an intramedullary location is most common , but hemangioblastomas with exophytic intramedullary , intradural - extramedullary , and extradural locations have been described in a few case reports . we found key differences in preoperative magnetic resonance imaging ( mri ) for hemangioblastomas in different locations that permit accurate diagnosis . our previous study revealed that preoperative diagnostic mri is particularly important in cases of intramedullary plus extramedullary ( ie ) hemangioblastoma for preparing a surgical plan for total resection , and a change in intramedullary high - intensity areas on the craniocaudal side of the tumor on sagittal t2-weighted imaging and a snowman sign on contrast axial t1-weighted imaging must not be missed for this type of tumor . however , the preoperative symptoms , intraoperative spinal cord monitoring , and surgical outcomes for different tumor locations have not been examined . however , preoperative motor paralysis and postoperative outcome in ie hemangioblastomas have not been clearly described because of the rarity at this location , which makes it difficult to determine the appropriate surgical timing . in 2009 , we reported the surgical results for 106 intramedullary spinal cord tumors , including 16 hemangioblastoma cases with intramedullary locations only , but we only described pre- and postoperative ambulatory status and extent of tumor resection because the focus of the article was on all intramedullary spinal cord tumors . thus , the progression of symptoms , surgical outcome , intraoperative spinal cord monitoring , pathologic findings for cell proliferative activity , and optimal surgical timing have not been examined for spinal hemangioblastomas with different locations . this study is the first to determine whether the tumor location affects preoperative progression of symptoms and motor paralysis ; to examine the relationship between preoperative status and surgical results ; to evaluate intraoperative spinal cord monitoring and pathologic findings with ki67 ; and to evaluate the optimal surgical timing for obtaining a better outcome for intramedullary and ie hemangioblastomas . the subjects were 28 consecutive patients ( 17 men and 11 women ) with intramedullary spinal hemangioblastoma who underwent surgery in our department between 1993 and 2013 . all patients gave informed consent , and the study plan was approved by the ethics committee of nagoya university . the mean age of the patients was 43 years old ( range 21 to 68 years old ) , and the mean postoperative follow - up period was 10.0 years ( 2 to 19 years ) . the tumor locations were intramedullary only in 23 cases ( 82% , group i ) and ie in 5 cases ( 18% , group ie ) . six cases with intramedullary tumors were complicated with von hippel lindau ( vhl ) disease ( 21% ) . the mri findings , preoperative symptoms , preoperative motor paralysis , period from onset of initial symptoms to paralysis , period from onset of initial symptoms to surgery , pre- and postoperative ambulatory abilities based on the mccormick scale , intraoperative spinal cord monitoring , extent of tumor resection , tumor recurrence , need for reoperation , and pathologic findings were compared between groups i and ie . ambulatory ability was evaluated using the modified mccormick scale ( i = normal gait , ii = mild gait disturbance not requiring support , iii = gait with support , iv = assistance required , and v = wheelchair needed ) , with mccormick grades i and ii defined as a good independent ambulatory status without support . the extent of tumor resection was evaluated using four categories : total resection , subtotal resection , partial resection , and biopsy . total resection was attempted in all cases and was defined in the standard manner as removal of 100% of the tumor based on a microscopically documented clean surgical field at the end of the procedure and a clean intraoperative surgical bed in ultrasonography . total resection was abandoned if the amplitude of evoked potentials in monitoring disappeared without intraoperative restoration , which indicates impending neurologic paralysis . spinal cord monitoring was performed using the somatosensory evoked potential ( ssep ) up to 1999 and the compound muscle action potential ( cmap ) from 2000 . a case in which a small tumor fragment was deliberately left in place was considered to have undergone subtotal resection , based on intraoperative ultrasonography indicating 80 to 99% resection . similarly , 50 to 80% and < 50% resection were defined as partial resection and biopsy , respectively . the tumor was pathologically diagnosed postoperatively based on the histologic type , and the ki67 activity was determined as an index of cell proliferative activity . this study was retrospective , but all the data was available for the factors described above in a prospective database of cases at our institute alone , in contrast to our previous multicenter study . an unpaired t test and fisher exact probability test in spss statistics 22 software ( spss , inc . , chicago , illinois , united states ) were used for statistical