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Case presentationA 39-year-old right-handed woman was admittedbecause of an acute episode of confusion and ageneralised tonic-clonic seizure. The patient had noclinically significant medical or family history. She didnot smoke, rarely drank alcohol, and did not misusedrugs. She had had three uneventful pregnanciesresulting in normal deliveries and had used the sameoral contraceptive for the past 4 years.

The patient had been well until 2 months previously,when she began to get intermittent episodes of mildfronto-occipital constricting headache and dizziness,lasting from a few minutes to several hours, withoutvertigo, visual disturbances, loss of consciousness, ornausea. The symptoms occurred mainly in the morningand late evening. 3 weeks before admission, she becameuncharacteristically forgetful, with brief moments ofdisorientation in space and difficulty in rememberingthe way home. The day before admission, she had asudden sense of nausea with vomiting and was taken toanother hospital. The patient was described as beingdrowsy and disoriented in time and space, with bilateralhand grasping, but no focal neurological abnormalities.In the emergency room, she had a generalised tonic-clonic seizure with a brief postcritical phase. A CT scanof her head showed bilateral temporal hypodensities. Alumbar puncture showed mild pleocytosis (sevenleucoytes per mm3) with normal protein and glucoseconcentrations in the CSF, and the patient was treatedempirically with intravenous aciclovir 10 mg/kg threetimes daily.

On admission to the Neurology Department of theCentre Hospitalier Universitaire Vaudois, Lausanne,24 h later, the patient was alert, but disoriented in timeand space. Neuropsychological bedside testing showedsevere anterograde memory impairment withoutattention deficit. There was no aphasia, agnosia, apraxia,or difficulty with motor sequencing tasks. Primitivereflexes or frontal signs were not present. There wasmild photophobia without meningismus. The visualfield was full on confrontation. Ocular fundus wasnormal. No nystagmus was evident; a mild saccadicbreakdown on smooth pursuit was noticed. Theremaining cranial nerves were normal. All reflexes werebrisk and the plantar responses flexor. Power, tone, andcoordination were normal except for slight difficultywith tandem gait. No myoclonus was noted. The sensoryexamination was normal, including pallaesthesia,graphaesthesia, and stereognosis. The physicalexamination was normal. Detailed neuropsychologicaltesting confirmed a severe anterograde visual and verbal

memory deficit. Procedural and semantic memory werepreserved. A mild anosognosia was present. Calculationand visuospatial perceptual functions were satisfactory.Her temperature was 37·2ºC, her pulse was 70 beats permin, and her blood pressure was 100/60 mm Hg. The results of laboratory tests were normal, except for a white-cell count of 12 cells per L (normal:4·0–10·0 cells per L) with a normal differential count,and normocytic-normochromic anaemia with a red cellcount of 3·13 cells per L (normal: 4·4–5·8 cells per L).The erythrocyte sedimentation rate was 10 mm/h andshe was negative for complement-reactive protein. Anelectroencephalogram showed no specific alterations.The CT brain scan revealed tenuous bilateralhypodensity of the hippocampus and parahippocampalarea, retrosplenium, and right posterior insular cortexwithout contrast enhancement. The arterial and venousintracerebral vessels were normal on the CT angiogram.

Clinical differential diagnosisThis 39-year-old woman presented with an insidious andfluctuating neuropsychological deterioration associatedwith intermittent headache, followed by an acute clinicalmanifestation with a seizure and persisting alteredmemory status. Although mild leucocytosis andanaemia were noted on the initial examination, therewas no fever or other signs of systemic illness. Therewas no evidence for encephalopathy due to closed headinjury, anoxia, hypoglycaemia, vitamin deficiency, drugtoxicity, toxins, withdrawal, or an autoimmune thyroiddisorder. A deep cerebral venous thrombosis was firstsuspected—a diagnosis to be considered with thepresence of suspected bilateral strokes involving deepstructures without coherence with arterial territories.This potentially treatable diagnosis was ruled out by anormal venous CT angiogram.

