You are here

Article Text

Article menu

other Versions

Download PDFPDF

Review
Imaging in low-grade glioma: a guide for neurologists
  1. Jennifer Larsen1,
  2. Nigel Hoggard1,
  3. Fiona M McKevitt2
  1. 1Department of Neuroradiology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
  2. 2Department of Neurology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
  1. Correspondence to Dr Fiona M McKevitt, Department of Neurology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals Foundation Trust, Sheffield, S10 2JF, UK; fionamckevitt{at}sth.nhs.uk

Abstract

The management of low-grade glioma (LGG) is shifting as evidence has emergedthat refutes the previously commonplace imaging-based ‘watch and wait’ approach, in favour of early aggressive surgical resection. This coupled with the recent 2016 update to the World Health Organisation Classification of Tumours of the Central Nervous System is changing LGG imaging and management. Recently in Practical Neurology the contemporary management of low-grade glioma and the changes to this grading system were discussed in detail.1 In this complementary article, we discuss the role of imaging in the diagnosis, surgical planning and post-treatment follow-up of LGG. We describe the principles of imaging these tumours and use several cases to highlight some difficult scenarios.

  • neurooncology
  • neuroradiology
  • tumours

https://doi.org/10.1136/practneurol-2017-001686

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Background

    Diffuse supratentorial low-grade gliomas (LGG) WHO II have the propensity to undergo malignant progression. It is estimated that within 5–10 years of diagnosis approximately 70% of LGG will have undergone malignant progression into higher grade tumours.2 How and when this progression occurs is unpredictable and varies between patients. Typical LGG management in the UK has therefore been expectant, using a ‘watch and wait’ policy; patients undergo regular MR imaging to monitor for signs of malignant progression, with the clinician considering surgical and/or oncological intervention when there are signs of progression. This management arose out of the presumption that the intervention of low grade, slow growing tumours – commonly arising in eloquent areas of the brain – might cause more adverse effects than benefits.

    Research into LGG has therefore concentrated on identifying non-invasive imaging-based changes that arise in tumours, before or at the point of malignant progression, to allow accurate prediction of malignant transformation and enable timely intervention. Advanced MRI techniques such as tumour growth rates,3–6 MR spectroscopy,7 8 perfusion-weighted imaging4 9–11 and diffusion-weighted imaging9 have been explored for this purpose. However, the results have varied and so far there is no universally accepted definitive imaging biomarker of malignant transformation.

    Some LGGs progress and undergo malignant transformation rapidly, whereas others change very slowly. The unpredictable nature in which LGG change, despite being categorised as the same grade using the 2007 WHO histological criteria, demonstrates a shortfall in this classification system. The two main reasons for this variability are tumour heterogeneity and molecular genetics. LGG can be histologically heterogeneous within a tumour, resulting in potential sampling errors when obtaining histological samples using biopsy. This gives a risk of under grading, particularly with anaplastic astrocytomas and low/intermediate grade gliomas.12 There are also large differences between individual patients; emerging research shows that this is almost certainly due to differences in the molecular genetic status of tumours. Tumour heterogeneity and differences in glioma oncogenetics appear to explain the differences in tumour behaviour and the prognostic inaccuracies of current radiological and clinical biomarkers of LGG transformation.

    As outlined in Caroline Hayhurst’s Practical Neurology review,1 we now widely recognise the importance of molecular genetics in the pathogenesis of gliomas. With this new knowledge, the 2016 update to the WHO Classification of Tumours of the Central Nervous System dramatically changed its approach to LGG classification. It now incorporates molecular genetics as a key feature of the neuropathological assessment, having moved away from the purely histological methods used for over 100 years.13 The key genetic markers currently identified and used as part of the WHO 2016 classification include the isocitrate dehydrogenase (IDH) status of tumours, the presence or absence of 1 p/19q co-deletion, alpha thalassaemia/mental retardation syndrome X-linked (ATRX) loss and alterations in tumour protein 53 (TP53).13 These genetic markers will hopefully reflect tumour behaviour and prognosis more accurately, and in the future potentially predict treatment sensitivity more reliably.13

    Besides the new developments in glioma oncogenetics, we have seen a gradual shift away from the expectant ‘watch and wait’ imaging-based approach to LGG, with studies over the past decade showing improved prognosis from early aggressive surgical resection.14 15

    However, imaging still has an important part to play in LGG management: it enables diagnosis and monitoring, assists in preparing for aggressive surgical resection and provides post-treatment follow-up. In this review, we shall overview the principles of LGG imaging, outline its role in surgical resection, use case histories to highlight some difficult scenarios and discuss how the latest 2016 WHO classification has changed the role of imaging in these tumours.

