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Neuro-oncology dilemma: Tumour or tumefactive demyelinating lesion

      Highlights

      • TDLs could be the first presentation of MS or seen in long-term known MS patients.
      • Brain tumours as co-morbidities can also arise in MS patients, mimicking TDLs.
      • There are no pathognomonic clinical, imaging or even pathological signs for TDLs.
      • There are characteristic clinical-imaging findings to diagnose TDLs vs Tumours.

      Abstract

      Tumefactive demyelinating lesions (TDLs) are not an uncommon manifestation of demyelinating disease but can pose diagnostic challenges in patients without a pre-existing diagnosis of multiple sclerosis (MS) as well as in known MS patients. Brain tumours can also arise in MS patients and can be seen in chronic MS patients as co-morbidities. Delayed diagnosis or unnecessary intervention or treatment will affect the ultimate prognosis of these patients. In this article, we will review some typical cases illustrating the dilemma and review the information that helps to differentiate the two conditions.
      The intention is not to present an extensive differential diagnosis of both entities, but to examine some typical examples when the decision arises to decide between the two. We take a somewhat different approach, by presenting the cases in “real time”, allowing the readers to consider in their own minds which diagnosis they favour, discussing in detail some of the pertinent literature, then revealing later the actual diagnosis. We would urge readers to consider re-visiting their first thoughts about each case after reading the discussion, before reading the follow-up of each case.
      The overall objective is to highlight the real possibility of being forced to decide between these two entities in clinical practise, present a reasonable approach to help differentiate them and especially to focus on the possibility of TDLs in order to avoid unnecessary biopsy.

      Keywords

      1. Introduction

      Typical demyelinating lesions in MS appear as small, often ovoid, T2 and fluid attenuated inversion recovery (FLAIR) hypersignal lesions which may involve corpus callosum, periventricular, deep white matter, juxtacortical regions, the infratentorial compartment and spinal cord. These lesions may enhance with gadolinium or show restricted diffusion in diffusion weighted imaging (DWI) in the acute phase. Chronic lesions are non-enhancing and demonstrate hypointensity or black holes on T1 sequences (
      • Barkhof F.
      • Filippi M.
      • Miller D.H.
      • et al.
      Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis.
      ).
      One of the rarer variants of demyelinating lesions is the tumefactive demyelinating lesion. Early reports described MS variants with tumour-like presentation as Shilder's disease or Marburg's variants (
      • Poser S.
      • Lüer W.
      • Bruhn H.
      • Frahm J.
      • Brück Y.
      • Felgenhauer K.
      Acute demyelinating disease. Classification and non-invasive diagnosis.
      ). There is no consensus however, regarding the definition of TDLs, but typically represent lesions larger than 2 cm in patients with or without an established diagnosis of MS. TDLs by definition are large and can present as a space occupying lesions (SOL), posing a particular diagnostic dilemma in patients with or without MS. There are some typical imaging and clinical manifestations of TDLs, but none are pathognomonic. Without a clear clinical or imaging differential such patients are often referred for brain biopsy, which itself carries certain morbidity and eventual results may be uninformative or misleading and could lead to unnecessary surgery, or even radiotherapy which could further aggravate TDLs.
      There are growing numbers of middle aged and older MS patients who experience other co-morbidities, including brain tumour, throughout the course of their long-lasting disease. Early presentation of brain tumour may not be easily differentiated from MS, or can be diagnosed incorrectly as a relapse, or even progressive multifocal leukoencephalopathy (PML) in a patient taking certain MS therapies and this further delays the actual diagnosis of brain tumour, thus postponing potentially life-saving treatment impacting overall prognosis.

      2. Case presentation

      2.1 Case A

      A 55-year-old female was diagnosed with MS in 2001 and took beta-interferon for more than 10 years with a stable course (Fig. A1). She then presented with burning dysesthesia in her right lower abdominal area and clumsiness of her right hand, but no new objective findings were seen. A “mild relapse” was considered but no acute treatment was given.
      2 months later, she returned with increased numbness with associated clumsiness in her right hand and a 3-day-course of high-dose oral prednisone was given as a relapse treatment. She only experienced a temporary improvement and her next month follow up visit showed increased weakness and numbness right upper extremity with spreading of numbness into her face. A 3-day-course of IVMP was given and a new MRI was performed (Fig. A2).

      2.2 Case B

      A 45-year-old right handed man presented to ER with a subacute onset of dysphasia and mild right-sided hemiparesis along with right central type facial paresis that evolved over 2 weeks.
      He had no headache, seizure or fever. His past health was unremarkable. A CT head showed a large oedematous lesion on the left side of deep cerebral white matter. He was given oral dexamethasone with the impression of a brain tumour and then discharged with an order for an urgent brain MRI. His right-sided weakness and speech difficulty responded well to corticosteroid therapy within a couple of days . His Brain MRI showed a large ring-enhancing lesion in the left periventricular white matter with several non-enhancing periventricular white matter lesions (Fig. B1)
      Figure thumbnail gr3
      Fig. B1Early Brain CT and MRI.

      2.3 Case C

      A 45-year-old man with known MS and a stable course for more than 10 years then developed gradual generalised weakness, increasing fatigue with worsening memory and speech difficulties, as well as seizures over the last 3 years. He was paricipating in a research study looking at cogntion and a new MRI (Fig. C1) demonstated a tumefactive lesion in the left parieto-occipital area. His next year follow-up MRI (Fig. C2) with gadolinium showed a heterodense tumefactive lesion with some enhancement.

