence points to contralateral corticospinal fibers as the predominant pathway for spinal motorneuron activation . The presence of ipsilateral MEPs has mostly been described in pathological conditions . Patients with congenital mirror movements -LSB- 11 -RSB- , schizencephaly -LSB- 12 -RSB- , and Kallmann 's syndrome -LSB- 13 -RSB- show ipsilateral MEPs , which likely result from abnormal structure and function of ipsilateral corticospinal fibers . However , functional reorganization and unmasking of ipsilateral corticospinal pathways may contribute to the generation of ipsilateral MEPs after adult stroke -LSB- 6 -RSB- and congenital hemiparesis -LSB- 18 -RSB- . One study involving 50 normal children suggested that presence of ipsilateral MEPs might be a normal state of ontogeny . Their disappearance after 10 years old is likely due to increasing transcallosal inhibitory influences -LSB- 16 -RSB- . In our study , all patients were above 10 years of age , and did not have clinical features to suggest presence of underlying conditions mentioned above . Another study comparing healthy adults with stroke patients has suggested ipsilateral MEPs may be conducted via corticoreticulospinal or corticopropriospinal pathways in normal subjects -LSB- 1 -RSB- . What are the possible underlying mechanisms , which explain our findings ? Firstly , it is possible that ipsilateral MEPs may be solely due to transcallosal stimulation of the contralateral motor cortex . Additionally , the effects of anesthesia on corticospinal excitability may facilitate this , hence resulting in significantly lower initial stimulation intensity to obtain ipsilateral MEPs . While evidence to suggest this is scarce , rat brain studies have demonstrated widespread action of anesthesia at multiple binding sites -LSB- 8 -RSB- . Magnetic resonance brain imaging has also demonstrated increased callosal T2 changes with anesthesia , suggesting structural alterations at a molecular level -LSB- 19 -RSB- . It is also possible that longstanding scoliosis has led to spinal cord plasticity changes . Motor pathway reorganization and spinal cord plasticity have been well documented in response to cord injury -LSB- 7 -RSB- in an activity-dependent manner -LSB- 10 -RSB- . Thus , structural and postural changes of longstanding scoliosis may have resulted in reorganization of cortical or subcortical motor pathways , including ipsilateral corticoreticular fibres leading to our observations -LSB- 17 -RSB- . However , lack of lateralization of MEP amplitudes with ipsilateral or contralateral stimulation was not supportive of this hypothesis . Additionally , lack of significant ipsilateral and contralateral latency differences suggest bilateral motor cortex stimulation has resulted in ipsilateral MEPs , which may have comprised early ipsilaterally conducted components and late transcallosally stimulated components -LRB- Fig. 1 -RRB- . This might also explain the larger amplitudes of ipsilateral MEPs obtained than MEPs derived from contralateral motor cortex stimulation . Further studies clarifying the predominant mechanisms responsible would be interesting . Are ipsilateral MEP responses useful and relevant in clinical settings ? Ipsilateral MEPs are readily elicited , as shown in this study . While the relative contributions of ipsilaterally and transcallosal conducted MEPs remain uncertain , bilateral MEP recordings during spinal surgery IOM may provide additional information regarding the integrity of descending motor tracts . Together with the electrophysiological findings presented here , future studies clarifying these aspects would be justified . It thus may be feasible to routinely monitor MEPs bilaterally in future IOM protocols for spinal surgery .

B I O O B O O O O B O B O O O O O O O O O O B I O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B O O B O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O B O O O O O O O O O O O B B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B B O O O O O O O O O B B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O B O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

motor evoked potential
ipsilateral
contralateral
corticospinal
intraoperative monitoring
scoliosis