    How to image LGG

    MR is the imaging modality of choice for diagnosing and monitoring LGG. These tumours appear as low-signal mass lesions on T1-weighted sequences and as high signal on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, often within eloquent areas of the brain. Gadolinium-based contrast agents are used to assess for contrast enhancement. LGG usually do not enhance; an enhancing area may indicate malignant progression of the tumour particularly in astrocytomas. However, oligodendrogliomas can show stable areas of contrast enhancement while remaining low grade, potentially confounding the picture.

    Conventional MRI is essential for the initial diagnosis as well as for treatment planning and monitoring treatment response.16 However, advanced MRI sequences can increase diagnostic accuracy, especially where there is diagnostic uncertainty.9 Such advanced MRI techniques include MR spectroscopy, perfusion-weighted imaging and diffusion-weighted imaging. Volume FLAIR imaging and volumetric sequences can also be used to calculate tumour volume and growth rate.

    MR spectroscopy can measure common metabolites in the brain; changes from the norm can help to diagnose tumours and to distinguish them from non-tumour lesions.16 A voxel is placed on an area of interest and the concentrations of various metabolites measured. Typically in LGG, choline (a measure of cell turnover) is increased, while N-acetyl-aspartate (NAA, a marker of normal neurones) is reduced, indicating neuronal loss. Further increases in choline and decreases in NAA, along with the presence of lipids or lactate, can suggest transformation into a higher-grade glioma. MR spectroscopy alone cannot grade the glioma accurately or reliably,16 but it can help to distinguish a small slowly growing LGG from a non-neoplastic lesion such as cortical dysplasia, since non-neoplastic lesions should not show increased choline.17

    Perfusion-weighted imaging uses the perfusion of tissues to indicate tumour vascularity, usually with gadolinium contrast, generating quantified measures such as relative cerebral blood volume (rCBV). This measurement has been extensively investigated in grading gliomas. It does appear to increase in astrocytomas undergoing malignant progression before there is evidence of contrast enhancement.10 Low-grade oligodendrogliomas often have an inherently raised rCBV,4 which may confound the results.16 However, the rate of change of rCBV in oligodendroglioma may predict early malignant transformation.10

    Diffusion-weighted imaging measures the cellular density by the diffusion of water within tissues; more densely packed tissues, such as higher grade gliomas, show restricted diffusion. However, tumours vary greatly in their diffusion and this measure cannot reliably predict their grade.16

    Tumour growth rate is one of the few imaging-based markers in LGG that can consistently predict the tumour grade, the risk of malignant progression and the overall prognosis.3–6 18 19 Importantly, growth rate studies have shown that LGG grow continuously before malignant progression, even when appearing static in size by subjective visual assessment, again refuting the idea of their ‘stable’ nature. A measure of tumour growth rate is the ‘volume of diametric expansion’ (VDE); the tumour volume is used to calculate a mean tumour diameter, and linear regression of this over time allows calculation of the VDE in mm/year.6 While remaining low-grade, a LGG may grow at a mean VDE of 4 mm/year.6 Patients with tumour growth rates above a VDE of 8 mm/year have worse overall survival than those with a VDE of <8 mm/year.19 Tumour volume at presentation also independently predicts the time to malignant progression.3 4 This can be obtained from volume FLAIR imaging, and is calculated by a semi-automated contouring technique of the tumour boundary.3 4 Volumetric imaging permits multiplanar reformats, is more informative than maximal diameters with orthogonal measurements, and so is more sensitive to tumour growth than measuring tumour diameter alone.3 It allows tumour (and indeterminate lesion) volume growth rates to be monitored over time (LGG have a mean annualised percentage growth rate of 16% with an increase in growth rate before malignant transformation).3 However, it is important to take care to avoid errors in volume measurement and to ensure images are obtained on the same scanner.