      2.4 Case D

      A 17-year old woman presented to ER with a one week history of progressive right sided hemiparesis and associated mild dysarthria and dyslexia. Her past health was unremarkable. Of note, there was no history of previous neurological problems or preceding infection, vaccination, fever, chills, rash or arthritis. A brain CT and then an MRI demonstrated an extensive temporoparietal deep white matter involvement with some peripheral enhancement and oedema (Fig. D1). Her CSF examination was unremarkable and there was no oligoclonal banding or increased IgG index. She was treated with a 5-day course of IV methylprednisolone with significant but incomplete recovery.
      Figure thumbnail gr6
      Fig. D1First Brain CT and MRI with contrast Case 4.

      2.5 Case E

      A 26-year-old woman presented to ER with subacute progressive left-sided weakness evolving over one week. There was no associated headache, nausea or visual impairment. She had no preceding illness or fever. Her past health was unremarkable. A brain CT and MRI demonstrated a 3.4×3.0×2.7 cm3 ring enhancing tumefactive lesion in right centrum semiovale/corona radiate(Fig. E1). There was no evidence of surrounding oedema or significant mass-effect. No other lesions were noted. The rest of the brain parenchyma was otherwise unremarkable.
      Figure thumbnail gr7
      Fig. E1First Brain CT and MRI with contrast.

      3. Tumefactive demyelinating lesions (TDLs)

      TDLs are defined as demyelinating lesions larger than 2 cm with or without oedema, mass effect or ring enhancement which could mimic brain tumours clinically and radiologically.
      The prevalence of TDLs is estimated to be 1–2/1000 cases of MS. The age group is similar to MS (mainly in the 2nd or 3rd decade of life) although paediatric or older patients also have been reported. In contrast to MS, there is no clear gender predilection reported (
      • Lucchinetti C.F.
      • Gavrilova R.H.
      • Metz I.
      • et al.
      Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis.
      ).

      4. Clinical presentation

      When a history of relapsing–remitting MS, vaccination or viral illness precedes the development of TDLs, then demyelinating disease is highly suspected, however the development of TDLs usually occurs with the first MS attack and is extremely rare in patients who have had established MS for several years (
      • Lucchinetti C.F.
      • Gavrilova R.H.
      • Metz I.
      • et al.
      Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis.
      ). TDLs develop acutely over a few weeks with progression of symptoms and signs. The clinical presentation often differs from typical MS, tending to resemble more a sinister space occupying lesion (SOL). New onset cortical signs are somewhat unusual in conventional MS and in the case of a patient taking a medication such as natalizumab, can raise the possibility of PML (
      • Greenlee J.E.
      Progressive multifocal leucoencephalopathy in the era of natalizumab: a review and discussion of the implications.
      ), but is much more common in TDLs, probably reflecting the larger lesion size and the effect of surrounding oedema. Depending on the size and anatomical site of the TDL, clinical features vary and may include decreased level of consciousness, seizure, visual field deficit, cognitive dysfunction, dysphasia, hemiparesis or hemisensory disturbance – all features more typical of a SOL. In children, symptoms are more acute and severe and usually include headache and vomiting resulting from intracranial hypertension. However, more paediatric cases tend to present with symptoms of optic neuritis, such as visual acuity loss and field changes (
      • Lucchinetti C.F.
      • Gavrilova R.H.
      • Metz I.
      • et al.
      Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis.
      ,
      • Hu W.
      • Lucchinetti C.F.
      The pathological spectrum of CNS inflammatory demyelinating diseases.
      ,
      • Xia L.
      • Lin S.
      • Wang Z.
      • et al.
      Tumefactive demyelinating lesions: nine cases and a review of the literature.
      ).

