Functional DTI tractography in brainstem cavernoma surgery

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  • 1 Department of Neurosurgery, Charité–Universitätsmedizin Berlin, Germany
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OBJECTIVE

Surgical resection of brainstem cavernomas is associated with high postoperative morbidity due to the density of local vulnerable structures. Classical mapping of pathways by diffusion tensor imaging (DTI) has proven to be unspecific and confusing in many cases. In the current study, the authors aimed to establish a more reliable, specific, and objective method for somatotopic visualization of the descending motor pathways with navigated transcranial magnetic stimulation (nTMS)–based DTI fiber tracking.

METHODS

Twenty-one patients with brainstem cavernomas were examined with nTMS prior to surgery. The resting motor threshold (RMT) and cortical representation areas of hand, leg, and facial function were determined on both hemispheres. Motor evoked potential (MEP)–positive stimulation spots were then set as seed points for tractography. Somatotopic fiber tracking was performed at a fractional anisotropy (FA) value of 75% of the individual FA threshold.

RESULTS

Mapping of the motor cortex and tract reconstruction for hand, leg, and facial function was successful in all patients. The somatotopy of corticospinal and corticonuclear tracts was also clearly depicted on the brainstem level. Higher preoperative RMT values were associated with a postoperative motor deficit (p < 0.05) and correlated with a lower FA threshold (p < 0.05), revealing structural impairment of the corticospinal tract (CST) prior to surgery. In patients with a new deficit, the distance between the lesion and CST was below 1 mm.

CONCLUSIONS

nTMS-based fiber tracking enables objective somatotopic tract visualization on the brainstem level and provides a valuable instrument for preoperative planning, intraoperative orientation, and individual risk stratification. nTMS may thus increase the safety of surgical resection of brainstem cavernomas.

ABBREVIATIONS

BSCM = brainstem cavernous malformation; CBT = corticobulbar tract; CST = corticospinal tract; DTI = diffusion tensor imaging; DTT = diffusion tensor tractography; FA = fractional anisotropy; FAT = FA threshold; FDI = first digital interosseus muscle; MEP = motor evoked potential; MRC = Medical Research Council; mRS = modified Rankin Scale; nTMS = navigated transcranial magnetic stimulation; RMT = resting motor threshold; ROI = region of interest.

OBJECTIVE

Surgical resection of brainstem cavernomas is associated with high postoperative morbidity due to the density of local vulnerable structures. Classical mapping of pathways by diffusion tensor imaging (DTI) has proven to be unspecific and confusing in many cases. In the current study, the authors aimed to establish a more reliable, specific, and objective method for somatotopic visualization of the descending motor pathways with navigated transcranial magnetic stimulation (nTMS)–based DTI fiber tracking.

METHODS

Twenty-one patients with brainstem cavernomas were examined with nTMS prior to surgery. The resting motor threshold (RMT) and cortical representation areas of hand, leg, and facial function were determined on both hemispheres. Motor evoked potential (MEP)–positive stimulation spots were then set as seed points for tractography. Somatotopic fiber tracking was performed at a fractional anisotropy (FA) value of 75% of the individual FA threshold.

RESULTS

Mapping of the motor cortex and tract reconstruction for hand, leg, and facial function was successful in all patients. The somatotopy of corticospinal and corticonuclear tracts was also clearly depicted on the brainstem level. Higher preoperative RMT values were associated with a postoperative motor deficit (p < 0.05) and correlated with a lower FA threshold (p < 0.05), revealing structural impairment of the corticospinal tract (CST) prior to surgery. In patients with a new deficit, the distance between the lesion and CST was below 1 mm.

CONCLUSIONS

nTMS-based fiber tracking enables objective somatotopic tract visualization on the brainstem level and provides a valuable instrument for preoperative planning, intraoperative orientation, and individual risk stratification. nTMS may thus increase the safety of surgical resection of brainstem cavernomas.

In Brief

The authors investigated a new method to noninvasively visualize eloquent fibers and their localization on the brainstem level. By combining neurophysiological data derived from navigated transcranial magnetic stimulation with diffusion tensor imaging (DTI), the authors were able to determine tract alteration and conductivity. This innovative protocol allows for an objective evaluation of tract location and functionality and is thus less operator dependent and prone to interobserver variability than conventional DTI.

Cavernous malformations are rare vascular lesions of the central nervous system with an estimated prevalence of 0.4%–0.8%,1–3 accounting for 10%–20% of all vascular malformations. Up to one-third4,5 are brainstem cavernous malformations (BSCMs), which arise in the brainstem and are associated with higher hemorrhage (2.3%–13.6%1,6) and repeat hemorrhage (15%–60.9%1,6) rates. Surgery is the primary treatment method, particularly in symptomatic patients presenting with recurrent bleeding. The complex anatomy of vulnerable structures on the brainstem level, however, makes surgical resections technically demanding and leads to a high rate of postoperative morbidity. Symptomatic patients with lesions abutting the pial or ependymal surface or present with anatomically safe entry zones are the primary candidates for surgery.5,7 In patients with lesions that are deep seated or inaccessible from safe entry zones, a conservative treatment is advocated due to the high risk of perioperative morbidity.5,8

Modern neuroimaging techniques based on diffusion MRI delineate the course of white matter pathways based on water molecule diffusion along neuronal axons.9,10 By exploration of each white matter tract voxel by voxel, a predictable pattern of diffusion and thus tract orientation in a 3D space can be displayed.11,12 Diffusion tensor tractography (DTT) is traditionally performed through anatomically predefined regions of interest (ROIs). These are used as starting points to track down specific fiber tracts at a specific fractional anisotropy threshold (FAT). The FA value is a parameter of mean diffusivity, i.e., the direction dependence of a diffusion process.11,13 This can therefore also be used as a measure of diffusion along neuronal axons, indicating tract integrity.

Recent studies have pointed out the benefit of diffusion tensor imaging (DTI) in determining the association between the lesion and the white matter tracts in order to establish the best neurosurgical approach8,14–18 in deep-seated lesions. However, no clear correlation between DTI parameters and postoperative outcomes has been demonstrated.16,17,19

Navigated transcranial magnetic stimulation (nTMS) is a noninvasive tool that creates a map of functional motor areas and allows the evaluation of cortical and corticospinal excitability.20,21 During the last decade, nTMS has proven to be a valuable tool for preoperative motor mapping in brain tumors located in eloquent motor and speech areas.22–25

nTMS-based fiber tracking was recently introduced in order to establish an objective algorithm to visualize motor pathways derived from functional data.26 Here, the “motor-positive” nTMS points are used as seed points to track functionally relevant motor pathways for hand, leg, and facial function. Compared with the traditional approach, this protocol allows for a specific tractography of each cortical region. In a cohort of patients with tumors located in or adjacent to the primary motor cortex, this method led to a change in operative strategy in nearly half of the patients.26

The aim of the present study was to evaluate whether nTMS-based fiber tracking is also beneficial for preoperative planning and risk stratification in the surgery of brainstem cavernomas.