    There is no standardised protocol or guideline for imaging LGG. Our institution’s protocol (see table 1) comprises conventional and advanced MRI sequences to assess every patient with confirmed or suspected LGG, with additional functional imaging in selected cases.

    View this table:
    Table 1

    The low-grade glioma protocol used at our institution

    Role of imaging in surgical resection

    The benefit of early aggressive surgical resection in low-grade glioma has become apparent over the past 10 years.14 15 Aggressive surgical resection is vital to maximise survival, although this needs to be balanced against minimising the risk of postoperative morbidity.16 The safest way to achieve this currently, particularly when the tumour lies within eloquent areas of the dominant hemisphere, is awake craniotomy with intraoperative electrical stimulation, resecting to the functional boundaries.20 21 Imaging plays an important role preoperatively, postoperatively, and more recently intraoperatively.

    Detailed preoperative anatomical imaging that accurately delineates the tumour margin is important for surgical planning. Functional imaging before resection can also reduce the risk of postoperative neurological deficit; this can be achieved using various imaging modalities including functional MRI (fMRI), positron emission tomography (PET) and/or diffusion-tension imaging.

    Research exploring the potential of fMRI as a non-invasive measure of functional tumour boundaries before resection has had promising results.22 Kapsalakis et al compared fMRI with intraoperative cortical stimulation in 87 patients with presumed glioma, showing good concordance for sensory-motor mapping between the two techniques, although fMRI was less accurate in language mapping.23

    Diffusion-tension imaging of language fibre tracks also concorded (in 81% of cases) with intraoperative subcortical language mapping. However, negative tractography did not exclude the presence of white matter tracts, particularly when there was tumour invasion.24 A retrospective study of almost 200 patients also showed that preoperative fMRI and fibre-tracking diffusion-tension imaging, combined with intraoperative functional mapping, can increase the extent of achievable resection.25 We need further research to optimise these imaging techniques before they can replace intraoperative mapping, but currently they provide a useful adjunct to increase the extent of resection and hence further improve patient survival.

    PET imaging provides metabolic information about gliomas and can be performed using various tracers to give information tumour metabolism. PET and MR images can be co-registered to locate the area of abnormality more accurately. The most commonly used tracer for brain PET imaging is 18F-2-fluoro-2-deoxy-D-glucose (FDG), which gives information about glucose metabolism in tumours when compared with the contralateral normal grey/white matter.26 Another commonly used tracer, 11C-methionine (MET), is an amino acid analogue, meaning it has higher differential uptake in tumours than the surrounding brain tissue.26 When planning surgical resection margins in gliomas, PET imaging using both FDG and MET can give metabolic information that is additional to that from conventional MR imaging: Pirotte et al27 showed that FDG and MET PET imaging gave tumour resection contours that differed from MRI alone in 80% of the 66 patients. Additionally, complete resection of abnormal tracer activity on PET imaging was associated with a significantly longer survival.27

    The difficulty in predicting the extent of resection during surgery15 28 offers a role for intraoperative imaging. Intraoperative MRI can help to show areas of remaining tumour during a resection and increases the possible extent of resection, compared with conventional neurosurgery.29 However, currently only a few UK centres have intraoperative MRI facilities and so early postoperative imaging is the more common way to guide the extent of resection. Initial postoperative imaging should be performed as soon as possible after surgery, and ideally before 48–72 hours, to reduce the chances of false-positive results caused by reactive postoperative inflammation and blood products. Intraoperative haemostatic material can cause reactive enhancement, restricted diffusion and further inflammatory reactions.30 Requesting clinicians should state if such material has been used and should interpret the imaging with this in mind, to ensure that haemostatic material is not mistaken for residual tumour.4

    Patients also require continued MRI surveillance following surgery to monitor for tumour recurrence and/or progression. Pallud et al31 showed that LGG tumour cells can invade up to 20 mm beyond the visible abnormal T2/FLAIR signal seen on MRI. This microscopic invasion beyond the tumour margin means that complete tumour resection in unlikely, even in those centres performing ‘supra-total’ resections (resecting beyond the imaged tumour margin).32 33 Postoperative imaging is therefore important even where surgeons believe they have achieved total resection, to monitor for tumour recurrence from undetected micro-invasion, as well as to monitor for tumour progression in patients where only a subtotal resection was achievable. This should be performed at regular intervals, initially 6 monthly and then 6–12 monthly depending on tumour type and degree of resection. This allows monitoring for tumour recurrence and progression, and to assess the response to any adjuvant treatment.