      5. Diagnostic tests

      5.1 MRI findings

      Although there are no pathognomonic imaging signs to indicate a TDL, there are characteristics which may be helpful in favouring TDLs over a SOL. Most of the TDL MRIs lack extensive areas of demyelination and most do not even fulfil the Barkhof MS criteria (65.5%) (
      • Altintas A.
      • Petek B.
      • Isik N.
      • et al.
      Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study.
      ). Most commonly TDLs are well circumscribed supratentorial lesions with a predilection for the frontal and parietal lobes (
      • Lucchinetti C.F.
      • Gavrilova R.H.
      • Metz I.
      • et al.
      Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis.
      ,
      • Altintas A.
      • Petek B.
      • Isik N.
      • et al.
      Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study.
      ). Butterfly lesions involving the corpus callosum as well as basal ganglia, infratentorial and spinal cord lesions can occur. Mass effect and perilesional oedema in TDLs are usually less conspicuous than malignancy, but increase with larger lesions and more acute TDLs (
      • Lucchinetti C.F.
      • Gavrilova R.H.
      • Metz I.
      • et al.
      Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis.
      ,
      • Xia L.
      • Lin S.
      • Wang Z.
      • et al.
      Tumefactive demyelinating lesions: nine cases and a review of the literature.
      ,
      • Altintas A.
      • Petek B.
      • Isik N.
      • et al.
      Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study.
      ). The majority of TDLs range in size from 2 to 6 cm but lesions of up to 12 cm have been reported (
      • Lucchinetti C.F.
      • Gavrilova R.H.
      • Metz I.
      • et al.
      Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis.
      ). More than half of TDLs enhance with gadolinium and almost any pattern of enhancement can be seen (e.g., homogeneous, heterogeneous, nodular, punctate, ring). Most pathologically proven TDLs have a closed ring appearance (
      • Altintas A.
      • Petek B.
      • Isik N.
      • et al.
      Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study.
      ,
      • Given C.A.
      • Stevens B.S.
      • Lee C.
      The MRI appearance of tumefactive demyelinating lesions.
      ). Open ring enhancement with the incomplete portion of the ring on the grey matter side of the lesion is reported in several studies as a characteristic finding of TDLs (
      • Given C.A.
      • Stevens B.S.
      • Lee C.
      The MRI appearance of tumefactive demyelinating lesions.
      ,
      • Masdeu J.C.
      • Quinto C.
      • Olivera C.
      • Tenner M.
      • Leslie D.
      • Visintainer P.
      Open-ring imaging sign: highly specific for atypical brain demyelination.
      ). The ring enhancement probably represents the advancing area of active inflammation in the periphery with a central and more chronic non-enhancing core in which the blood–CSF-barrier defect has been partly or completely repaired (
      • He J.
      • Grossman R.I.
      • Ge Y.
      • Mannon L.J.
      Enhancing patterns in multiple sclerosis: evolution and persistence.
      ). Patterns of gadolinium enhancement on MRI were compared with pathological pictures of TDLs and open-ring and irregular rim patterns of gadolinium enhancement were associated with macrophage infiltrations and angiogenesis at the inflammatory border. An inhomogeneous pattern of gadolinium enhancement was associated with perivascular lymphocytic cuffing. Central necrosis was seen in cases of severe MS and haemorrhagic leukoencephalopathy. These results suggest that the radiological features of TDLs may be related to different pathological processes, and indicate that MRI may be useful in understanding their pathophysiology (
      • Kobayashi M.
      • Shimizu Y.
      • Shibata N.
      • Uchiyama S.
      Gadolinium enhancement patterns of tumefactive demyelinating lesions: correlations with brain biopsy findings and pathophysiology.
      ).
      Other features typical of a demyelinating aetiology include a T2 hypointense rim, peripheral restriction on DWI and peri-venular enhancement. Unusual for demyelination, there may be cortical as well as subcortical involvement (
      • Lucchinetti C.F.
      • Gavrilova R.H.
      • Metz I.
      • et al.
      Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis.
      ,
      • Kiriyama T.
      • Kataoka H.
      • Taoka T.
      • et al.
      Characteristic neuroimaging in patients with tumefactive demyelinating lesions exceeding 30 mm.
      ). DWI shows that TDLs have mildly increased diffusion coefficients which may help to distinguish them from abscesses in which diffusion is reduced, however restricted diffusion preceding gadolinium enhancement in TDLs is also reported (
      • Hyland M.
      • Bermel R.A.
      • Cohen J.A.
      Restricted diffusion preceding gadolinium enhancement in large or tumefactive demyelinating lesions.
      ). Necrotic neoplasms may display a similar increase in diffusion coefficients centrally within the lesion, making diffusion less helpful in differentiating them from neoplasms. Additional white matter lesions are present in 85% of patients with TDLs and these may be reassuring if their distribution is typical for MS and if the TDLs have radiological characteristics in keeping with a demyelinating aetiology (
      • Altintas A.
      • Petek B.
      • Isik N.
      • et al.
      Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study.
      ).

      5.2 CT Scan

      Non-contrast brain CT in addition to MRI imaging can improve diagnostic accuracy of TDLs compared with MRI alone. CT hypoattenuation of MR enhanced regions was observed in 14 (93%) of 15 patients with TDLs but in only two (4%) of 48 patients with tumour. The CT attenuation of MR enhanced regions was significantly lower for patients with TDLs than for those with tumour (
      • Kim D.S.
      • Na D.G.
      • Kim K.H.
      • et al.
      Distinguishing tumefactive demyelinating lesions from glioma or central nervous system lymphoma: added value of unenhanced CT compared with conventional contrast-enhanced MR imaging.
      ). The finding of blood or calcium in the centre of a lesion would favour tumour (
      • Berberat J.
      • Grobholz R.
      • Boxheimer L.
      • Rogers S.
      • Remonda L.
      • Roelcke U.
      Differentiation between calcification and hemorrhage in brain tumors using susceptibility-weighted imaging: a pilot study.
      ) vs. TDL, and some tumours (e.g. lymphoma) can appear hyperintense on CT even without CT contrast dye (
      • Goldstein J.D.
      • Zeifer B.
      • Chao C.
      • et al.
      CT appearance of primary CNS lymphoma in patients with acquired immunodeficiency syndrome.
      ).