On the basis of the data for the acute clinicalpresentation, the most likely diagnosis, for whichimmediate treatment is needed, was an infectiousencephalitic process. Herpes simplex virus (HSV)encephalitis is the most common sporadic, acute, focalencephalitis, with an estimated incidence of one per500 000 person years in Europe. HSV type 1 accounts forabout 10% of all cases of encephalitis; there is noseasonal variation in incidence and it can affectindividuals of any age. The presence of mild pleocytosis,in the absence of evidence for other pathogenic agents,suggests herpes encephalitis until proven otherwise.1 Inour patient, the combination of a seizure, involvement ofthe temporal lobe and limbic system, and CSFpleocytosis was consistent with HSV encephalitis. On the

Lancet Neurol 2005; 4: 683–88

Department of Neurology(C Cereda MD,J Bogousslavsky MD) andDepartment of Radiology(P Maeder MD), CHUV, BH13,CH-1011 Lausanne,Switzerland; Department ofPathology, HUG, Geneva,Switzerland (J A Lobrinus MD)

Correspondence to: Dr Carlo Ceredacarlo.cereda@chuv.ch

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Carlo Cereda, Johannes Alexander Lobrinus, Philippe Maeder, Julien Bogousslavsky

Memory impairment and tonic-clonic seizure in a39-year-old woman

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other hand, the insidious progression of neuro-psychological symptoms, the absence of general clinicaldeterioration, the lack of raised protein and red cells inthe CSF, and no contrast enhancement made thediagnosis of infectious encephalitis unlikely. Aciclovirtreatment was discontinued on the second day in hospitalafter PCR analysis of CSF showed no evidence of HSVinfection. PCR to detect HSV-1 has a specificity of about95%. If the CSF sample is taken between 48 h and10 days then the sensitivity of PCR is also about 95%.2

On preliminary imaging studies, there was evidence ofhippocampal formation and paralimbic cortical andwhite-matter disease, confirming the clinical suspicion offunctional involvement of the hippocampus and Papez’scircuit, as seen in the limbic encephalitic disease process.Other forms of infectious limbic encephalitis have beendescribed with human herpes virus type 6 after stem-celltransplantation for treatment of neoplasia or geneticdiseases.3 Varicella-zoster virus can also be responsiblefor focal limbic encephalitis in immunodeficientpatients.4 In our patient, serological screening for HIVvirus was negative and there was no clinical evidence forthe patient being immunocompromised. There was alsono evidence for a diffuse white matter disease—such asprogressive multifocal leucoencephalopathy, a rareprogressive demyelinating disorder that typically occursas a late complication of chronic illness with secondaryimpaired cellular immunity. The absence of foreigntravel reasonably ruled out other categories ofencephalitis, such as Japanese B or West Nileencephalitis, which typically have subacute progression.A similar pattern could be present with tuberculosismeningitis, an insidious disease excluded by a negativeCSF culture. Prion disease, especially the variant form ofCreutzfeldt-Jakob disease, characteristically involving thelimbic system and the thalamus, should be considered in young patients presenting with focal cognitivedeterioration. In our patient, the absence of otherneurological abnormalities on the clinical examination,the lack of myoclonus, the preliminary imagingsuggesting white-matter involvement, and the absence ofthe typical electroencephalographic changes areinconsistent with the diagnosis of sporadic spongiformencephalopathy and the progression was probably toofast for the variant form.

The focal clinical and radiological involvement of thelimbic and paralimbic systems suggested limbicencephalitis of paraneoplastic origin. This clinico-pathological entity was first described by Brierley in1960,5 and the frequent association with neoplasia hasbeen documented over the past few decades.6 Limbicdisease is commonly the expression of a multifocalencephalomyelitis, but occasionally occurs in isolation.The disease generally has a subacute onset, typicallypresenting as an amnestic syndrome or psychiatricdisturbances with main affective disorders (depression,anxiety, and emotional lability). A combination of these

two principal features has also been well described.7

Paranoid delusions and hallucinations have also beenreported.7 Neuropsychological deficits mainly consist ofshort-term anterograde amnesia, with frequentanosognosia and confabulations and, rarely, elements ofthe Klüver-Bucy syndrome, such as hyperphagia andaltered sexual behaviour.7 Generalised or partial complexseizures are common and can be the first manifestationof limbic encephalitis of paraneoplastic origin. Raremanifestations that suggest hypothalamic ordiencephalic dysfunction include abnormal sleep-wakecycles, thermal deregulation, haemodynamic instability,and inappropriate antidiuretic-hormone secretion. Thisuncommon paraneoplastic disease is associated withcancers of many organs, but is most commonly acomplication of small-cell carcinoma of the lung.7 Themost prevalent autoantibodies are polyclonal IgG anti-Hu autoantibodies, associated with pulmonarymicrocytoma in many cases.