Methods

The study proposal was approved by the local ethics commission. Patients provided written informed consent for all medical evaluations and treatments.

Patient Selection

Twenty-one patients (mean age 44 years, range 25–67 years; 11 female) with BSCMs were enrolled in this study. The radiological diagnosis was assessed by an experienced neuroradiologist. Exclusion criteria were other pathologies in the vicinity of the corticospinal tract (CST) above the lesion site (i.e., tumor or infarction), high-grade paresis of the upper extremity (grade < 3, British Medical Research Council [MRC] scale for muscle strength), neuroinflammatory or neurodegenerative disease, and pregnancy.

Assessment of Clinical Neurological Status

At the time of enrollment, all patients underwent neurological examination. The severity of paresis was assessed based on the MRC scale (grade range 0–5). Patient disability in daily life practice was categorized according to the modified Rankin Scale (mRS; score range 0–6). Neurological recovery was reassessed after 3 months in the outpatient clinic.

MRI Protocol

Conventional MRI was performed on a 1.5-T or 3-T imaging unit (Siemens 3 T, GE Healthcare) with a 1.0-mm section thickness T1 inversion recovery (TR/TE/TI/α 7.8 msec/3.1 msec/500 msec/16°) 3D gradient-echo sequence (IR 3D-FSPGR). A diffusion-weighted single-shot echo-planar sequence along 23 different geometrical directions at a b value of 1000 sec/mm2 was repeated to sample a diffusion tensor. Scan parameters were TR/TE 11,000 msec/83 msec, matrix size 128 × 128, and FOV 240 × 240 mm.

Navigated Transcranial Magnetic Stimulation

All patients underwent preoperative nTMS brain mapping (eXimia, Nexstim) using a high-precision, figure-eight stimulation coil, combined with MRI-based neuronavigation and analytical software to deliver biphasic magnetic stimulation to spots on the motor cortex. The muscle output was recorded on the system’s integrated electromyogram using surface electrodes (Neuroline 720, Ambu) attached to the mentalis muscle, first digital interosseus muscle (FDI), and tibialis anterior muscle bilaterally.

Resting Motor Threshold

The resting motor threshold (RMT) serves as a measure of cortical excitability. The hotspots for the FDI and respective RMT were determined as previously described for both hemispheres.27,28 The RMT was defined by an automated algorithm approximating the lowest output intensity producing reliable motor evoked potentials (MEPs) ≥ 50 μV with a 95% confidence interval of ± 2.0.

Diffusion Tensor Tractography

Visualization of tracts was performed according to our previously published algorithm on nTMS-based tractography11,13,29 using a commercial software package (Elements, Brainlab; Fig. 1). Briefly, nTMS spots that elicited an MEP on the cortical surface for hand, face, and leg muscles were imported into the DTI software and enlarged to a diameter of 3 mm to create a continuous seed point area. Then another ROI was set according to the color-coded conventional FA map on the level of the pons, including the corticospinal or corticobulbar projections.30 The FAT was determined for each ROI by stepwise increases of the FA value until the complete disappearance of tracts. Fiber tracking was then performed at 75% FAT using an anterograde direction with a vector step length of 1.6 mm, an angular threshold of 30°, and a minimum tract length of 110 mm. The resulting tracts were then classified depending on their radiological appearance as 1) normal, 2) displaced but intact, 3) deformed, or 4) interrupted.17,31 Then, the shortest distance between the lesion and the CST/corticobulbar tract (CBT) was measured. After surgical resection, the preoperative nTMS-DTI plan was fused with the postoperative MRI in order to analyze the condition of tracts beneath the resection cavity.

FIG. 1.
FIG. 1.

Workflow for nTMS-based DTI fiber tracking. A: nTMS determination of primary motor area (hand, leg, face). B: Transfer of nTMS-based seed points. C: Individual FAT determination. D: Somatotopy of tracts on brainstem level (orange, CST arm; blue, CST leg; pink, CBT). Figure is available in color online only.

Surgical Management

The decision for surgical treatment was individually tailored to every patient depending on lesion localization and associated anatomical structures. The nTMS-DTI results were used as additional information to evaluate the risk for perioperative morbidity and determine the surgical approach that would spare the CST. During surgery, the tractography results were presented via a heads-up display outline. Additional neuromonitoring procedures in the form of motor and sensory evoked potentials and electrophysiological monitoring of the cranial nerves were performed to guide the operative approach and microsurgical resection.

Statistical Analysis

The data are expressed as mean ± SEM. Comparison of groups was done with t-testing. While for dependent variables a paired design was considered, in nonparametric data the Wilcoxon signed-rank test was applied. Relationships between FAT and RMT, as well as motor status and FAT and RMT, were tested with Pearson correlation analysis.

To assess predictive values for a new motor deficit, we performed a multiple logistic regression analysis with new motor deficit as the dependent variable and RMT, FAT, distance to CST > 5 mm, and tract disruption as the independent variables. Differences were considered statistically significant at p < 0.05 (GraphPad Prism 8.0.2).

Results

Clinical Results

A total of 21 patients (age range 24–66 years, mean 42.8 years) were enrolled in this study. At admission, most of the patients presented in a good clinical condition (average mRS score 1.9), mainly complaining about cranial nerve deficits (12/21 patients), followed by sensory disturbances (7/21) and motor weakness of the limbs (6/21). Microsurgical resection was performed in 15 patients (Table 1). All of the surgical patients were symptomatic prior to admission and had signs of bleeding around the cavernous lesion on cranial MRI. Based on the additional information gained from the nTMS-DTI results, operative resection was performed in 5 patients and conservative treatment in 2 patients. Six patients received conservative treatment. The mutual decision to withdraw from surgery was made in patients with complete remission of symptoms (6/6) after thorough consultation about the surgical risks and natural history of the disease. Further criteria were close anatomical relation to functional tracts (3/6 patients), deep-seated location (2/6), pregnancy (1/6), and personal decision (against surgeon’s advice, 1/6).

TABLE 1.