      5.3 MRS and PET Scan

      The role of magnetic resonance spectroscopy (MRS) in distinguishing TDLs versus tumour is not clearly defined. TDLs may cause an increased choline to N-acetyl-aspartate ratio, which is also a common finding in neoplastic lesions. Increased glutamate/glutamine peaks may be in favour of TDLs, but this has been studied in only a small group of patients (
      • Kiriyama T.
      • Kataoka H.
      • Taoka T.
      • et al.
      Characteristic neuroimaging in patients with tumefactive demyelinating lesions exceeding 30 mm.
      ). Serial MRS may be more useful than one-off imaging because as TDLs age, their MRS findings change, whereas those associated with neoplasm tend to remain stable (
      • Butteriss D.J.A.
      • Ismail A.
      • Ellison D.W.
      • Birchall D.
      Use of serial proton magnetic resonance spectroscopy to differentiate low grade glioma from tumefactive plaque in a patient with multiple sclerosis.
      ). TDLs show characteristic imaging findings with distinct features at different depths of the lesion on conventional MRI, MRS, and DWI (
      • Kobayashi M.
      • Shimizu Y.
      • Shibata N.
      • Uchiyama S.
      Gadolinium enhancement patterns of tumefactive demyelinating lesions: correlations with brain biopsy findings and pathophysiology.
      ).
      Fluoro-deoxyglucose (FDG) PET (FDG-PET) scanning may be a useful adjunct to MRI and CT in the investigation of TDLs. While acute demyelinating lesions, including TDLs, may demonstrate increased hypermetabolism on FDG-PET, in general the degree of hypermetabolism appears to be less than that seen in neoplastic lesions and was only marginally above of normal cortex (
      • Schiepers C.
      • Van Hecke P.
      • Vandenberghe R.
      • et al.
      Positron emission tomography, magnetic resonance imaging and proton NMR spectroscopy of white matter in multiple sclerosis.
      ,
      • Takenaka S.
      • Shinoda J.
      • Asano Y.
      • et al.
      Metabolic assessment of monofocal acute inflammatory demyelination using MR spectroscopy and (11)C-methionine-, (11)C-choline-, and (18)F-fluorodeoxyglucose-PET.
      ). In a limited study using methionine PET, a modality for evaluating amino acid metabolism in a tissue, hypermetabolism was significantly less than that seen for anaplastic astrocytoma or glioblastoma multiforme (GBM), suggesting the possible utility of the combination with methionine PET for distinguishing TDLs from malignant gliomas (
      • Takenaka S.
      • Shinoda J.
      • Asano Y.
      • et al.
      Metabolic assessment of monofocal acute inflammatory demyelination using MR spectroscopy and (11)C-methionine-, (11)C-choline-, and (18)F-fluorodeoxyglucose-PET.
      ). Similarly, another limited study showed that average increased FDG uptake seen in primary CNS lymphoma (PCNSL) is not significantly changed following low doses of corticosteroids (
      • Rosenfeld S.S.
      • Hoffman J.M.
      • Coleman R.E.
      • Glantz M.J.
      • Hanson M.W.
      • Schold S.C.
      Studies of primary central nervous system lymphoma with fluorine-18-fluorodeoxyglucose positron emission tomography.
      ). This might be helpful for distinguishing TDLs from PCNSL that gives a similar clinical and radiological presentation (
      • Bromberg J.E.C.
      • Siemers M.D.
      • Taphoorn MJB
      Is a “vanishing tumor” always a lymphoma?.
      ).

      5.4 CSF examination

      The cerebrospinal fluid (CSF) examination may be useful in identifying TDLs over alternative pathology if a lumbar puncture is safe to perform. In a study of CSF examination of 33 patients with TDLs, the rates for positive OCB were 52.17% in those who presented with a TDL as part of their first clinical event, and 90% in patients with a pre-established diagnosis of MS who developed TDLs (
      • Altintas A.
      • Petek B.
      • Isik N.
      • et al.
      Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study.
      ). This is approximately close to what was reported for Clinically Isolated Syndrome (CIS) and relapsing remitting MS (RRMS), respectively (
      • Dobson R.
      • Ramagopalan S.
      • Davis A.
      • Giovannoni G.
      Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude.
      ). The presence of unmatched OCBs in the CSF could provide an additional reassurance in favour of demyelination rather than neoplasm, but radiological follow-up of a TDL is still necessary. A finding of CSF-specific positive OCBs also predicts the later conversion to MS. Application of the third principle of “no better diagnosis” in clinical practise requires neurologists to address the question of typical CSF analysis in MS to avoid diagnostic errors. In some patients, for example, those who are HIV positive or who are otherwise immunocompromised, CSF is important for excluding cytological evidence of neoplasm or evidence of infection. The finding of clono-specific B cells rather than inflammatory T cells would also help to rule out lymphoma if that consideration is a possibility.

      5.5 Biopsy

      Biopsy can possibly help to confirm the demyelinating nature of the lesion, but is usually done because of the higher suspicion that the lesion is a tumour. Biopsy should be avoided if the presumption is that it is a TDL, but may also be inconclusive, and contribute to unnecessary morbidity. The histologic features observed on intraoperative frozen section preparations can be deceptive and difficult to interpret in the case of TDLs and as a result, frozen sections rarely suggest a diagnosis of TDLs. The histologic tableau of TDLs consists of astrocytosis, atypical appearing reactive astrocytes with mitotic figures and lymphocytic infiltrates, which can closely mimic that of gliomas. The key to avoiding misdiagnosis of demyelinating disease is to identify the macrophage infiltrate. However, the presence of Creuztfeldt–Peters cells (astrocytes with fragmented nuclear inclusions) can be mistaken for mitotic glial cells. The immunohistochemical staining for histiocytes (anti-HAM 56 and CD68 antibody) is helpful. Anti-HAM 56 and CD68 antibody label human macrophages and demonstrate reactive macrophages in a wide variety of normal and pathological specimens (
      • Hu W.
      • Lucchinetti C.F.
      The pathological spectrum of CNS inflammatory demyelinating diseases.
      ,
      • Xia L.
      • Lin S.
      • Wang Z.
      • et al.
      Tumefactive demyelinating lesions: nine cases and a review of the literature.
      ,
      • Erana-Rojas I.E.
      • Barboza-Quintana A.
      • Ayala A.G.
      • Fuller G.N.
      Demyelinating pseudotumor.
      ).
      In practise, the patients who usually end up going to biopsy are those without a pre-existing diagnosis of MS, with inconclusive or suspicious imaging including PET, negative OCBs or those in whom a diagnosis of MS would be unusual, such as in older or very young patients. In those patients who appear to have a picture consistent with a typical TDL and in whom no other cause has been identified, we would advocate treating first as presumed TDL with corticosteroids (see below) and monitoring clinically and radiologically for response (
      • Hardy T.A.
      • Chataway J.
      Tumefactive demyelination: an approach to diagnosis and management.
      ).