analysis , with p < 0.05 taken to indicate statistical significance . after exposure of the dura mater , ultrasound was used to confirm the tumor location . especially , power doppler images clearly show feeding vessels , and the hemangioblastoma is easily identified . if a reddish orange tumor is seen through the pia mater , entry can be performed at the site , but if the tumor is not visible , the approach is from the dorsal median sulcus . although the tumor is separated from the spinal cord with mucosal elevator and hook - type microdissector , inflow and outflow vessels are coagulated and resected , and then the tumor is coagulated , shrank , and solidified . it can then be removed as a single mass . because the tumor bleeds easily and may cause heavy bleeding , incision of the tumor should be avoided . for an ie tumor , the extramedullary component the spinal cord is monitored during surgery , and if amplitude reduction to < 30% is detected , the operation is interrupted and the operative field is filled with warm saline . the operation can be resumed when the waveform recovers . cysts and syrinxes associated with the tumor may remain on intraoperative ultrasound and mri immediately after the operation , but these gradually reduce and finally disappear after total resection of the tumor , and shunting is not needed ( fig . ( a ) characteristic magnetic resonance imaging findings for intramedullary hemangioblastoma at c5 include a wide high - intensity area on the craniocaudal sides of the tumor on t2-weighted imaging . ( b ) syrinxes naturally disappear postoperatively after total tumor resection , and shunting is not needed . ( c ) a clearly and densely contrasted tumor on contrast t1-weighted imagining ( t1wi ) as a  focal sign ( d ) an intramedullary plus extramedullary hemangioblastoma showing a characteristic  snowman sign  on contrast t1wi . an extramedullary tumor occupied all the spinal canal in all cases in the intramedullary plus extramedullary hemangioblastoma group , and the spinal cord was severely compressed from the intramedullary and extramedullary sides . after exposure of the dura mater , ultrasound was used to confirm the tumor location . especially , power doppler images clearly show feeding vessels , and the hemangioblastoma is easily identified . if a reddish orange tumor is seen through the pia mater , entry can be performed at the site , but if the tumor is not visible , the approach is from the dorsal median sulcus . although the tumor is separated from the spinal cord with mucosal elevator and hook - type microdissector , inflow and outflow vessels are coagulated and resected , and then the tumor is coagulated , shrank , and solidified . it can then be removed as a single mass . because the tumor bleeds easily and may cause heavy bleeding , incision of the tumor should be avoided . for an ie tumor , the extramedullary component the spinal cord is monitored during surgery , and if amplitude reduction to < 30% is detected , the operation is interrupted and the operative field is filled with warm saline . the operation can be resumed when the waveform recovers . cysts and syrinxes associated with the tumor may remain on intraoperative ultrasound and mri immediately after the operation , but these gradually reduce and finally disappear after total resection of the tumor , and shunting is not needed ( fig . ( a ) characteristic magnetic resonance imaging findings for intramedullary hemangioblastoma at c5 include a wide high - intensity area on the craniocaudal sides of the tumor on t2-weighted imaging . ( b ) syrinxes naturally disappear postoperatively after total tumor resection , and shunting is not needed . ( c ) a clearly and densely contrasted tumor on contrast t1-weighted imagining ( t1wi ) as a  focal sign ( d ) an intramedullary plus extramedullary hemangioblastoma showing a characteristic  snowman sign  on contrast t1wi . an extramedullary tumor occupied all the spinal canal in all cases in the intramedullary plus extramedullary hemangioblastoma group , and the spinal cord was severely compressed from the intramedullary and extramedullary sides . age in group ie tended to be higher than that in group i , but with no significant difference . four of the five ie tumors were located in the conus region ( 80% ) . on the preoperative mri , intramedullary syrinxes or edema on t2-weighted imaging strong contrast enhancement of the tumor was present on t1-weighted imaging in all 28 cases , and the axial images were particularly useful for differentiation between tumors in groups i and ie ( fig . ie , the extramedullary components fully occupied the spinal canal and compressed the spinal cord from the outside . preoperative differences in mri and symptom course based on the tumor location abbreviations : bbd , bladder bowel disturbance ; group i , intramedullary tumor group ; group ie , intramedullary plus extramedullary tumor group ; hia , high - intensity area ; mmt , manual muscle test ; mri , magnetic resonance imaging ; t1wi , t1-weighted image ; t2wi , t2-weighted image . note : parentheses indicate standard deviation or number of cases . 