We gave serious thought to the idea that this relativeselective disease of the limbic system could be aparaneoplastic process because the onset andcharacteristics of the neurological symptoms and theneuropsychological profile were highly consistent withthis notion. On the psychiatric side, the patientpresented a mild reactive anxious state. No otherbehavioural abnormalities or signs of dysautonomiawere reported. A complete neoplasia screen wasnegative, including normal thoracic-abdominal-pelvicconventional CT and extra cerebral fluorine-18-labelleddeoxyglucose PET. Gynaecological examinations as wellas mammography and breast sonography were normal.A dermatological inspection was also negative. Theresult of screening for anti-Hu (ANNA-1) and anti-amphiphysin autoantibodies was normal.

Did these results rule out our diagnostic hypothesis?Since the first report of limbic encephalitis as aclinicopathological entity, many cases have beendescribed with a clinical manifestation and pathologicalresults identical to those of paraneoplastic limbicencephalitis, but without evidence of an underlyingneoplasia, even at autopsy.8 Vincent and colleagues9

identified a potassium-channel-antibody-associatedencephalopathy, recognised to be a potentially reversibleand immunotherapy-responsive form of non-neoplasticlimbic encephalitis. In our patient, screening for thisantibody would have been very useful to identify thisvariable form of limbic encephalitis.

Could the limbic system disease have resulted from aprimary brain tumour?

A primary neoplastic disease with diffuse infiltration ofmultiple CNS structures, especially the limbic system,could be related to an uncommon infiltrative glioma,gliomatosis cerebri. This rare disease, with an undefinednatural history and poor response to treatment, tends toaffect the brainstem, thalamus, and cerebral lobes andaffects both the white and grey matter. The clinical

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presentation is often a recapitulation of low-gradeastrocytoma.10 The age at presentation in adults is veryvariable (17–85 years) and most patients are men, with amedian age of 44 years. The onset of the disease iscommonly a syndrome progressing insidiously overseveral months, with headache, cognitive impairment,hemiparesis, and seizures (partial seizures with orwithout secondary generalisation), all of which havevaried in frequency in different studies.10–13 Abnormalitieson neurological examination include corticospinal signs,aphasia, gait disorders, and signs of raised intracranialpressure. An unusual clinical manifestation, withatypical Parkinson’s disease, has also been reported,14

reflecting the variability of focal CNS involvement. CTimaging is poor for visualisation of gliomatosis cerebribecause of the subtle widespread infiltration of the whitematter, no focal tumour mass, and the typical absence ofcontrast enhancement.10 MRI is essential for establishingthe diagnosis: in a retrospective study of 22 patients,there was involvement of the basal ganglia and thalamusin 17, the corpus callosum in 12, the brainstem in three,and the cerebellum in two.11 Electroencephalographicabnormalities, typically focal or diffuse slowing, arepronounced late in the course of the disease.

Our patient’s case raised the possibility of primaryCNS lymphoma, another infiltrating pathological entitythat rarely occurs in immunocompetent individuals.This non-Hodgkin lymphoma typically occurs in thebrain as an intracranial, commonly multifocal, mass, butcan also affect the spinal cord, leptomeninges, and eyes.The disease usually has a rapidly progressive clinicalmanifestation, evolving over several months, which,according to a review of 66 patients,15 includespersonality changes in 24%, cerebellar signs in 21%,headache in 14%, seizures in 13%, motor dysfunction in11%, and visual changes in 8%. The CSF is oftenabnormal with raised protein concentrations, butnormal proteinorachia have also been reported.16 Mostpatients have a lymphocytic pleocytosis, but only25–30% have malignant tumour cells on cytologicalexamination. There is no absolute CT or MRIradiological pattern that can make the definitivediagnosis of primary CNS lymphoma; however,characteristic features, described below, should stronglysuggest the diagnosis and differentiate it from othercerebral tumours. In most immunocompetent patients,primary CNS lymphoma is isodense or hyperdense on acontrast naive CT scan or isointense or hyperintense ona T1-weighted MRI scan without contrast. Cerebrallymphoma typically has a dense and uniformenhancement pattern after contrast injection. A fewpatients have diffuse tumours that are not enhancedwith contrast medium on the CT scan—a characteristicpossibly due to long-term corticotherapy.17 The almostnormal CSF findings in our patient (the mild pleocytosiswas thought to be an inflammatory reaction in thecontext of the generalised seizure) and the lack of