Clinical data for the surgical group patients

Motor Status (MRC grade)mRS Score
Patient No.Age (yrs)/SexLevel, PositionDistance to Surface, mmOp ApproachPreopPostop3-Mo FUPreop3-Mo FURMT, %*FAT*CST Dist, mmTract Integrity (CST)
144/FPons, dorsal1Kawase4+4+531530.153Displaced
232/FMes, ventral0Transcall544+42350.341Displaced
344/FMes/thal, ventral2Transcall33433500.080Displaced
431/MPons, ventral0Ant petros55510350.382.6Normal
525/MPons, dorsal0Med subocc55523260.332.5Normal
659/MMo, dorsal0Med subocc55511310.226.7Normal
735/MPons, dorsal0Med subocc44−433640.280Interrupted
841/FMes, dorsal2Subtemp55521340.314Displaced
952/FPons, ventral0Retrosigmoid55512330.391.5Interrupted
1042/FMes/pons, dorsal0Supracereb55513470.133Displaced
1140/MMo, vent-dors2Med subocc55522390.352.1Displaced
1235/MPons/mo, vent-dors2Retrosig4+34−23530.120Interrupted
1330/FPons, ventral0Med subocc43422700.320Interrupted
1456/FMo, dorsal1.5Med subocc55511390.355.3Displaced
1548/MMes, ventral0Pterional55511430.384.2Displaced

Ant = anterior; dist = distance; FU = follow-up; Kawase = approach through the middle fossa; med = medial; mes = mesial; mo = motor cortex; petros = petrosal; subocc = suboccipital; subtemp = subtemporal; supracereb = supracerebellar; thal = thalamic; transcall = transcallosal; vent-dors = ventrodorsal.

Affected hemisphere.

Distance between CST and cavernoma.

Partial resection due to intraoperative reduction of MEP amplitude.

In the surgical group, 53% of the lesions presented with a pial surface, the other 47% were deep seated. A gross-total resection was achieved in 14 patients (93%). Postoperatively, only 1 patient (7%) encountered a new motor deficit, and 3 patients (20%) experienced worsening of preoperative paresis. At the 3-month follow-up, all 6 patients reported a partial regression of motor weakness. A new cranial nerve deficit was seen in 2 patients (13%), but no new sensory deficit was reported (Table 1). At the follow-up examination, most patients presented with an excellent clinical status (mRS score 0–2 in 50% of the patients, average mRS score 2.2; Table 1). In 28% of the patients the preoperative mRS score improved, and in 43% it remained stable.

Navigated Transcranial Stimulation

Resting Motor Threshold

We compared the RMTs of patients with lateralized lesions divided into two groups, patients with and those without a preoperative deficit. Laterality was determined by the distance between the lesion and the CST. From previous studies on supratentorial lesions, it is known that a higher RMT correlates with a worse postoperative outcome.30,32 In this study, patients presenting with a preoperative motor weakness showed significantly higher RMT values and thus lower cortical excitability than those without (p < 0.05). This was also true for all patients with a postoperative motor deficit (p < 0.05; Fig. 2A). In the subgroup of patients who developed a new or worsened motor deficit, the preoperatively assessed RMT was also higher than in the patients who remained stable (51.3 vs 37.7, p = 0.06). This comparison, however, did not reach significance, which is probably mainly due to the small sample size of patients with postoperative motor deterioration (n = 4).

FIG. 2.
FIG. 2.

A: Comparison of RMT in patients with a new motor deficit (MRC grade < 5) and those without (MRC grade 5). *p < 0.05. B: Correlation of FAT and rRMT, p < 0.05, r2 = −0.57. C: Comparison of FAT in patients with (MRC grade 1) and without (MRC grade 5) a preoperative motor deficit. *p < 0.05. D: Distance to CST in patients with (MRC grade < 5) and without (MRC grade 5) a postoperative motor deficit.

Fractional Anisotropy

Applying our proposed algorithm, we defined an individual FAT for each cortical region separately (mean ± SD FAT: CST 0.3 ± 0.1, CBT 0.23 ± 0.08). There was a negative correlation between the FAT and RMT values (p < 0.05, r2 = −0.57; Fig. 2B), confirming that alterations of FAT reflect disturbance of CST integrity. We furthermore encountered lower FA values in patients presenting with a preoperative motor deficit (0.16 vs 0.32, p < 0.05; Fig. 2C).

nTMS-Based Tractography

Motor mapping with definition of cortical areas for the hand, leg, and face regions was feasible in all patients. The nTMS coordinates were used as seed points to perform a selective tractography for each of the 3 cortical regions and display a somatotopy of tracts on the brainstem level, and then the distance between the lesion and tracts was determined (mean distances: CBT 4.1 mm, CST 4.1 mm). Fiber disruption was observed in 13% of the cases and a clear fiber displacement in 67% of the cases. In all of the patients who presented with a new postoperative motor deficit, the distance between the tracts and the lesion was below 1 mm (sensitivity 100%, specificity 90%, positive predictive value [PPV] 80%; Fig. 2D; also see Figs. 4 and 6). Similarly, in those with the development of a new facial deficit, the distance to the CBT was 2 mm (sensitivity 100%, specificity 67%, PPV 66%). In 75% of the patients with interruption of tracts, a new postoperative deficit occurred, whereas in patients without tract interruption, 54% of the patients showed intact fibers and 36% showed displaced fibers (Table 1). In patients for whom the resection cavity was observed to enclose the tracts on the postoperative MRI, 75% developed a new deficit (see Figs. 4 and 5; patients 7, 9, 12, and 13 in Table 1). On the contrary, only 25% of the patients showed an aggravation of neurological function if the tracts were just beneath the lines of resection (see Figs. 3 and 6; patients 1, 2, 3, 4, and 15 in Table 1).

FIG. 3.
FIG. 3.

Illustrative case 1. A 56-year-old female patient (patient 14 in Table 1) with preoperative double vision and vertigo. A: Cavernous malformation in the central part of the medulla oblongata. B: Distance > 2 mm to all tracts. C: No effect on tracts visible on preoperative DTI. D: Patient experienced no postoperative deficits. E: Conventional tractography does not display CBT but does show closeness to leg fibers. The patient did not show any disturbance in leg function in the postoperative period. Figure is available in color online only.

FIG. 4.
FIG. 4.

Illustrative case 2. A 35-year-old male patient (patient 12 in Table 1) with preoperative hemiparesis (MRC grade 4) and facial palsy (House-Brackmann grade II). A: Cavernous malformation in the left part of the pons. B: Close anatomical correlation to the right CBT/CST with partial disruption; distance to CST, 0 mm (yellow arrow). C: Disruption of left CST and CBT. D: Postoperative MRI display tracts at the rim of the resection cavity (red star); the patient experienced an aggravation of motor deficit (MRC grade 3) and facial palsy (House-Brackmann grade III). E: Mainly CST for hand function was found in the vicinity of the lesion. Nevertheless, the patient’s facial function deteriorated. Figure is available in color online only.