 fisher exact probability test or unpaired t test . preoperative pain tended to be more common in group ie ( 80% ) , with a similar tendency for preoperative bladder and bowel disturbance ( table 1 ) . there was a significantly higher rate of preoperative motor paralysis in group ie ( 5/5 [ 100% ] versus 6/23 [ 26% ] , p < 0.005 ) , with a preoperative manual muscle test score of about 1 point lower in group ie . the mean periods from onset of the initial symptom to motor paralysis and to surgery were significantly shorter in group ie , indicating aggravation of symptoms in a significantly shorter period in group ie ( p < 0.05 ) . significantly fewer patients were in preoperative mccormick classes i and ii in group ie ( 20% versus 78% , p < 0.05 ; fig . 2 ) . the percentage of cases with stable independent ambulation ( mccormick classes i and ii ) preoperatively was significantly lower in the intramedullary plus extramedullary hemangioblastoma group ( group ie ) than in the intramedullary group ( group i ) . the extent of tumor resection , postoperative course , perioperative systemic complications , intraoperative spinal cord monitoring findings , and pathologic findings in the two groups are shown in table 2 . total resection was achieved in 24 cases ( 86% ) , and there were 2 cases with subtotal resection and 2 with partial resection . all 4 patients in whom total resection was not achieved had worsening of symptoms postoperatively and underwent reoperation . tumor resection , reoperation , perioperative systemic complications , intraoperative spinal cord monitoring , and pathologic findings based on the tumor location abbreviations : cmap , compound muscle action potential ; group i , intramedullary tumor group ; group ie , intramedullary plus extramedullary tumor group . ssep was used in 7 cases and cmap in 21 . in monitoring using cmap , the amplitude was stable in 17 of the 21 cases ( 81% ) and paralysis did not occur postoperatively . the amplitude increased in 1 case and decreased to < 30% in 4 ( to a mean of 19% in all 21 cases ) , with recovery of the amplitude in 2 of these cases during the operation . in the other 2 cases ( both in group ie ) , the amplitude at the end of the operation was smaller than that before resection of the tumor . both of these patients had temporary lower extremity muscle weakness postoperatively but had recovered from motor paralysis at 3 and 8 days after surgery , respectively . as shown in table 2 , significantly more cases in group ie had an intraoperative decrease of amplitude in cmap monitoring ( p < 0.05 ) . the mean ki67 activity was significantly higher in group ie compared with that in group i ( 15 versus 1% , p < 0.05 ) . three of these cases were monitored using ssep , and the ssep findings did not change in these cases . only 2 of the 21 cases ( 9.5% ) that underwent surgery with cmap monitoring had a worsened mccormick class at final follow - up : a patient with a history of several operations for vhl disease who worsened from class i to iii and a patient with deterioration of symptoms after partial tumor resection who worsened from class ii to iii . pre- and postoperative ambulatory ability based on the mccormick scale in all cases 
 cases in the intramedullary plus extramedullary group . cases with postoperative aggravation of gait ability ( all in the intramedullary group ) . the cases in mccormick classes i and ii at final follow - up had better preoperative mccormick grades ( fig . in contrast , only 22% of patients in preoperative mccormick classes iii , iv , and v achieved independent ambulation postoperatively ( p < 0.05 ) . in groups i and ie , the percentage of cases in mccormick classes i and ii at final follow - up was also related to the preoperative independent ambulation status ( fig . however , there was no significant difference in the rate of postoperative independent ambulation ( 65% in group i and 40% in group ie , fig . better preoperative ambulatory ability was significantly associated with good postoperative ambulation , with probabilities of achieving good postoperative results for patients in preoperative classes i and ii of 79% in all patients , 78% in the intramedullary only group ( group i ) , and 100% in the intramedullary plus extramedullary group ( group ie ) . in contrast , improvement of postoperative independent ambulatory ability was difficult for cases with severe preoperative symptoms , with probabilities for patients in preoperative classes iii , iv , and v of 22% in all patients , 20% in group i , and 25% in group ie . the percentage of cases with stable independent ambulation ( mccormick classes i and ii ) postoperatively did not differ significantly between groups i and ie , although there was a significant difference preoperatively . abbreviation : group i , intramedullary only ; group ie , intramedullary plus extramedullary ; ns , not significant . we previously reported 16 cases of intramedullary