    Illustrative cases

    Case 1 : the benefit of MR spectroscopy

    A 47-year-old woman presented to her local hospital with focal seizures. Brain imaging showed an abnormality within the left frontal lobe (figure 1A). There was erosion of the skull vault, suggesting a long-standing lesion. There was no contrast enhancement. MR spectroscopy identified a late lactate peak, indicating anaerobic respiration and perfusion-weighted imaging showed an elevated rCBV of 1.81 (figure 1B and C), suggesting higher metabolic demands and a faster growing, more aggressive tumour. A further scan at 3 months found no volume change nor contrast enhancement but the MR spectroscopy and perfusion-weighted imaging abnormalities persisted. She underwent resective surgery and histology demonstrated anaplastic oligodendroglioma WHO III, IDH mutant, 1 p/19q co-deleted.

    Figure 1
    Figure 1

    (A) T2-weighted image showing a high T2 signal lesion involving the middle frontal gyrus with no contrast enhancement. The conventional MR images gave no indication that this was a more aggressive anaplastic oligodendroglioma. (B) MR spectroscopy with inverted doublet (see arrow) consistent with a high lactate concentration. (C) Perfusion-weighted MRI showing an elevated relative cerebral blood volume.

    Case 2: the benefit of volumetric analysis

    A 43-year-old right-handed woman presented with episodes of short-lived speech arrest with stiffening of the right arm and leg. Imaging showed a left frontal lobe abnormality consistent with a LGG. Surgical resection was considered and fMRI, tractography and a repeat MRI at 3 months were planned.

    The repeat MRI scan (Figure 2A) showed no change in size on visual inspection. MR spectroscopy showed minor changes with a slightly increasing choline-to-creatine ratio and a slightly reduced NAA compared with the previous study. There was no postcontrast enhancement and cerebral perfusion imaging was stable. However, volumetric analysis showed an increase in volume from 16.25 to 17.84 mL, equivalent to a high annualised percentage growth rate of 44.3% (figure 2B). This difference was not appreciated on the standard radiological review and was of concern. She underwent an awake craniotomy without complication. Histology revealed an anaplastic astrocytoma WHO III, IDH 1 mutant, non-1 p/19q co-deleted.

    Figure 2
    Figure 2

    (A) Volumetric scan of the brain using a three-dimensional FLAIR sequence. The yellow line represents the tumour edge (placement of this outline is used to calculate the tumour volume). (B) Annualised growth rate of the tumour over a 3-month interval.

    Case 3: indeterminate lesions

    It can be challenging to manage indeterminate lesions found on brain imaging—whether to biopsy or not; whether to undergo surveillance scanning and if so how frequently and for how long. The imaging techniques outlined above over time can give some reassurance regarding the stable and benign nature of indeterminate findings in people with LGG.

    A 15-year-old girl presented following a focal bilateral tonic-clonic seizure. Before this she had experienced intermittent clawing of the left hand. Imaging showed an abnormality in the right motor strip with thickened cortex and non-enhancing high T2 signal (figure 3A). We considered a differential diagnosis of either focal cortical dysplasia with balloon cells or a cortically based LGG. MR spectroscopy was normal and rCBV was slightly reduced. The lesion was unchanged on subsequent imaging, initially 6 monthly and then annually, up to 5 years after the initial presentation (figure 3B). The advanced imaging features helped to decide to maintain imaging surveillance rather than undertake a biopsy, as it more likely represented focal cortical dysplasia. For complete reassurance, we plan a final scan 10 years after presentation.