FIG. 5.
FIG. 5.

Illustrative case 3. A 52-year-old female patient (patient 9 in Table 1) with preoperative double vision. A: Cavernous malformation in the central part of the pons. B: Right and left CSTs adjacent to the lesion; distance of CST from lesion, 1 mm. Intraoperatively, only a partial resection (red star) was performed due to loss of MEP amplitude for the right hand during surgery (yellow arrow). C: Disruption and dislocation of CST. D: No new neurological deficit after partial resection (red star). E: Leg CST within and closest to the lesion, although there were no alterations in leg MEP amplitude during surgery. Figure is available in color online only.

FIG. 6.
FIG. 6.

Illustrative case 4. A 42-year-old female patient (patient 10 in Table 1) with preoperative double vision and vertigo. A: Cavernous malformation in the right part of the mesencephalon. B: Distance to CBT, 0 mm (yellow arrow); distance to CST, 3 mm. C: Displacement of left CBT. D: Patient experienced postoperative dysphagia, left CBT bordering (yellow arrow) resection cavity (red star). E: Left CST (hand/leg) and CBT abutting the lesion. However, the patient did not suffer from postoperative paresis of the extremities. Figure is available in color online only.

Multiple logistic regression analysis was then performed to display the association of the four crucial parameters (RMT, FAT, distance to CST, and tract disruption) with the dependent variable, a new motor deficit. This analysis resulted in ORs for the RMT of 0.9 (95% CI 0.6021–1.097); for the FAT, 0.003 (95% CI 5.646e-018 to 21,540,537); for the distance to CST, 23.81(95% CI 0.5818–9085); and for tract integrity, 1.927 (95% CI 0.006588–216.2), with a negative predictive power of 75% and positive predictive power of 81.8% (p = 0.007, pseudo R2 = 0.53). According to this model of risk stratification, a patient with an elevated RMT, low FAT, distance to tracts < 1 mm, and disruption of tracts would carry a risk of 84% for a new motor deficit.

Comparisons of the nTMS tractography results with conventional DTI fiber tracking (predefined anatomical ROI, FA 0.2) are illustrated in Figs. 36. Intraoperative neuromonitoring was also used to confirm tractography data (Fig. 5). The traditional algorithm led to a higher number of fibers. However, in most cases this finding did not show any correlation with intraoperative neuromonitoring (Fig. 5) or postoperative outcome (Figs. 36).

Case Illustrations

Case 1

This 56-year-old female patient (Fig. 3) presented with a 2-week history of double vision and vertigo (patient 14 in Table 1). Upon clinical examination, there was no further deficit. The MRI revealed a hemorrhagic mass on the midportion of the medulla oblongata (Fig. 3). The nTMS-based tractography depicted the CBT and the CST for the lower extremity abutting the lesion laterally (Fig. 3B) but without any fiber disruption (Fig. 3C). The RMT (39%) and FAT (0.35) did not show any aberration (Table 1). The traditional deterministic algorithm displayed the CST (leg) and CBT in the ventrolateral portion of the lesion, which might suggest a perioperative impairment (Fig. 3E). Based on the nTMS DTI results, a suboccipital craniotomy and dorsomedian brainstem entry point was chosen, sparing the left CBT (Fig. 3D). After surgery, the patient presented without a new neurological deficit, and her preoperative diplopia resolved gradually.

Case 2

This 35-year-old male patient presented with a history of right-sided hemiparesis (MRC grade 4) and facial palsy (House-Brackmann grade II, patient 12 in Table 1). There was a cavernous lesion on the ventral-left part of the pons with signs of subacute bleeding on the preoperative MRI (Fig. 4A). nTMS DTI revealed a close anatomical correlation to tracts of both hemispheres (Fig. 4B), in particular the left CST/CBT, which also showed partial disruption (Fig. 4C). The elevated RMT value (53%) and low FAT (0.12) suggested an alteration of the left CST (Table 1). Deterministic DTI showed closeness mainly to the hand region CST (Fig. 4E). Postoperatively, the patient suffered from aggravation of right-sided hemiparesis (MRC grade 3) and facial palsy (House-Brackmann grade III), which confirmed the nTMS DTI data (Fig. 4B and D).

Case 3

This 52-year-old female patient presented with double vision (patient 9 in Table 1). The preoperative MRI displays a cavernous malformation in the central part of the pons (Fig. 5A). The preoperative nTMS DTI plan depicts both CST adjacent (< 1 mm) to the lesion (Fig. 5B) with partial disruption and dislocation of the left CST. Both the RMT (33%) and FAT (0.39) were unremarkable (Table 1). Traditional DTI depicts CST fiber for leg function closest to the lesion (Fig. 5E). Intraoperatively, only a partial resection was possible due to a loss of MEP amplitude of the right hand region (Fig. 5B, yellow arrow), as previously indicated in the nTMS DTI plan. After surgery, the patient remained neurologically intact.

Case 4

This 42-year-old female patient had a history of double vision and vertigo (patient 10 in Table 1). Further MRI confirmed a cavernoma in the right part of the mesencephalon. The nTMS DTI plan showed displacement of the left CBT (Fig. 6C) and abutting the lesion (Fig. 6B). The RMT (49%) appears elevated, and the FAT (0.13) was decreased (Table 1). The conventional DTI fiber tracking suggested closeness to the CBT and right CST (Fig. 6E). Postoperatively, the patient suffered from severe dysphagia but no motor deficit in the extremities, as indicated by the nTMS DTI data (Fig. 6B and D).