spinal hemangioblastoma , with the conclusion that good preoperative ambulatory ability was associated with postoperative independent ambulatory ability and that total excision of tumors was required . however , we did not evaluate the preoperative symptoms , duration from initial symptoms to motor paralysis , intraoperative spinal cord monitoring , surgical outcome , and pathologic findings for cell proliferative activity , and ie spinal hemangioblastomas were not examined in our previous study . this information is also lacking in other studies because the ie location has only been described in a few cases . thus , this work is the first comparative study of these factors in intramedullary and ie spinal hemangioblastomas . cases with ie tumors had obviously severe spinal cord damage preoperatively based on the higher rates of bladder and bowel disturbance and motor paralysis , shorter duration from initial symptoms to motor paralysis , and lower rate of independent gait , compared with cases with an intramedullary tumor location alone . in all ie cases , the intramedullary tumor had ruptured the pia mater of the spinal cord , progressed into the extramedullary area , occupied the whole of the spinal canal , and caused severe spinal canal stenosis . thus , for ie tumors , the severity of damage to the spinal cord may be related to the size of the extramedullary tumor component . mechanical compression of the spinal cord from the ie sides after onset of initial symptoms may increase damage to the spinal cord in a short time . ozawa et al also suggested that the pia mater maintains the elastic force of the spinal cord . therefore , once the pia mater is ruptured and the elastic force is reduced , the spinal cord may weaken and become less able to resist mechanical compression by the tumor , with subsequent worsening of symptoms . interestingly , in pathologic findings , the ki67 activity was less than 1% in all cases with an intramedullary tumor , but averaged 15% in ie cases in which the tumor progressed from the intramedullary to the extramedullary region . this result suggests that ie tumors have high cell proliferative activity and grow faster than an intramedullary tumor . therefore , an ie tumor can be diagnosed using characteristic contrast mri findings , and rapid aggravation of spinal cord impairment is possible , even if compression of the spinal cord and spinal cord  related symptoms are mild . high ki67 activity has only been reported in two previous reports , including one case of intradural - extramedullary hemangioblastoma , in which the reason for high proliferation was not described . in an investigation of 25 cases of hemangioblastoma with vhl disease , shively et al found ki67 activities of < 2% in the mesenchymal structure , 3 to 30% in the epithelioid structure , and 100% in red blood cell precursors of extramedullary hematopoiesis foci . thus , proliferative activity differed in the different stages of progression , and it was concluded that downstream hemangioblastoma differentiation is associated with increasing proliferative activity . all our ie cases were sporadic without vhl disease , but the same idea of increased proliferative activity with tumor progression may apply in sporadic ie tumors that have differentiated over a long time course and have a tendency to be found in older patients . alternatively , intramedullary and ie hemangioblastomas may differ in proliferation activity because they are different original phenotypes of hemangioblastoma . in this study , ie hemangioblastoma was mostly located at the conus ( 80% ) , which may account for the high rate of preoperative pain in ie tumors . stromal cells in hemangioblastoma are derived from the vascular stroma of the pia - arachnoid region , and exophytic growth may occur at any level of the spinal cord . previous reviews have described hemangioblastoma in the thoracic spinal cord , but the detailed level of the tumor location has been unclear . corr et al reported an ie hemangioblastoma at t7 . in a study of intramedullary spinal cord tumors , ishikawa et al described 22 spinal intramedullary tumors , and exophytic growth was seen in only 5 cases , including 2 astrocytomas and 1 case each of mixed glioma , ependymoma , and hemangioblastoma . collection of more cases is clearly required to define the common location of ie hemangioblastoma . however , we speculate that frequent exophytic growth may be anatomically related to thin white matter at the conus and associated with gradient spinal cerebrospinal fluid velocity or pressure impact in this region . the current study also suggests that the wide subarachnoid space at the conus may allow massive exophytic growth with severe spinal cord symptoms at the first hospital visit . early surgery is recommended for intramedullary spinal hemangioblastoma based on the finding of an association of better preoperative ambulatory ability with better postoperative ambulatory