      6. Differential diagnosis

      It is important that other pathologies such as vasculitis, granuloma, infection, abscess and malignancy are excluded as far as possible MS before reaching the point where TDL is considered vs. tumour. Vigilant monitoring of patients after corticosteroid therapy is crucial to avoid misdiagnosis of TDLs with other “vanishing tumours” (
      • Bromberg J.E.C.
      • Siemers M.D.
      • Taphoorn MJB
      Is a “vanishing tumor” always a lymphoma?.
      ). Currently, there is no evidence based guideline for timing and frequency of imaging after treatment; of TDLs, like other acute demyelinative lesions, may show significant resolution post-corticosteroids until 12 weeks, but 2% of enhancing demyelinative lesions can show enhancement even after 6 months.
      • He J.
      • Grossman R.I.
      • Ge Y.
      • Mannon L.J.
      Enhancing patterns in multiple sclerosis: evolution and persistence.
      This would be the basis for recommending MRI monitoring of treated TDLs after 1.5–6 months (
      • Hardy T.A.
      • Chataway J.
      Tumefactive demyelination: an approach to diagnosis and management.
      ).
      Neoplastic lesions such as glioblastoma multiforme (GBM) and PCNSL are often initially responsive to corticosteroids due an effect at reducing perilesional oedema. This early dramatic response is however, only temporary and lesions will rebound in a few weeks or months. PCNSL can pose a major diagnostic challenge if based solely on the response to corticosteroids, as they demonstrate more sustained clinical and radiological improvement which might lasting 6–12 months, and rarely up to 5 years (
      • Bromberg J.E.C.
      • Siemers M.D.
      • Taphoorn MJB
      Is a “vanishing tumor” always a lymphoma?.
      ,
      • Alderson L.
      • Fetell M.R.
      • Sisti M.
      • Hochberg F.
      • Cohen M.
      • Louis D.N.
      Sentinel lesions of primary CNS lymphoma.
      ,
      • Okita Y.
      • Narita Y.
      • Miyakita Y.
      • et al.
      Long-term follow-up of vanishing tumors in the brain: how should a lesion mimicking primary CNS lymphoma be managed?.
      ,
      • Ng S.
      • Butzkueven H.
      • Kalnins R.
      • Rowe C.
      Prolonged interval between sentinel pseudotumoral demyelination and development of primary CNS lymphoma.
      ,
      • Kürtüncü M.
      • Tüzün E.
      • Durmuş H.
      • Mutlu M.
      • Akman-Demir G.
      • Eraksoy M.
      Primary cerebral lymphoma with a 5-year remission to single-agent corticosteroids.
      ). Reported “sentinel demyelinating lesions” several months prior to the onset of PCNSL also pose another diagnostic challenge (
      • Alderson L.
      • Fetell M.R.
      • Sisti M.
      • Hochberg F.
      • Cohen M.
      • Louis D.N.
      Sentinel lesions of primary CNS lymphoma.
      ). Using corticosteroids prior to biopsy in PCNSL decreases the sensitivity of this test. It might be a prudent action to delay corticosteroid therapy in suspicious case of PCNSL until further clarification with FDG-PET or biopsy is performed (
      • Hardy T.A.
      • Chataway J.
      Tumefactive demyelination: an approach to diagnosis and management.
      ).
      TDLs can occur in diseases other than MS and there are case reports of these lesions being due to viral infections including HIV, other autoimmune diseases such as systemic lupus erythematosis, Sjogren's syndrome, Behcet's disease and neuromyelitis optica (NMO) and drugs such as tacrolimus. There are also cases describing an association with malignancy, particularly renal cell carcinoma (
      • Hardy T.A.
      • Chataway J.
      Tumefactive demyelination: an approach to diagnosis and management.
      ). An exhaustive discussion of the differential of MS or tumour is beyond the focus of this particular review.
      We summarised characteristic findings in TDLs and highlighted differential clues versus CNS tumours and typical demyelinative events in Table 1.
      Table 1Differential diagnosis of TDLs versus Brain tumours and Typical demyelinative lesions of MS.
      TDLsCNS tumours in MSTypical demyelinating lesions
      TimeUsually in first/early disease stageUsually in late/established MSMore common in earlier disease stage
      EvolutionA few weeksA few monthsFew days
      PresentationSOL-Like, Cortical symptoms, Raised ICP signSOL-Like, Cortical symptoms, Raised ICP signRare cortical sign or Raised ICP
      CourseRelapsing demyelinative event in 2/3, monphasic in 1/3, might relapse with TDLsMostly progressiveMostly relapsing
      MRI>2 cm, Little mass effect and perilesional oedema, may show enhancementMore conspicuous mass effect, perilesional oedema and necrosisTypical lesions of MS
      Commonly seen with other demyelinative lesionsTypical MS lesions in background
      CT ScanHypoattenuation of MR enhanced regionsCalcification or haemorrhage in lesionNonspecific findings
      CSF(+)OCBs 50–90%OCBs as background MS, Tumoral cells might be seen+OCBs 50–90%
      TDLs=Tumefactive demyelinative lesions; MS=Multiple sclerosis; CNS= Central nervous system; SOL= Space occupying lesions: ICP=Intracranial pressure; OCBs=Oligoclonal bandings; CSF=Cerebrospinal fluid; MRI=Magnetic resonance imaging; CT Scan= Computerised tomography scan.