    Figure 3
    Figure 3

    (A) An indeterminate lesion of the posterolateral right frontal lobe (see arrow). (B) The lesion unchanged after 5 years.

    Case 4: false-positive scan secondary to recent seizure activity

    Case 4 is about a man aged 20 years in whom seizure activity confounded the clinical picture. He had previously undergone resection of a right temporal lobe astrocytoma WHO II. On routine follow-up scan imaging there was an area of new contrast enhancement, suggesting disease progression. He opted for a further scan at 3 months, which revealed complete resolution of the enhancement. Further inquiry identified that he had had a seizure shortly before the MR scan (figure 4).

    Figure 4
    Figure 4

    (A) Postcontrast T1-weighted image showing new enhancement (see arrow) in tumour involving the posteromedial right temporal lobe and the tail of the hippocampus. (B) Follow-up imaging at 3 months shows the enhancement has resolved.

    Seizure activity can result in areas of transient MRI T2-hyperintensity and T1-hypointensity in the peri-ictal and postictal period. These can occur at the site of primary seizure activity or in functionally connected areas.34 MRI abnormalities secondary to seizure activity occasionally persist, and even become permanent.34 Importantly, seizure-related changes can mimic LGG and other neoplasms.35 Accurate clinical information when requesting imaging is therefore key, as well as asking the patient about recent seizure activity when they attend for their MRI examination.

    The changing role of imaging for LGG

    The shift of the 2016 WHO classification towards using the molecular genetic markers, plus the trend to early aggressive surgical resection, will change the role of imaging for LGG. There will be a transition away from expectant monitoring of imaging biomarkers towards establishing a confident early diagnosis of LGG, distinguishing it from non-neoplastic lesions that do not need early surgical intervention. Advanced MRI sequences can still help in this situation, giving additional information about the perfusion, cellular density and metabolism of the abnormal tissue. Clinicians will still have to make difficult decisions when lesions are indeterminate, particularly when deciding optimal management and setting time frames for repeat imaging.

    Accurate perioperative imaging is needed for planning safe surgery, optimising the extent of surgical resection and accurately giving and following up postoperative and adjuvant treatment. The role of fMRI and diffusion-tension imaging in defining tumour boundaries and safe functional resection margins remains uncertain, and needs further exploration before it can replace intraoperative cortical mapping; currently, these imaging modalities only complement surgical planning. The use of intraoperative MRI may increase in centres that have these facilities. And finally, as patient survival improves, the need for post-treatment follow-up imaging will increase, and is set to become a large part of the workload of managing LGG.

    We need more radiology research in LGG to help to decide the optimum timing for follow-up imaging and whether this should differ according to tumour genetics. Furthermore, we need to continue to explore new imaging-based biomarkers to determine glioma molecular genetics. For example, the use of MR spectroscopy to measure 2-hydroxyglutarate (2-HG), a metabolite that accumulates in association with IDH-mutated gliomas. There have been very few in vivo studies of MR spectroscopy to detect 2-HG in gliomas, using several different imaging methods.36 The results have been promising, with several groups showing MR spectroscopy may prove a non-invasive means to determine IDH status (mutant vs wild-type),37–39 as well as distinguishing between IDH-1 and IDH-2 mutations; however, this work used 7T MR imaging, which is not currently widely available.40

    Overall, the role of imaging in LGG management is set to change from one of monitoring for malignant progression, to a role of early and accurate diagnosis, assistance in surgical planning and post-treatment follow-up imaging for tumour recurrence.

    Key points

    • The role of imaging in low-grade glioma management is set to change from one of monitoring for malignant progression, to a role of early and accurate diagnosis, assistance in surgical planning and post-treatment follow-up imaging for tumour recurrence.

    • Advanced MR imaging techniques, such as MR spectroscopy, perfusion-weighted imaging and tumour volume and growth rate analysis have improved brain tumour imaging; they provide additional physiological information concerning tumour metabolism and haemodynamics, and may help to diagnose indeterminate lesions.

    • Transient postictal MR gadolinium enhancement can lead to a misdiagnosis of tumour progression.