Discussion

Due to their critical neuroanatomical location, BSCMs that present with hemorrhage are highly associated with severe neurological deficits. Bleeding rates vary from 2.4% to 4.6% per patient-year and increase up to 5%–34.7% for rebleeding once bleeding has occurred.2,3,6 Surgical resection represents the best treatment method to prevent further hemorrhagic events. Naturally, the highly eloquent localization of BSCM is associated with significant perioperative morbidity and mortality (5%–27.7% and 0%–6.3%, respectively4,33,34), with transient postoperative deficits reported in up to 86% of cases.35,36

DTI in Brainstem Cavernoma

Technical advances in DTI have made this a promising preoperative tool to visualize white matter tracts and thereby enhance surgical planning and postoperative outcome.8,16,18 Due to the space-occupying effects of BSCMs, high anatomical variability may occur by displacement or disruption of tracts.16,17 Traditionally, DTI is carried out through predefined anatomical landmarks used as seed points and custom FA values,37 which highlights the main limitation of this technique in a situation of obscured anatomy and signal alterations that might result from the lesion itself, surrounding edema, or hemosiderin deposits.38 In such cases, an objective definition of seed points and individual FAT would help to account for pathological anatomy and disturbed tract integrity. By localization of essential tracts, nTMS-based DTI can deliver crucial information to define safe entry zones and guide intraoperative orientation and monitoring.26 Furthermore, the sole visualization of white matter tracts does not carry information about their functionality and vulnerability. While these features crucially depend on the FA profile of the tracts and the FAT set for tractography, determining an individual threshold level by using supplemental functional data might overcome this methodological weakness.26

Seed Region Definition Based on nTMS

nTMS noninvasively establishes a link between stimulation of a cortical area and registration of motor output, a process analogous to the gold standard of direct cortical stimulation (DCS).20,21,23 The resulting functional maps obtained with nTMS have been demonstrated to provide high reliability and precision of results compared with DCS findings.20,21 Using individually defined seed points derived from the nTMS measurement helps to define essentially functional tracts. A customized FAT determination has furthermore proven to be a superior method for reducing aberrant fibers and interexaminer variability, as recently shown in supratentorial lesions.26,30 In the present study, seed regions for hand, leg, and facial function were defined and used to track functionally relevant fibers and successfully reconstruct a somatotopy of tracts on the brainstem level.

Preoperative Risk Stratification

Due to the density of highly eloquent anatomical structures surrounding BSCMs on the one hand and the natural course of BSCMs on the other hand, defining the individual risk profile of surgical morbidity is a crucial step in the decision-making process for surgical treatment. Of equal importance is the ability to counsel the patient about the risks of a postoperative deficit before deciding on a specific treatment option based on objective data.

nTMS-based DTI is a noninvasive method that not only allows for a preoperative visualization of essential tracts, but also combines radiographic and electrophysiological features. Estimating the excitability and conductivity of the tracts adds important information to the topographical data, i.e., the minimal distance between tract and lesion, by providing information on the vulnerability of the tracts. In our series, we were able to show a negative correlation between the FAT and RMT, i.e., measure of anisotropy or tract integrity and cortical excitability. A disturbance in fiber conductivity was thus associated with a low excitability. Both parameters also correlate to a pre- and postoperative motor deficit. Patients with disturbed fiber integrity and thus low FAT also presented with a lower cortical excitability displayed by a high RMT. Also, a distance of 1 mm between lesion and tracts appears to be the critical lower limit: all patients who developed a new motor deficit or an increased paresis had a minimal distance between lesion and tract of 1 mm or less. Of equal importance is the development of a new cranial nerve deficit, particularly dysarthria or dysphagia, since it significantly restricts quality of life and might result in the need for further surgical therapy, i.e., tracheostomy. In our study, the critical distance to CBT for a new facial deficit was 2 mm.

Surgical Planning and Intraoperative Orientation

Choosing the right surgical approach is a crucial step in the surgery of brainstem lesions.7,35,36 Visualization of the CST and CBT in relation to the tumor is essential to define a safe surgical corridor and brainstem entry point. In the present study, the tractography results were used in all of the surgical procedures to set up an individually tailored surgical plan with the lowest risk of affecting the CST or CBT. By intraoperative navigation, the nTMS DTI results can be made readably available during surgery through a heads-up display in the surgical microscope and serve as a guide for microsurgical dissection as well as direct electrical stimulation.

Clinical Outcome

In our series of 15 patients undergoing brainstem cavernoma resection, we observed a new motor deficit in only 1 patient (7%) and a progression of a preexisting paresis in 3 patients. These results are comparable to previously reported results on DTI in BSCM (8.7%–9%).16,17,35 However, in our patient sample we were able to include a higher number of high-risk, deep-seated lesions without a pial surface (47%) than in previously reported studies.17 All of our patients showed at least a partial regression of motor deficits during follow-up, with a favorable overall outcome in 50% (mRS score 0–2) and a stable or improved mRS score in 72% of the patients.

Perspective

DTT is an emerging method that allows noninvasive visualization of eloquent fibers and their localization on the brainstem level. However, users must be aware of the limits of this method to prevent misinterpretation of findings. Because the DTI methodology enables the display of mainly long fibers, tractography results might be affected by MRI artifacts (i.e., hemorrhage and hemosiderin deposits), and no information is provided on the localization of cranial nuclei. To address this limitation, electrophysiological data might provide valuable information about tract alteration and conductivity. Furthermore, conventional DTI is to a certain degree operator dependent, and results are prone to high interobserver variability. The latter might be overcome by a standardized protocol with individual seed points and FAT determinations. Our proposed nTMS-based tractography protocol combines radiological with electrophysiological data and allows for an objective visualization of relevant motor pathways on the brainstem level. In the current series of patients, our data not only helped to guide surgical planning and intraoperative orientation, but also enabled us to define individual risk factors (distance to tracts, RMT, tract disruption) for postoperative morbidity.

Conclusions

nTMS-based tractography allows for an objective visualization of relevant motor pathways on the brainstem level. By combining functional and radiographical data, an evaluation of fiber vulnerability and lesion-to-tract distance can be achieved. We feel that with the use of nTMS-DTI complex brainstem cavernomas become more amenable to surgical resection and neurological postoperative deterioration can be prevented. This method provides valuable information that can positively impact patient consultation, preoperative planning, and intraoperative orientation.

Acknowledgments

We thank our study nurse H. Schneider (Department of Neurosurgery, Charité–Universitätsmedizin, Berlin) for research assistance.

Disclosures

T. Picht has served as a speaker for Nexstim Oy but is not a contracted consultant.

Author Contributions

Conception and design: Vajkoczy, Zdunczyk. Acquisition of data: Zdunczyk, Roth. Analysis and interpretation of data: Zdunczyk, Roth. Drafting the article: Zdunczyk. Critically revising the article: Vajkoczy, Zdunczyk, Picht. Reviewed submitted version of manuscript: Vajkoczy, Roth, Picht. Statistical analysis: Zdunczyk. Study supervision: Zdunczyk.

Supplemental Information

Previous Presentations

The results reported in this paper (resting motor threshold, fractional anisotropy threshold, distance to tracts) were presented orally at the annual scientific meeting of the German Society for Neurosurgery, Würzburg, Germany, May 15, 2019.

References

  • 1

    Gross BA , Lin N , Du R , Day AL . The natural history of intracranial cavernous malformations . Neurosurg Focus . 2011 ;30 (6 ):E24 .