      7. Clinical course

      Long term data are limited to evaluate the later clinical course of TDLs in patients, but the available evidence suggests that approximately two-thirds will follow a relapsing remitting course typical of conventional MS after a first TDL and the remaining patients will have no further attacks of demyelination consistent with a monophasic CIS or ADEM. Primary progressive neurological decline from onset is very rare (
      • Lucchinetti C.F.
      • Gavrilova R.H.
      • Metz I.
      • et al.
      Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis.
      ,
      • Altintas A.
      • Petek B.
      • Isik N.
      • et al.
      Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study.
      ).
      A small group of patients who suffer a second clinical episode will relapse with further TDLs (
      • Häne A.
      • Bargetzi M.
      • Hewer E.
      • Bruehlmeier M.
      • Khamis A.
      • Roelcke U.
      Recurrent tumefactive demyelination without evidence of multiple sclerosis or brain tumour.
      ,
      • Selkirk S.M.
      • Shi J.
      Relapsing-remitting tumefactive multiple sclerosis.
      ). In 54 patients with TDLs, 16.7% of patients developed new TDLs over a median follow-up period of 38 months (
      • Altintas A.
      • Petek B.
      • Isik N.
      • et al.
      Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study.
      ). On occasion, tumefactive relapses occur in the context of other more typical MS demyelinating lesions, but there may be a rare subset of individuals who only experience relapse with TDLs (
      • Häne A.
      • Bargetzi M.
      • Hewer E.
      • Bruehlmeier M.
      • Khamis A.
      • Roelcke U.
      Recurrent tumefactive demyelination without evidence of multiple sclerosis or brain tumour.
      ). It may be that recurrent TDLs are simply a phenotypic variant of conventional MS but the possibility exists that patients with recurrent TDLs may have a distinct subtype of demyelinating disease (
      • Poser S.
      • Lüer W.
      • Bruhn H.
      • Frahm J.
      • Brück Y.
      • Felgenhauer K.
      Acute demyelinating disease. Classification and non-invasive diagnosis.
      ). At this stage, it is not possible to predict which patients are more likely to develop a further tumefactive event and who will develop conventional MS lesions.

      8. Treatment

      TDLs are sufficiently rare that randomised controlled therapeutic trials have not been possible and treatment is based on the results of physician experience supported by individual reports and case series. There is broad agreement that, as with any disabling MS relapse, treatment with corticosteroids should be first line therapy for an acute symptomatic tumefactive lesion. The largest case series in which treatment of TDLs was assessed showed that more than 80% of patients had a significant response to treatment with corticosteroids (
      • Altintas A.
      • Petek B.
      • Isik N.
      • et al.
      Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study.
      ).
      PLEX is beneficial in patients with mixed CNS inflammatory demyelinating disease who have failed to respond to corticosteroids. PLEX was used in a few case studies of TDLs with poor response to corticosteroid and had a considerable response (
      • Dastgir J.
      • DiMario F.J.
      Acute tumefactive demyelinating lesions in a pediatric patient with known diagnosis of multiple sclerosis: review of the literature and treatment proposal.
      ,
      • Weinshenker B.G.
      • O’Brien P.C.
      • Petterson T.M.
      • et al.
      A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease.
      ,
      • Seifert C.L.
      • Wegner C.
      • Sprenger T.
      • et al.
      Favourable response to plasma exchange in tumefactive CNS demyelination with delayed B-cell response.
      ,
      • Mao-Draayer Y.
      • Braff S.
      • Pendlebury W.
      • Panitch H.
      Treatment of steroid-unresponsive tumefactive demyelinating disease with plasma exchange.
      ).
      A variety of other Immunosuppressive treatments have been proposed in refractory cases as an acute treatment for refractory relapses. Rituximab, an anti-CD20 B cell monoclonal antibody, recently was used as a corticosteroid sparing drug in patients with refractory TDLs. Combination therapy with Cyclophosphamide–Rituximab was suggested in very reluctant cases (
      • Fan X.
      • Mahta A.
      • De Jager P.L.
      • Kesari S.
      Rituximab for tumefactive inflammatory demyelination: a case report.
      ,
      • Haupts M.R.
      • Schimrigk S.K.
      • Brune N.
      • et al.
      Fulminant tumefactive multiple sclerosis: therapeutic implications of histopathology.
      ,
      • Sempere A.P.
      • Feliu-Rey E.
      • Sanchez-Perez R.
      • Nieto-Navarro J.
      Neurological picture. Rituximab for tumefactive demyelination refractory to corticosteroids and plasma exchange.
      ,
      • Siffrin V.
      • Müller-Forell W.
      • von Pein H.
      • Zipp F.
      How to treat tumefactive demyelinating disease?.
      ). Cyclophosphamide and intravenous immunoglobulin also have been tried mainly in the paediatric refractory population (
      • Dastgir J.
      • DiMario F.J.
      Acute tumefactive demyelinating lesions in a pediatric patient with known diagnosis of multiple sclerosis: review of the literature and treatment proposal.
      ).