    References

    1. ↵
      1. Hayhurst C
      . Contemporary management of low--grade glioma: a paradigm shift in neuro-oncology. Pract Neurol 2017;17:183–90.doi:10.1136/practneurol-2017-001604
      OpenUrlAbstract/FREE Full Text
    2. ↵
      1. Furnari FB,
      2. Fenton T,
      3. Bachoo RM, et al
      . Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 2007;21:2683–710.doi:10.1101/gad.1596707
      OpenUrlAbstract/FREE Full Text
    3. ↵
      1. Rees J,
      2. Watt H,
      3. Jäger HR, et al
      . Volumes and growth rates of untreated adult low-grade gliomas indicate risk of early malignant transformation. Eur J Radiol 2009;72:54–64.doi:10.1016/j.ejrad.2008.06.013
      OpenUrlCrossRefPubMed
    4. ↵
      1. Brasil Caseiras G,
      2. Ciccarelli O,
      3. Altmann DR, et al
      . Low-grade gliomas: six-month tumor growth predicts patient outcome better than admission tumor volume, relative cerebral blood volume, and apparent diffusion coefficient. Radiology 2009;253:505–12.doi:10.1148/radiol.2532081623
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      1. Pallud J,
      2. Mandonnet E,
      3. Duffau H, et al
      . Prognostic value of initial magnetic resonance imaging growth rates for World Health Organization grade II gliomas. Ann Neurol 2006;60:380–3.doi:10.1002/ana.20946
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Pallud J,
      2. Taillandier L,
      3. Capelle L, et al
      . Quantitative morphological magnetic resonance imaging follow-up of low-grade glioma: a plea for systematic measurement of growth rates. Neurosurgery 2012;71:729-39-40.doi:10.1227/NEU.0b013e31826213de
    7. ↵
      1. Hollingworth W,
      2. Medina LS,
      3. Lenkinski RE, et al
      . A systematic literature review of magnetic resonance spectroscopy for the characterization of brain tumors. AJNR Am J Neuroradiol 2006;27:1404–11.
      OpenUrlAbstract/FREE Full Text
    8. ↵
      1. Stadlbauer A,
      2. Gruber S,
      3. Nimsky C, et al
      . Preoperative grading of gliomas by using metabolite quantification with high-spatial-resolution proton MR spectroscopic imaging. Radiology 2006;238:958–69.doi:10.1148/radiol.2382041896
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      1. Zonari P,
      2. Baraldi P,
      3. Crisi G
      . Multimodal MRI in the characterization of glial neoplasms: the combined role of single-voxel MR spectroscopy, diffusion imaging and echo-planar perfusion imaging. Neuroradiology 2007;49:795–803.doi:10.1007/s00234-007-0253-x
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      1. Danchaivijitr N,
      2. Waldman AD,
      3. Tozer DJ, et al
      . Low-grade gliomas: do changes in rCBV measurements at longitudinal perfusion-weighted MR imaging predict malignant transformation? Radiology 2008;247:170–8.doi:10.1148/radiol.2471062089
      OpenUrlCrossRefPubMed
    11. ↵
      1. Law M,
      2. Young RJ,
      3. Babb JS, et al
      . Gliomas: predicting time to progression or survival with cerebral blood volume measurements at dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. Radiology 2008;247:490–8.doi:10.1148/radiol.2472070898
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      1. Jackson RJ,
      2. Fuller GN,
      3. Abi-Said D, et al
      . Limitations of stereotactic biopsy in the initial management of gliomas. Neuro Oncol 2001;3:193–200.doi:10.1093/neuonc/3.3.193
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. Louis DN,
      2. Perry A,
      3. Reifenberger G, et al
      . The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016;131:803–20.doi:10.1007/s00401-016-1545-1
      OpenUrlCrossRefPubMed
    14. ↵
      1. Jakola AS,
      2. Myrmel KS,
      3. Kloster R, et al
      . Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA 2012;308:1881.doi:10.1001/jama.2012.12807
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Capelle L,
      2. Fontaine D,
      3. Mandonnet E, et al
      . Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization Grade II gliomas: a series of 1097 cases: clinical article. J Neurosurg 2013;118:1157–68.doi:10.3171/2013.1.JNS121
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Soffietti R,
      2. Baumert BG,
      3. Bello L, et al
      . Guidelines on management of low-grade gliomas: report of an EFNS-EANO Task Force. Eur J Neurol 2010;17:1124–33.doi:10.1111/j.1468-1331.2010.03151.x
      OpenUrlCrossRefPubMed
    17. ↵
      1. Horská A,
      2. Barker PB
      . Imaging of brain tumors: MR spectroscopy and metabolic imaging. Neuroimaging Clin N Am. NIH Public Access 2010;20:293–310.
      OpenUrl
    18. ↵
      1. Hlaihel C,
      2. Guilloton L,
      3. Guyotat J, et al
      . Predictive value of multimodality MRI using conventional, perfusion, and spectroscopy MR in anaplastic transformation of low-grade oligodendrogliomas. J Neurooncol 2010;97:73–80.doi:10.1007/s11060-009-9991-4
      OpenUrlCrossRefPubMed
    19. ↵
      1. Pallud J,
      2. Blonski M,
      3. Mandonnet E, et al
      . Velocity of tumor spontaneous expansion predicts long-term outcomes for diffuse low-grade gliomas. Neuro Oncol 2013;15:595–606.doi:10.1093/neuonc/nos331
      OpenUrlCrossRefPubMed
    20. ↵
      1. De Witt Hamer PC,
      2. Robles SG,
      3. Zwinderman AH, et al
      . Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol 2012;30:2559–65.doi:10.1200/JCO.2011.38.4818
      OpenUrlAbstract/FREE Full Text
    21. ↵
      1. Duffau H,
      2. Lopes M,
      3. Arthuis F, et al
      . Contribution of intraoperative electrical stimulations in surgery of low grade gliomas: a comparative study between two series without (1985-96) and with (1996-2003) functional mapping in the same institution. J Neurol Neurosurg Psychiatry 2005;76:845–51.doi:10.1136/jnnp.2004.048520
      OpenUrlAbstract/FREE Full Text
    22. ↵
      1. Ottenhausen M,
      2. Krieg SM,
      3. Meyer B, et al
      . Functional preoperative and intraoperative mapping and monitoring: increasing safety and efficacy in glioma surgery. Neurosurg Focus 2015;38:E3.doi:10.3171/2014.10.FOCUS14611
      OpenUrl
    23. ↵
      1. Kapsalakis IZ,
      2. Kapsalaki EZ,
      3. Gotsis ED, et al
      . Preoperative evaluation with FMRI of patients with intracranial gliomas. Radiol Res Pract 2012;2012:1–17.doi:10.1155/2012/727810
      OpenUrl
    24. ↵
      1. Leclercq D,
      2. Duffau H,
      3. Delmaire C, et al
      . Comparison of diffusion tensor imaging tractography of language tracts and intraoperative subcortical stimulations. J Neurosurg 2010;112:503–11.doi:10.3171/2009.8.JNS09558
      OpenUrlCrossRefPubMedWeb of Science
    25. ↵
      1. Ius T,
      2. Isola M,
      3. Budai R, et al
      . Low-grade glioma surgery in eloquent areas: volumetric analysis of extent of resection and its impact on overall survival. A single-institution experience in 190 patients: clinical article. J Neurosurg 2012;117:1039–52.doi:10.3171/2012.8.JNS12393
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      1. Fink JR,
      2. Muzi M,
      3. Peck M, et al
      . Multimodality Brain Tumor Imaging: MR Imaging, PET, and PET/MR Imaging. J Nucl Med 2015;56:1554–61.doi:10.2967/jnumed.113.131516
      OpenUrlAbstract/FREE Full Text
    27. ↵
      1. Pirotte BJM,
      2. Levivier M,
      3. Goldman S, et al
      . Positron emission tomography-guided volumetric resection of supratentorial high-grade gliomas. Neurosurgery 2009;64:471–81.doi:10.1227/01.NEU.0000338949.94496.85
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. Shaw EG,