contrast enhancement strongly argue against thediagnosis of primary CNS lymphoma. Primary angiitisof the CNS and an aggressive form of vasculitis,idiopathic granulomatous angiitis, is a possiblediagnosis that should be considered in this case becauseit results in diffuse encephalopathy with insidiousprogression. Nevertheless, in our patient themorphological predilection for the limbic system makesthis diagnosis possible, but unlikely.

In conclusion, at this stage, paraneoplastic or non-paraneoplastic encephalitis versus a low-grade glioma,manifesting as gliomatosis cerebri, suggested by thespecific involvement of the splenium corpi callosi, werethe most likely diagnoses. The clinical progressionwould probably be crucial for establishing the finaldiagnosis. At this time, review of the cerebral CT scanand the MRI undertaken on the day of admission wouldbe useful before a cerebral biopsy is done, which isneeded for histological confirmation.

Brain imagingBecause the patient was admitted as an emergency, abrain CT with contrast was first undertaken and revealedill-defined hypodensities in the splenium of the corpuscallosum, in the posterior part of the cingulate gyrus,bilaterally in the adjacent white matter, and in the righthippocampus, with a moderate mass effect, but withoutcontrast enhancement. We decided to do further MRIinvestigation after a preliminary diagnosis of acuteencephalitis. MRI was done and included diffusion-weighted and perfusion-weighted imaging, protonspectroscopy (1H-MRS), and gadolinium injection. TheT2-FLAIR images showed a hyperintense lesioninfiltrating the hippocampus, insula, cingulate gyrus,and parietal regions bilaterally, together with thesplenium of the corpus callosum. A moderate diffusemass effect was present (figure 1). There was noenhancement on T1 images after gadolinium injection.The radiological differential diagnoses of the lesionincluded infectious or paraneoplastic encephalitis,lymphoma, diffuse low-grade glioma, or gliomatosiscerebri. How can special magnetic-resonancetechniques help differentiate these entities?

Apparent diffusion coefficientDiffusion weighted images are widely used in stroke, forwhich they can show the extent of ischaemic brainlesions at a very early stage. Furthermore, diffusionweighted images are sensitive to the cellularity of lesions(highly cellular lesions have a reduced apparentdiffusion coefficient). These images are also sensitive togrey-matter cytotoxic oedema encountered in infectiousbrain diseases, such as herpes encephalitis. In ourpatient, the apparent diffusion coefficient was close tothat of normal brain parenchyma. This finding ruled outencephalitis and lymphoma, but can be reported in bothdiffuse glioma and gliomatosis cerebri.

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Perfusion, blood volume, and cerebral blood flowThe relative regional cerebral blood volume is increasedin cerebral vasogenic oedema, which can be present inencephalitis and is sensitive to neoangiogenesis inmalignant brain tumour, even in the absence ofblood–brain barrier breakdown. The relative regionalcerebral blood flow can also be increased in highlyvascular fast growing tumours. In our patient, cerebralblood flow was slightly increased in some parts of thelesion, whereas the blood volume was comparable to thatin normal brain. This finding argued against oedema ornecrosis and high vascularisation of the lesion.