      9. Disease modifying therapy

      At the moment there is insufficient evidence for starting MS disease modifying therapy (DMT) after an initial TDL in the absence of clinical or collateral radiological evidence of dissemination in space and time. Many clinicians would favour using DMTs only after MS diagnostic criteria have been fulfilled according to the 2010 revised McDonald criteria (
      • Comi G.
      Multiple sclerosis: pseudotumoral forms.
      ,
      • Polman C.H.
      • Reingold S.C.
      • Banwell B.
      • et al.
      Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.
      ). Others consider the first TDL event as the equivalent of a demyelinating CIS which warrants commencing DMT to decrease the risk of a second clinical attack and therefore conversion to active MS. There may also be minimal improvement in long term disability as a result of this more aggressive approach (
      • Freedman M.S.
      • Comi G.
      • De Stefano N.
      • et al.
      Moving toward earlier treatment of multiple sclerosis: Findings from a decade of clinical trials and implications for clinical practice.
      ). It is not clear how often a single isolated TDL at presentation may progress to MS. At present, the available evidence indicates that the time to a second attack following an initial TDL is already delayed compared with conventional CIS and that a subset of patients may even have a more benign course. Starting a long term DMT with possible side effects would need to be weighed carefully. A DMT could be commenced if the TDL CIS was particularly severe or disabling or if there were other markers to suggest a high risk of conversion to MS, for example, positive CSF specific OCBs or multiple other typical asymptomatic demyelinating lesions (
      • Hardy T.A.
      • Chataway J.
      Tumefactive demyelination: an approach to diagnosis and management.
      ).
      When DMT therapies are commenced, the available data suggest that traditional first line MS therapies such as interferon-β and glatiramer acetate are the most commonly used (
      • Altintas A.
      • Petek B.
      • Isik N.
      • et al.
      Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study.
      ). There are no data available to determine whether the efficacy of these first line treatments is different in patients with TDLs compared with typical RRMS or whether interferon-β should be preferred to glatiramer acetate.
      Fingolimod is a sphingosine-1-phosphate receptor modulator that acts to reduce egress of lymphocytes from peripheral lymph nodes. Several cases were reported recently regarding the development of TDLs after switching or less likely, withdrawal of Fingolimod (
      • Castrop F.
      • Kowarik M.C.
      • Albrecht H.
      • et al.
      Severe multiple sclerosis relapse under fingolimod therapy: incident or coincidence?.
      ,
      • Daelman L.
      • Maitrot A.
      • Maarouf A.
      • Chaunu M.P.
      • Papeix C.
      • Tourbah A.
      Severe multiple sclerosis reactivation under Fingolimod 3 months after natalizumab withdrawal.
      ,
      • Leypoldt F.
      • Münchau A.
      • Moeller F.
      • Bester M.
      • Gerloff C.
      • Heesen C.
      Hemorrhaging focal encephalitis under fingolimod (FTY720) treatment: a case report.
      ,
      • Visser F.
      • Wattjes M.P.
      • Pouwels P.J.W.
      • WHJP Linssen
      • van Oosten B.W.
      Tumefactive multiple sclerosis lesions under fingolimod treatment.
      ,
      • Jander S.
      • Turowski B.
      • Kieseier B.C.
      • Hartung H.-P.
      Emerging tumefactive multiple sclerosis after switching therapy from natalizumab to fingolimod.
      ,
      • Ghezzi A.
      • Rocca M.A.
      • Baroncini D.
      • et al.
      Disease reactivation after fingolimod discontinuation in two multiple sclerosis patients.
      ,
      • Pilz G.
      • Harrer A.
      • Wipfler P.
      • et al.
      Tumefactive MS lesions under fingolimod: a case report and literature review.
      ,
      • Hellmann M.A.
      • Lev N.
      • Lotan I.
      • et al.
      Tumefactive demyelination and a malignant course in an MS patient during and following fingolimod therapy.
      ,

      N. Nealon Severe multiple sclerosis relapse on Fingolimod. Risk management for disease-modifying treatments 1. In: Proceedings 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple SclerosisAmsterdam, The Netherlands 2011.October

      ,
      • Min J.-H.
      • Kim B.J.
      • Lee K.H.
      Development of extensive brain lesions following fingolimod (FTY720) treatment in a patient with neuromyelitis optica spectrum disorder.
      ). If inhibitory immune cells were preferentially affected in a subset of individuals, then a paradoxical effect of Fingolimod could be imagined in which large demyelinating lesions and increased disease activity could result. A potential role for Fingolimod in the treatment of MS with TDLs is yet to be determined, but recent published cases would indicate that a cautious approach to using this agent is warranted.
      There is one report of Natalizumab being beneficial in a patient with rapidly evolving relapsing tumefactive disease who remained relapse free 12 months after initiation of treatment (
      • Seifert C.L.
      • Wegner C.
      • Sprenger T.
      • et al.
      Favourable response to plasma exchange in tumefactive CNS demyelination with delayed B-cell response.
      ). On the other hand, TDLs have been frequently reported in patients with MS and NMO undergoing treatment with Natalizumab or more commonly after withdrawal of it, which justifies more cautious usage of Natalizumab in TDLs (
      • Barnett M.H.
      • Prineas J.W.
      • Buckland M.E.
      • Parratt J.D.E.
      • Pollard J.D.
      Massive astrocyte destruction in neuromyelitis optica despite natalizumab therapy.
      ,
      • Berger J.R.
      Paradoxically aggressive multiple sclerosis in the face of natalizumab therapy.
      ,
      • Beume L.-A.
      • Dersch R.
      • Fuhrer H.
      • Stich O.
      • Rauer S.
      • Niesen W.D.
      Massive exacerbation of multiple sclerosis after withdrawal and early restart of treatment with natalizumab.
      ,
      • Borriello G.
      • Prosperini L.
      • Marinelli F.
      • Fubelli F.
      • Pozzilli C.
      Observations during an elective interruption of natalizumab treatment: a post-marketing study.
      ,
      • Fox R.J.
      • Cree B.A.C.
      • De Sèze J.
      • et al.
      MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study.
      ,
      • Grimaldi L.M.E.
      • Prosperini L.
      • Vitello G.
      • Borriello G.
      • Fubelli F.
      • Pozzilli C.
      MRI-based analysis of the natalizumab therapeutic window in multiple sclerosis.
      ,
      • Jokubaitis V.G.
      • Li V.
      • Kalincik T.
      • et al.
      Fingolimod after natalizumab and the risk of short-term relapse.
      ,
      • O’Connor P.W.
      • Goodman A.
      • Kappos L.
      • et al.
      Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis.
      ,
      • Twyman C.
      • Berger J.R.
      A giant MS plaque mimicking PML during natalizumab treatment.
      ,
      • Vellinga M.M.
      • Castelijns J.A.
      • Barkhof F.
      • Uitdehaag B.M.J.
      • Polman C.H.
      Postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated MS patients.
      ). There is also the additional concern that a TDL arising in an individual taking Natalizumab, and now Fingolimod and dimethyl fumarate as well, could indicate the presence of PML – a clear indication for the rapid discontinuation of that MS treatment.