      2. Berkey B,
      3. Coons SW, et al
      . Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial. J Neurosurg 2008;109:835–41.doi:10.3171/JNS/2008/109/11/0835
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      1. Senft C,
      2. Bink A,
      3. Franz K, et al
      . Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. Lancet Oncol 2011;12:997–1003.doi:10.1016/S1470-2045(11)70196-6
      OpenUrlCrossRefPubMedWeb of Science
    30. ↵
      1. Graber JJ,
      2. Tabar V,
      3. Brennan C, et al
      . Acute inflammatory reactions to hemostatic materials mimicking post-operative intracranial abscess. Interdisciplinary Neurosurgery 2014;1:5–7.doi:10.1016/j.inat.2014.01.002
      OpenUrl
    31. ↵
      1. Pallud J,
      2. Varlet P,
      3. Devaux B, et al
      . Diffuse low-grade oligodendrogliomas extend beyond MRI-defined abnormalities. Neurology 2010;74:1724–31.doi:10.1212/WNL.0b013e3181e04264
      OpenUrlCrossRefPubMed
    32. ↵
      1. Yordanova YN,
      2. Moritz-Gasser S,
      3. Duffau H
      . Awake surgery for WHO Grade II gliomas within “noneloquent” areas in the left dominant hemisphere: toward a “supratotal” resection. J Neurosurg 2011;115:232–9.doi:10.3171/2011.3.JNS101333
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      1. Duffau H
      . Long-term outcomes after supratotal resection of diffuse low-grade gliomas: a consecutive series with 11-year follow-up. Acta Neurochir 2016;158:51–8.doi:10.1007/s00701-015-2621-3
      OpenUrl
    34. ↵
      1. Palmeri B,
      2. Talamanca S,
      3. Ragonese P, et al
      . MRI abnormalities following repeated and incoming seizures. Seizure 2011;20:90–2.doi:10.1016/j.seizure.2010.09.012
      OpenUrlCrossRefPubMed
    35. ↵
      1. Cohen-Gadol AA,
      2. Britton JW,
      3. Worrell GA, et al
      . Transient cortical abnormalities on magnetic resonance imaging after status epilepticus: case report. Surg Neurol 2004;61:479–82.doi:10.1016/S0090-3019(03)00540-8
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      1. Kim H,
      2. Kim S,
      3. Lee HH, et al
      . In-Vivo Proton Magnetic Resonance Spectroscopy of 2-Hydroxyglutarate in Isocitrate Dehydrogenase-Mutated Gliomas: A Technical Review for Neuroradiologists. Korean J Radiol 2016;17:620–32.doi:10.3348/kjr.2016.17.5.620
      OpenUrl
    37. ↵
      1. Pope WB,
      2. Prins RM,
      3. Albert Thomas M, et al
      . Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy. J Neurooncol 2012;107:197–205.doi:10.1007/s11060-011-0737-8
      OpenUrlCrossRefPubMed
    38. ↵
      1. Choi C,
      2. Ganji SK,
      3. DeBerardinis RJ, et al
      . 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 2012;18:624–9.doi:10.1038/nm.2682
      OpenUrlCrossRefPubMed
    39. ↵
      1. Natsumeda M,
      2. Igarashi H,
      3. Nomura T, et al
      . Accumulation of 2-hydroxyglutarate in gliomas correlates with survival: a study by 3.0-tesla magnetic resonance spectroscopy. Acta Neuropathol Commun 2014;2:158.doi:10.1186/s40478-014-0158-y
      OpenUrl
    40. ↵
      1. Emir UE,
      2. Larkin SJ,
      3. de Pennington N, et al
      . Noninvasive Quantification of 2-Hydroxyglutarate in Human Gliomas with IDH1 and IDH2 Mutations. Cancer Res 2016;76:43–9.doi:10.1158/0008-5472.CAN-15-0934
      OpenUrlAbstract/FREE Full Text

    Footnotes

    • Contributors JL wrote the initial manuscript. FMM conceived the idea for publication, provided the case vignettes and edited the manuscript. NH provided the images, provided the neuro-imaging text and reviewed the manuscript.

    • Competing interests None declared.

    • Provenance and peer review Commissioned. Externally peer reviewed. This paper was reviewed by Josh Klein, Boston, USA and Jeremy Rees, London, UK.