  • 2

    Kim PY , Park YG , Choi JU , et al. An analysis of the natural history of cavernous malformations . Surg Neurol . 1997 ;48 (1 ):9 18 .

  • 3

    Robinson JR Jr , Awad IA , Little JR . Natural history of the cavernous angioma . J Neurosurg . 1991 ;75 (5 ):709 714 .

  • 4

    Dukatz T , Sarnthein J , Sitter H , et al. Quality of life after brainstem cavernoma surgery in 71 patients . Neurosurgery . 2011 ;69 (3 ):689 695 .

  • 5

    Hauck EF , Barnett SL , White JA , Samson D . Symptomatic brainstem cavernomas . Neurosurgery . 2009 ;64 (1 ):61 71 .

  • 6

    Gross BABH , Batjer HH , Awad IA , Bendok BR . Brainstem cavernous malformations . Neurosurgery . 2009 ;64 (5 ):E805 E818 .

  • 7

    Gross BA , Batjer HH , Awad IA , et al. Brainstem cavernous malformations: 1390 surgical cases from the literature . World Neurosurg . 2013 ;80 (1-2 ):89 93 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Cao Z , Lv J , Wei X , Quan W . Appliance of preoperative diffusion tensor imaging and fiber tractography in patients with brainstem lesions . Neurol India . 2010 ;58 (6 ):886 890 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Berman J. Diffusion MR tractography as a tool for surgical planning . Magn Reson Imaging Clin N Am . 2009 ;17 (2 ):205 214 .

  • 10

    Sarubbo S , De Benedictis A , Merler S , et al. Towards a functional atlas of human white matter . Hum Brain Mapp . 2015 ;36 (8 ):3117 3136 .

  • 11

    Basser MJ , Mattiello J , LeBihan D . MR diffusion tensor spectroscopy and imaging . Biophys J . 1994 ;66 (1 ):259 267 .

  • 12

    Sundgren PC , Dong Q , Gómez-Hassan D , et al. Diffusion tensor imaging of the brain: review of clinical applications . Neuroradiology . 2004 ;46 (5 ):339 350 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Basser PJ , Pajevic S , Pierpaoli C , et al. In vivo fiber tractography using DT-MRI data . Magn Reson Med . 2000 ;44 (4 ):625 632 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Chen X , Weigel D , Ganslandt O , et al. Diffusion tensor-based fiber tracking and intraoperative neuronavigation for the resection of a brainstem cavernous angioma . Surg Neurol . 2007 ;68 (3 ):285 291 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Faraji AH , Abhinav K , Jarbo K , et al. Longitudinal evaluation of corticospinal tract in patients with resected brainstem cavernous malformations using high-definition fiber tractography and diffusion connectometry analysis: preliminary experience . J Neurosurg . 2015 ;123 (5 ):1133 1144 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Flores BC , Whittemore AR , Samson DS , Barnett SL . The utility of preoperative diffusion tensor imaging in the surgical management of brainstem cavernous malformations . J Neurosurg . 2015 ;122 (3 ):653 662 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Li D , Jiao YM , Wang L , et al. Surgical outcome of motor deficits and neurological status in brainstem cavernous malformations based on preoperative diffusion tensor imaging: a prospective randomized clinical trial . J Neurosurg . 2018 ;130 (1 ):286 301 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Ulrich NH , Kockro RA , Bellut D , et al. Brainstem cavernoma surgery with the support of pre- and postoperative diffusion tensor imaging: initial experiences and clinical course of 23 patients . Neurosurg Rev . 2014 ;37 (3 ):481 492 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Januszewski J , Albert L , Black K , Dehdashti AR . The usefulness of diffusion tensor imaging and tractography in surgery of brainstem cavernous malformations . World Neurosurg . 2016 ;93 :377 388 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Ruohonen J , Karhu J . Navigated transcranial magnetic stimulation . Neurophysiol Clin . 2010 ;40 (1 ):7 17 .

  • 21

    Picht T , Mularski S , Kuehn B , et al. Navigated transcranial magnetic stimulation for preoperative functional diagnostics in brain tumor surgery . Neurosurgery . 2009 ;65 (6 )(suppl):93 99 .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Lefaucheur JP , Picht T . The value of preoperative functional cortical mapping using navigated TMS . Neurophysiol Clin . 2016 ;46 (2 ):125 133 .

  • 23

    Picht T , Schmidt S , Brandt S , et al. Preoperative functional mapping for rolandic brain tumor surgery: comparison of navigated transcranial magnetic stimulation to direct cortical stimulation . Neurosurgery . 2011 ;69 (3 ):581 588 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Picht T . Current and potential utility of transcranial magnetic stimulation in the diagnostics before brain tumor surgery . CNS Oncol . 2014 ;3 (4 ):299 310 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Krieg SM , Shiban E , Buchmann N , et al. Utility of presurgical navigated transcranial magnetic brain stimulation for the resection of tumors in eloquent motor areas . J Neurosurg . 2012 ;116 (5 ):994 1001 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Frey D , Strack V , Wiener E , et al. A new approach for corticospinal tract reconstruction based on navigated transcranial stimulation and standardized fractional anisotropy values . Neuroimage . 2012 ;62 (3 ):1600 1609 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Jussen D , Zdunczyk A , Schmidt S , et al. Motor plasticity after extra-intracranial bypass surgery in occlusive cerebrovascular disease . Neurology . 2016 ;87 (1 ):27 35 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Awiszus F , Feistner H , Urbach D , Bostock H . Characterisation of paired-pulse transcranial magnetic stimulation conditions yielding intracortical inhibition or I-wave facilitation using a threshold-hunting paradigm . Exp Brain Res . 1999 ;129 (2 ):317 324 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Nimsky C , Ganslandt O , Merhof D , et al. Intraoperative visualization of the pyramidal tract by diffusion-tensor-imaging-based fiber tracking . Neuroimage . 2006 ;30 (4 ):1219 1229 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Rosenstock T , Giampiccolo D , Schneider H , et al. Specific DTI seeding and diffusivity-analysis improve the quality and prognostic value of TMS-based deterministic DTI of the pyramidal tract . Neuroimage Clin . 2017 ;16 :276 285 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Kovanlikaya I , Firat Z , Kovanlikaya A , et al. Assessment of the corticospinal tract alterations before and after resection of brainstem lesions using diffusion tensor imaging (DTI) and tractography at 3T . Eur J Radiol . 2011 ;77 (3 ):383 391 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Rosenstock T , Grittner U , Acker G , et al. Risk stratification in motor area-related glioma surgery based on navigated transcranial magnetic stimulation data . J Neurosurg . 2017 ;126 (4 ):1227 1237 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Cantu C , Murillo-Bonilla L , Arauz A , et al. Predictive factors for intracerebral hemorrhage in patients with cavernous angiomas . Neurol Res . 2005 ;27 (3 ):314 318 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Pandey P , Westbroek EM , Gooderham PA , Steinberg GK . Cavernous malformation of brainstem, thalamus, and basal ganglia: a series of 176 patients . Neurosurgery . 2013 ;72 (4 ):573 589 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Garcia RM , Ivan ME , Lawton MT . Brainstem cavernous malformations: surgical results in 104 patients and a proposed grading system to predict neurological outcomes . Neurosurgery . 2015 ;76 (3 ):265 278 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Walcott BP , Choudhri O , Lawton MT . Brainstem cavernous malformations: Natural history versus surgical management . J Clin Neurosci . 2016 ;32 :164 165 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Mori S , van Zijl PC . Fiber tracking: principles and strategies—a technical review . NMR Biomed . 2002 ;15 (7-8 ):468 480 .