ability , which is consistent with results from our previous study . additionally , the current study indicated that this strategy should be applied to both i and ie tumors . earlier surgical intervention in ie tumors resulted in all cases having improved postoperative ambulatory ability ; however , the rate of postoperative independent gait ability was only 60% because of preoperative severe spinal cord damage . thus , further improvement of surgical results for ie tumors requires tumor resection as soon as possible after diagnosis . total surgical resection of spinal hemangioblastoma is required because all cases in which total resection was not achieved showed postoperative tumor enlargement and intramedullary syrinxes or edema , with worsening of symptoms , and all required reoperation for total tumor resection . worsening of symptoms caused by a residual tumor is probably inevitable in this tumor , and total tumor resection is especially essential for ie tumors with the high cell proliferative activity . intraoperative spinal cord monitoring caused significant aggravation in ie cases , which may be because of the more severe preoperative spinal cord damage from the intra- and extramedullary directions in ie tumors . however , although ie cases had significantly more severe motor paralysis and poor ambulatory ability , all these cases had improved ambulatory status after total tumor resection and without reoperation . thus , these findings suggest the need for prudent surgical procedures and suspension based on intraoperative spinal cord monitoring ( cmap ) for ie hemangioblastoma . because total tumor resection is required for hemangioblastoma , the cases with severe preoperative symptoms , including paralysis , should be especially carefully monitored during surgery . the recent use of multimodal monitoring combining ssep , cmap , and d - wave may avoid missing subtle spinal disorders during surgery . the small number of cases is a limitation of this study , which is unavoidable given the rarity of intramedullary spinal cord hemangioblastoma and the even more uncommon ie location . accumulation of more cases is needed , including comparative data with cases with nonsurgical treatment . however , this study provides useful data on symptom aggravation , surgical outcome , and pathologic cell proliferative activity for spinal hemangioblastomas in different locations . patients with ie spinal hemangioblastoma have rapid preoperative progression of symptoms over a short period , severe spinal cord damage including preoperative motor paralysis , and poor gait ability compared with those with an intramedullary tumor only . total resection of the tumor is required in surgery for spinal hemangioblastoma to avoid the need for reoperation . intraoperative spinal cord monitoring is required for total resection and a good surgical outcome , particularly for an ie tumor . these results and the high cell proliferative activity in ie tumors found in this study suggest that earlier surgery is particularly important for these tumors .
study designa retrospective analysis of a prospective database.objectiveto compare preoperative symptoms , ambulatory ability , intraoperative spinal cord monitoring , and pathologic cell proliferation activity between intramedullary only and intramedullary plus extramedullary hemangioblastomas , with the goal of determining the optimal timing for surgery.methodsthe subjects were 28 patients ( intramedullary only in 23 cases [ group i ] and intramedullary plus extramedullary in 5 cases [ group ie ] ) who underwent surgery for spinal hemangioblastoma . 
 preoperative symptoms , ambulatory ability on the mccormick scale , intraoperative spinal cord monitoring , and pathologic findings using ki67 were compared between the groups.resultsin group ie , preoperative motor paralysis was significantly higher ( 100 versus 26% , p < 0.005 ) , the mean period from initial symptoms to motor paralysis was significantly shorter ( 3.5 versus 11.9 months , p < 0.05 ) , and intraoperative spinal cord monitoring aggravation was higher ( 65 versus 6% , p < 0.05 ) . all 5 patients without total resection in group i underwent reoperation . 
 ki67 activity was higher in group ie ( 15% versus 1% , p < 0.05 ) . 
 preoperative ambulatory ability was significantly poorer in group ie ( p < 0.05 ) , but all cases in this group improved after surgery , and postoperative ambulatory ability did not differ significantly between the two groups.conclusionsintramedullary plus extramedullary spinal hemangioblastoma is characterized by rapid preoperative progression of symptoms over a short period , severe spinal cord damage including preoperative motor paralysis , and poor gait ability compared with an intramedullary tumor only . 
 earlier surgery with intraoperative spinal cord monitoring is recommended for total resection and good surgical outcome especially for an ie tumor compared with an intramedullary tumor .