Using the Vitrea® workstation (Vital Images, Minnetonka, MN) we performed volumetric tumor analyses on axial FLAIR sequences, and post-gadolinium axial T1 images with user-assisted semi-automated software; and then recorded tumor volumes on FLAIR and enhancement and cyst/necrosis on T1 gadolinium images [11
Post-processing of the diffusion tensor imaging was performed using in house software written in IDL (ITT Visual Information Solutions™, Boulder, CO). Fractional anisotropy (FA), apparent diffusion coefficient (ADC), and the three eigenvector maps were generated for each series. FA color maps color-coded based on the direction of the principal eigenvector were also generated. The major white matter tracts running through the brainstem were located on each FA color map using visual inspection and reference to a white matter atlas. Regions of interest (ROIs) were drawn within the left/right corticospinal tracts, the left and right sides of the anterior transverse pontine fibers, the left and right sides of the posterior transverse pontine fibers, and the left/right medial lemnisci. If the tract could not be reliably identified, an ROI was placed in the approximate location of the tract in the brainstem. If the approximate location of the tract showed only necrosis, no ROI was chosen. These ROIs were then used to obtain the ADC, FA, and individual eigenvalues through the left and right side of each tract, and the average of the left and right FA graphed for each structure.
DTI data from age-matched controls were also obtained from the current NIH MRI database of normal brain development [12
]. ADC, FA, and eigenvalues were extrapolated from DTI data of these controls and used to identify a baseline of normal values through the corticospinal, transverse pontine and medial lemniscal tracts of age-matched children.
Fiber tractography was performed based on the FACT algorithm and used to visualize the corticospinal tracts passing through the length of the brainstem. Superiorly, the corticospinal tract was visualized as far as practicable above the level of the corpus callosum. Using the Diffusion Toolkit and TrackVis software (Ruopeng Wang, Van J. Wedeen, TrackVis.org, Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA), fibers were tracked with an angle threshold of 35 degrees, FA threshold 0.2, and length threshold 10 mm. Attention was given to changes in the degree of disruption and displacement of the corticospinal tracts with reduction in size of tumor and tumor recurrence.
Patient 1 was a previously well 17-year-old male with a history of progressive blurred vision, particularly when looking left, as well as coughing or choking when drinking liquids. In addition, he had approximately two months of early morning headaches.
MRI at presentation showed a T2 hyperintense pontine lesion on FLAIR images extending inferiorly into the upper medulla, posteriorly into the middle cerebellar peduncles and superiorly into the midbrain (). Treatment was instituted on protocol PBTC 007 including radiation and concurrent gefitinib. Subsequent imaging performed after completion of radiotherapy showed decrease in tumor size (). Imaging performed fourteen months after therapy showed progression of tumor, with increased size as seen on FLAIR images () and increased enhancement(not shown).
Fig 1A–C. Patient 1 Conventional MRI images
Tractography performed at these three time points shows initial attenuation of the corticospinal and transverse pontine fibers at diagnosis (). In contrast, the scan performed after completion of radiotherapy demonstrated improved visualization of the tracts coursing through the brainstem (), with recovery of the fractional anisotropy () and alignment in response to therapy, possibly as a result of reduction in edema within the tracts. Subsequently, tract visualization deteriorated () in conjunction with progression of the tumor.
Fig 2A–C. Patient 1 DTI Tractography Analysis
Patient 1 Correlation of Fractional anisotropy (FA) of Brainstem White Matter Tracts with Tumor Volume
Patient 2 was a previously healthy seven-year-old who presented with a two week history of excessive blinking and squinting with subsequent progression to diplopia at the time of presentation to the hospital. MRI at presentation showed a non-enhancing lesion with T2 prolongation on FLAIR images (). Follow-up MRI performed at 8 weeks after presentation and institution of treatment on PBTC protocol 007 with gefitinib and concurrent radiation therapy showed decrease in size of the nonenhancing T2 prolongation within the pons compared to the prior study (). Clinical symptoms improved at this time. Imaging performed seven months after therapy showed increased size of the tumor, indicating tumor progression ().
Fig 4A–C. Patient 2 Conventional MRI images
Tractography showed decreased visualization of the corticospinal and transverse pontine fibers at diagnosis (). Scan performed following completion of radiotherapy demonstrated improved visualization of the tracts coursing through the brainstem (), with recovery of the fractional anisotropy () and alignment in response to therapy. Subsequently, tracts in the brainstem were attenuated in conjunction with progression of the tumor ().
Fig 5A–C. Patient 2 DTI Tractography Analysis
Patient 2 Correlation of Fractional anisotropy (FA) of Brainstem White Matter Tracts with Tumor Volume
Patient 3 was a previously healthy four-year-old male who presented with a 4 day history of unsteady gait and ataxia, with more acute facial nerve palsy. An MRI performed at presentation demonstrated a T2 hyperintense mass in the pons () with an enhancing central component and three smaller nodular areas of enhancement on the right side of the lesion (not shown). Treatment was instituted on protocol PBTC 014 using tipifarnib and radiation therapy. After an initial decrease in size of the tumor (), there was tumor progression with central necrosis seven months after treatment ().
Fig 7A–C. Patient 3 Conventional MRI images
Tractography at presentation () demonstrated posterior displacement of medial lemnisci and anterior transverse pontine fibers and infiltration of the corticospinal tracts and posterior transverse pontine fibers. Subsequent imaging performed showed slightly improved visualization of the long tracts in the brainstem () soon after completion of radiotherapy. At the time of tumor progression, tract visualization in the brainstem was poor (), indicating that the tracts were severely compromised, and individual tracts could not be identified on the color FA maps. Due to these limitations, calculation of exact ADC values within the tumor was not considered diagnostic in this case.
Fig 8A–C. Patient 3 Tractography analysis
Tumor volume versus time
After radiation there was decrease in tumor volume in all patients. At the time of progression of tumor there was increased tumor volume. Enhancement at baseline was present in 2 of the 3 patients with mean gadolinium enhancing volume of 1.81 cc (range 0.63– 2.99 cc).
The ADC values for the corticospinal tracts were compared to age-matched controls (AMC) in each case, and the results are shown in the graph (). In all cases there was increase in ADC values within the tumor at baseline compared to age matched controls.
Fig 9 Apparent diffusion coefficient (ADC) ratio in the three patients compared to normal controls before and after radiation therapy shows decreased ADC tumor values after radiation therapy and subsequent increased ADC tumor values during tumor progression. (more ...)