  • 38

    Leclercq D , Delmaire C , de Champfleur NM , et al. Diffusion tractography: methods, validation and applications in patients with neurosurgical lesions . Neurosurg Clin N Am . 2011 ;22 (2 ):253 268 , ix .

    • Crossref
    • Search Google Scholar
    • Export Citation

Artist’s illustration of the classic mulberry appearance of a cavernoma. This illustration represents the Seven Cavernomas series by Dr. Michael Lawton, a collection of articles defining the tenets and techniques for the treatment of cavernous malformations, a taxonomy for classifying these lesions, and the nuances of their surgical approaches. Artist: Peter M. Lawrence. Used with permission from Barrow Neurological Institute, Phoenix, Arizona. See the article by Garcia et al. (pp 671–682).

  • View in gallery

    Workflow for nTMS-based DTI fiber tracking. A: nTMS determination of primary motor area (hand, leg, face). B: Transfer of nTMS-based seed points. C: Individual FAT determination. D: Somatotopy of tracts on brainstem level (orange, CST arm; blue, CST leg; pink, CBT). Figure is available in color online only.

  • View in gallery

    A: Comparison of RMT in patients with a new motor deficit (MRC grade < 5) and those without (MRC grade 5). *p < 0.05. B: Correlation of FAT and rRMT, p < 0.05, r2 = −0.57. C: Comparison of FAT in patients with (MRC grade 1) and without (MRC grade 5) a preoperative motor deficit. *p < 0.05. D: Distance to CST in patients with (MRC grade < 5) and without (MRC grade 5) a postoperative motor deficit.

  • View in gallery

    Illustrative case 1. A 56-year-old female patient (patient 14 in Table 1) with preoperative double vision and vertigo. A: Cavernous malformation in the central part of the medulla oblongata. B: Distance > 2 mm to all tracts. C: No effect on tracts visible on preoperative DTI. D: Patient experienced no postoperative deficits. E: Conventional tractography does not display CBT but does show closeness to leg fibers. The patient did not show any disturbance in leg function in the postoperative period. Figure is available in color online only.

  • View in gallery

    Illustrative case 2. A 35-year-old male patient (patient 12 in Table 1) with preoperative hemiparesis (MRC grade 4) and facial palsy (House-Brackmann grade II). A: Cavernous malformation in the left part of the pons. B: Close anatomical correlation to the right CBT/CST with partial disruption; distance to CST, 0 mm (yellow arrow). C: Disruption of left CST and CBT. D: Postoperative MRI display tracts at the rim of the resection cavity (red star); the patient experienced an aggravation of motor deficit (MRC grade 3) and facial palsy (House-Brackmann grade III). E: Mainly CST for hand function was found in the vicinity of the lesion. Nevertheless, the patient’s facial function deteriorated. Figure is available in color online only.

  • View in gallery

    Illustrative case 3. A 52-year-old female patient (patient 9 in Table 1) with preoperative double vision. A: Cavernous malformation in the central part of the pons. B: Right and left CSTs adjacent to the lesion; distance of CST from lesion, 1 mm. Intraoperatively, only a partial resection (red star) was performed due to loss of MEP amplitude for the right hand during surgery (yellow arrow). C: Disruption and dislocation of CST. D: No new neurological deficit after partial resection (red star). E: Leg CST within and closest to the lesion, although there were no alterations in leg MEP amplitude during surgery. Figure is available in color online only.

  • View in gallery

    Illustrative case 4. A 42-year-old female patient (patient 10 in Table 1) with preoperative double vision and vertigo. A: Cavernous malformation in the right part of the mesencephalon. B: Distance to CBT, 0 mm (yellow arrow); distance to CST, 3 mm. C: Displacement of left CBT. D: Patient experienced postoperative dysphagia, left CBT bordering (yellow arrow) resection cavity (red star). E: Left CST (hand/leg) and CBT abutting the lesion. However, the patient did not suffer from postoperative paresis of the extremities. Figure is available in color online only.

  • 1

    Gross BA , Lin N , Du R , Day AL . The natural history of intracranial cavernous malformations . Neurosurg Focus . 2011 ;30 (6 ):E24 .

  • 2

    Kim PY , Park YG , Choi JU , et al. An analysis of the natural history of cavernous malformations . Surg Neurol . 1997 ;48 (1 ):9 18 .

  • 3

    Robinson JR Jr , Awad IA , Little JR . Natural history of the cavernous angioma . J Neurosurg . 1991 ;75 (5 ):709 714 .

  • 4

    Dukatz T , Sarnthein J , Sitter H , et al. Quality of life after brainstem cavernoma surgery in 71 patients . Neurosurgery . 2011 ;69 (3 ):689 695 .

  • 5

    Hauck EF , Barnett SL , White JA , Samson D . Symptomatic brainstem cavernomas . Neurosurgery . 2009 ;64 (1 ):61 71 .

  • 6

    Gross BABH , Batjer HH , Awad IA , Bendok BR . Brainstem cavernous malformations . Neurosurgery . 2009 ;64 (5 ):E805 E818 .

  • 7

    Gross BA , Batjer HH , Awad IA , et al. Brainstem cavernous malformations: 1390 surgical cases from the literature . World Neurosurg . 2013 ;80 (1-2 ):89 93 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Cao Z , Lv J , Wei X , Quan W . Appliance of preoperative diffusion tensor imaging and fiber tractography in patients with brainstem lesions . Neurol India . 2010 ;58 (6 ):886 890 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Berman J. Diffusion MR tractography as a tool for surgical planning . Magn Reson Imaging Clin N Am . 2009 ;17 (2 ):205 214 .