Proton spectroscopy Multivoxel proton spectroscopy (CSI TR 1500, TE 135)was done covering large parts of the lesion, including thehippocampus and insula and some part of the normal

brain (figure 1). Absence of lactate and lipids arguedagainst high-grade tumour, necrosis, and encephalitis.18,19

A moderate decrease in N-acetyl aspartate (NAA) wasnoted, but was not specific since the reductioncorresponds to reversible neuronal injury and can beseen in neoplastic and non-neoplastic processes. Incerebral glioma, the decrease in NAA correlates with theseverity of infiltration by tumoral cells.20 The moderateincrease in choline concentration recorded in our patientlent support to increased membrane turnover andcellular proliferation. The choline to NAA ratio wasvariable at different locations in the lesion, typically lowerthan 2, suggesting a low-grade tumour, but in a fewlocations higher values were suggested with malignancy.More surprising was the large increase in creatineconcentrations. Creatine concentrations are rather stablein brain disease, apart from necrosis in which it isdecreased, but can be slightly decreased in low-gradeglioma due to the replacement of normal brainparenchyma by tumour cells that synthesise less creatinethan neurons or astrocytes.21 Myoinositol, slightly high inour patient, may be related to proliferation, but also to theactivation of glial cells. An increase in creatine andmyoinositol and a moderate increase in the choline toNAA ratio are more suggestive of an infiltrative processthan destructive process, with high activation of thenormal glial cells. This spectroscopic pattern has been forinstance claimed to be reasonably specific for gliomatosiscerebri,22 but further studies with larger number ofpatients are needed.

Clinical progressionAt the 1 month follow-up, the patient presented with apersistent headache associated with important diurnalsleepiness that fluctuated during the day. She alsoexperienced new visual symptoms characterised by shortepisodic blurred vision with blackouts and fluorescentvision, lasting several seconds with spontaneousrecovery. The neuropsychological test results wereunchanged, with persistent severe mnestic syndrome.On neurological examination we noticed a new bilateralpapilloedema with preserved visual function, which wasconfirmed by a specialist. The cerebral MRI wasunchanged. We managed to undertake the cerebralbiopsy, previously declined by the patient, thinking thatthe diagnosis of gliomatosis cerebri was the bestexplanation for what was happening to this patient.

At the 3 month follow-up, despite being given aspecific treatment on the basis of published research,12

the patient presented with a rapidly progressive clinicaldeterioration, which led to an acute comatose state anddeath due to severe intracranial hypertension.

Pathology and autopsyStereotaxic brain biopsies done about a month beforedeath showed moderately cellular diffuse infiltration ofthe brain tissue. The infiltrating cells were elongated,

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–0·2

0·0

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Creatine 2I : 1·09

CreatineI : 4·19

I : Integral

CholineI : 2·19

N-acetyl aspartateI : 0·521

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A

C

B

D

Figure 1: Magnetic-resonance assessmentA: transverse FLAIR MRI showing hypersignal in posterior hippocampus and insula on both sides. B: coronal T2 MRIshowing hyperintensity in hippocampus, para-hippocampal gyrus, cingulated gyrus on both sides, and corpuscallosum. C: magnetic-resonance proton spectroscopy (chemical shift imaging spino-echo (CSI SE) 90 time ofrepetition (TR): 1500 time of echo (TE): 135 showing reduced N-acetyl aspartate and increased creatine peaks inthe lesions. D: magnetic-resonance proton spectroscopy (CSI SE/90 TR: 1500 TE: 135), creatine map showingincrease in the lesions.

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slightly irregular neoplastic cells, immunoreactive for glialfibrillary acidic protein (GFAP), consistent with low-gradeastrocytoma. At autopsy, left-sided bronchopneumoniaand slight left-sided cardiac hypertrophy were recorded.Brain weight was 1480 g (normal upper limit 1300 g) andthe brain had narrowed sulci, flattened gyri, and bilateraluncal herniation on external examination, consistent withlarge brain volume. Frontal sections showed a narrowedventricular system, important enlargement of the fornixand corpus callosum with focal grey discoloration, adiffusely augmented white matter volume, and somewhatblurred white–grey matter limits (figure 2). No focal lesioncould be identified, apart from a 2 cm diameterhaemorrhagic area in the white matter of the right parietallobe. Anteroposterior elongation of the rostral brainstemwith a petechial haemorrhage in the pons suggestedterminal severe intracranial hypertension. At histology, adiffusely infiltrating bihemispheric glioma was foundthroughout the brain, except for infratentorial structures.