  • 10

    Sarubbo S , De Benedictis A , Merler S , et al. Towards a functional atlas of human white matter . Hum Brain Mapp . 2015 ;36 (8 ):3117 3136 .

  • 11

    Basser MJ , Mattiello J , LeBihan D . MR diffusion tensor spectroscopy and imaging . Biophys J . 1994 ;66 (1 ):259 267 .

  • 12

    Sundgren PC , Dong Q , Gómez-Hassan D , et al. Diffusion tensor imaging of the brain: review of clinical applications . Neuroradiology . 2004 ;46 (5 ):339 350 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Basser PJ , Pajevic S , Pierpaoli C , et al. In vivo fiber tractography using DT-MRI data . Magn Reson Med . 2000 ;44 (4 ):625 632 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Chen X , Weigel D , Ganslandt O , et al. Diffusion tensor-based fiber tracking and intraoperative neuronavigation for the resection of a brainstem cavernous angioma . Surg Neurol . 2007 ;68 (3 ):285 291 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Faraji AH , Abhinav K , Jarbo K , et al. Longitudinal evaluation of corticospinal tract in patients with resected brainstem cavernous malformations using high-definition fiber tractography and diffusion connectometry analysis: preliminary experience . J Neurosurg . 2015 ;123 (5 ):1133 1144 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Flores BC , Whittemore AR , Samson DS , Barnett SL . The utility of preoperative diffusion tensor imaging in the surgical management of brainstem cavernous malformations . J Neurosurg . 2015 ;122 (3 ):653 662 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Li D , Jiao YM , Wang L , et al. Surgical outcome of motor deficits and neurological status in brainstem cavernous malformations based on preoperative diffusion tensor imaging: a prospective randomized clinical trial . J Neurosurg . 2018 ;130 (1 ):286 301 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Ulrich NH , Kockro RA , Bellut D , et al. Brainstem cavernoma surgery with the support of pre- and postoperative diffusion tensor imaging: initial experiences and clinical course of 23 patients . Neurosurg Rev . 2014 ;37 (3 ):481 492 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Januszewski J , Albert L , Black K , Dehdashti AR . The usefulness of diffusion tensor imaging and tractography in surgery of brainstem cavernous malformations . World Neurosurg . 2016 ;93 :377 388 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Ruohonen J , Karhu J . Navigated transcranial magnetic stimulation . Neurophysiol Clin . 2010 ;40 (1 ):7 17 .

  • 21

    Picht T , Mularski S , Kuehn B , et al. Navigated transcranial magnetic stimulation for preoperative functional diagnostics in brain tumor surgery . Neurosurgery . 2009 ;65 (6 )(suppl):93 99 .

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Lefaucheur JP , Picht T . The value of preoperative functional cortical mapping using navigated TMS . Neurophysiol Clin . 2016 ;46 (2 ):125 133 .

  • 23

    Picht T , Schmidt S , Brandt S , et al. Preoperative functional mapping for rolandic brain tumor surgery: comparison of navigated transcranial magnetic stimulation to direct cortical stimulation . Neurosurgery . 2011 ;69 (3 ):581 588 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Picht T . Current and potential utility of transcranial magnetic stimulation in the diagnostics before brain tumor surgery . CNS Oncol . 2014 ;3 (4 ):299 310 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Krieg SM , Shiban E , Buchmann N , et al. Utility of presurgical navigated transcranial magnetic brain stimulation for the resection of tumors in eloquent motor areas . J Neurosurg . 2012 ;116 (5 ):994 1001 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Frey D , Strack V , Wiener E , et al. A new approach for corticospinal tract reconstruction based on navigated transcranial stimulation and standardized fractional anisotropy values . Neuroimage . 2012 ;62 (3 ):1600 1609 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Jussen D , Zdunczyk A , Schmidt S , et al. Motor plasticity after extra-intracranial bypass surgery in occlusive cerebrovascular disease . Neurology . 2016 ;87 (1 ):27 35 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Awiszus F , Feistner H , Urbach D , Bostock H . Characterisation of paired-pulse transcranial magnetic stimulation conditions yielding intracortical inhibition or I-wave facilitation using a threshold-hunting paradigm . Exp Brain Res . 1999 ;129 (2 ):317 324 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Nimsky C , Ganslandt O , Merhof D , et al. Intraoperative visualization of the pyramidal tract by diffusion-tensor-imaging-based fiber tracking . Neuroimage . 2006 ;30 (4 ):1219 1229 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Rosenstock T , Giampiccolo D , Schneider H , et al. Specific DTI seeding and diffusivity-analysis improve the quality and prognostic value of TMS-based deterministic DTI of the pyramidal tract . Neuroimage Clin . 2017 ;16 :276 285 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Kovanlikaya I , Firat Z , Kovanlikaya A , et al. Assessment of the corticospinal tract alterations before and after resection of brainstem lesions using diffusion tensor imaging (DTI) and tractography at 3T . Eur J Radiol . 2011 ;77 (3 ):383 391 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Rosenstock T , Grittner U , Acker G , et al. Risk stratification in motor area-related glioma surgery based on navigated transcranial magnetic stimulation data . J Neurosurg . 2017 ;126 (4 ):1227 1237 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Cantu C , Murillo-Bonilla L , Arauz A , et al. Predictive factors for intracerebral hemorrhage in patients with cavernous angiomas . Neurol Res . 2005 ;27 (3 ):314 318 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Pandey P , Westbroek EM , Gooderham PA , Steinberg GK . Cavernous malformation of brainstem, thalamus, and basal ganglia: a series of 176 patients . Neurosurgery . 2013 ;72 (4 ):573 589 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Garcia RM , Ivan ME , Lawton MT . Brainstem cavernous malformations: surgical results in 104 patients and a proposed grading system to predict neurological outcomes . Neurosurgery . 2015 ;76 (3 ):265 278 .

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Walcott BP , Choudhri O , Lawton MT . Brainstem cavernous malformations: Natural history versus surgical management . J Clin Neurosci . 2016 ;32 :164 165 .

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Mori S , van Zijl PC . Fiber tracking: principles and strategies—a technical review . NMR Biomed . 2002 ;15 (7-8 ):468 480 .

  • 38

    Leclercq D , Delmaire C , de Champfleur NM , et al. Diffusion tractography: methods, validation and applications in patients with neurosurgical lesions . Neurosurg Clin N Am . 2011 ;22 (2 ):253 268 , ix .

    • Crossref
    • Search Google Scholar
    • Export Citation

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