The neoplastic cells were elongated and slightly atypical,and numerous mitoses were present (grade III glioma).The fornix and corpus callosum were highly infiltratedcompared with the lobar white matter (figure 2). Theastrocytic nature of the neoplastic cells was shown bypositive GFAP immunolabelling. Proliferative activity,shown by Ki-67 immunolabelling, was slight to moderate.The grey matter was massively permeated by neoplasticcells, especially in the structures of the limbic system—ie,the hippocampus, cingulum, and amygdala. Thethalamus and nucleus caudatus were also substantiallyaffected. Focally, in the corpus callosum and near thehaemorrhagic parietal zone, microvascular proliferationand necrosis were noted, both of which are cardinalfeatures of grade IV glioma (figure 2). Immunohisto-chemically, the neoplastic cells were also positive forS-100 protein, but negative for the microglial markerCD68, and did not show nuclear accumulation of thetumour-suppressor gene p53, even in the high-grade area.

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Figure 2: Post-mortem anatomical and histological assessmentA: frontal section of the brain at the chiasma level, showing an enlarged fornix (long arrow), enlarged corpus callosum with focal grey discoloration (short arrow), andthe amygdaloid nucleus with blurred margins (asterisk). B: left panel shows high cellular proliferation in the corpus callosum, with mitotic figures (arrow)(hematoxylin and eosin staining [HE], original magnification �400); upper-right panel shows slight GFAP immunoreactivity of the neoplastic cells (anti-GFAPimmunohistochemistry, �200) and lower-right panel shows proliferative activity of the neoplastic cells, with Ki-67-positive nuclei (brown; anti-Ki-67immunohistochemistry, �400). C: left panel shows ischaemic neurons in the hippocampal convolution (arrows), surrounded by neoplastic cells (HE, �400); rightpanel shows neoplastic cells permeating the cortex and reaching the subpial region (arrow) of the right temporal lobe (HE, �100). D: left panel shows microvascularproliferation (HE, �200) and right panel shows palisading (arrows) around an area of necrosis (asterisk; HE, �100), two cardinal diagnostic features of grade IVglioma, in the macroscopically grey discoloured area of the corpus callosum.

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The neurons, especially those in the hippocampus, had anacidophilic cytoplasm, indicating terminal brain hypoxia.

Pathological diagnosis The neuropathological diagnosis was gliomatosis cerebri,WHO grade III, with focal progression to grade IV.Gliomatosis cerebri, a term introduced by Nevin in 1938,23

is a rare neuroepithelial tumour characterised by diffuseinfiltration of neoplastic glial cells in varying stages ofdifferentiation, with relative preservation of theunderlying anatomical architecture.24,25 The cell of origin isnot known, and the tumour is classified as aneuroepithelial tumour of uncertain origin.26 In mostpatients, the neoplastic cells show some similarities toastrocytomas, but some cases have a predominantlyoligodendrocytic appearance.27 Furthermore, thepathogenesis of this particular invasive subform of gliomais still an issue of debate. Diffuse simultaneous neoplastictransformation, single-cell transformation, blastomatousdysgenesis, or a multicentric origin have all beenproposed.23,28,29 A monoclonal origin of gliomatosis cerebrihas recently been suggested by a detailed post-mortemanalysis, which identified similar genetic alterations invarious tumour samples.30 On the other hand, thedistribution of p53 alterations in one case showed theexistence of topographically different clones.31

In gliomatosis cerebri, life expectancy after theappearance of the first symptom is variable, ranging fromweeks to decades, reflecting the varying pathologicalspectrum.10,12,32 In a small study, the Ki-67 index(reflecting proliferative activity) was prognosticallysignificant on univariate analysis.33 Radiation therapy isregarded as a standard treatment, but has important toxicside-effects.10,32 Initial chemotherapy with temozolomidewas shown to be of some benefit, with a recognised betterresponse in oligodendroglial tumours.34

Authors’ contributionsCC, JB, JAL, and PM did literature searches and wrote the manuscript;CC and JB coordinated the preparation of the manuscript; and AL andPM provided the figures.

Conflicts of interest statementWe have no conflicts of interest.

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