      10. Prognosis

      It is possible that patients with MS-associated TDLs do not share the same prognosis as those with solitary TDL, which appear to occur more often without supporting evidence for MS, or as patients who have relapsing TDL disease without conventional MS lesions. Bearing this in mind, the largest and most rigorous study of patients with TDLs examined 168 patients with biopsy confirmed disease (
      • Lucchinetti C.F.
      • Gavrilova R.H.
      • Metz I.
      • et al.
      Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis.
      ). In that study, patients with both MS and non-MS associated TDL, the time to a second event in patients presenting with a TDL as their first clinical event (i.e. fulfilling dissemination in time) was 4.8 years compared with 1.9–3 years for a typical demyelinating event (
      • CHAMPS Study Group
      Interferon beta-1a for optic neuritis patients at high risk for multiple sclerosis.
      ,
      • Confavreux C.
      • Vukusic S.
      Natural history of multiple sclerosis: implications for counselling and therapy.
      ,
      • Placebo-controlled
      multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS.
      ). However, the presence of TDLs did not appear to greatly impact the overall prognosis of MS. There was a slight trend for more favourable prognosis in those patients with TDLs when accompanied by more typical MS demyelinating lesions on MRI. This group of patients was marginally slower to reach expanded disability scale score 3.0 at median 38 months of follow-up compared with those who had a single TDL at presentation with no other demyelinating lesions (
      • Hardy T.A.
      • Chataway J.
      Tumefactive demyelination: an approach to diagnosis and management.
      ).
      Another study examined 14 patients with TDLs as their first clinical event, of which eight had biopsy proven TDLs (
      • Wattamwar P.R.
      • Baheti N.N.
      • Kesavadas C.
      • Nair M.
      • Radhakrishnan A.
      Evolution and long term outcome in patients presenting with large demyelinating lesions as their first clinical event.
      ). This smaller cohort was more homogeneous in its baseline characteristics in that none of the patients had any additional typical demyelinating lesions at the time of their presentation with TDL and only one had CSF positive OCBs. At a median follow-up of 3.5 years only two patients had developed clinically definite MS (i.e. experienced a second or more attack). Even in long-term follow-up of recurrent TDLs, good recovery and more favourable clinical prognosis were reported (
      • Ikonomidou V.N.
      • Richert N.D.
      • Vortmeyer A.
      • et al.
      Evolution of tumefactive lesions in multiple sclerosis: a 12-year study with serial imaging in a single patient.
      ).
      The reason for the delay to a second clinical episode is unclear and could, at least in part, reflect more aggressive immunomodulatory treatments given to patients with TDLs. It could also reflect a difference in the fundamental immunopathogenesis of TDLs as compared with lesions of conventional RRMS, but too little is known and more research is needed (
      • Hardy T.A.
      • Chataway J.
      Tumefactive demyelination: an approach to diagnosis and management.
      ).

      11. Brain tumour in multiple sclerosis

      The immune system (in particular regulatory T cells) has a crucial role in both cancer and multiple sclerosis [
      • Cools N.
      • Ponsaerts P.
      • Van Tendeloo V.F.I.
      • Berneman Z.N.
      Regulatory T cells and human disease.
      ]. MS patients exposed to long-term immunosupressive–immunomodulatory treatment may have an increased risk for cancer (
      • Kingwell E.
      • Tremlett H.
      Interferons and multiple sclerosis: is it plausible that beta-IFN treatment could influence the risk of cancer among MS patients?.
      ). Studies of cancer co-morbidity in MS have yielded inconsistent findings, with rates higher (
      • Kingwell E.
      • Tremlett H.
      Interferons and multiple sclerosis: is it plausible that beta-IFN treatment could influence the risk of cancer among MS patients?.
      ,
      • Møller H.
      • Kneller R.W.
      • Boice J.D.
      • Olsen J.H.
      Cancer incidence following hospitalization for multiple sclerosis in Denmark.
      ), lower (
      • Bahmanyar S.
      • Montgomery S.M.
      • Hillert J.
      • Ekbom A.
      • Olsson T.
      Cancer risk among patients with multiple sclerosis and their parents.
      ,
      • Kingwell E.
      • Bajdik C.
      • Phillips N.
      • et al.
      Cancer risk in multiple sclerosis: findings from British Columbia, Canada.
      ,
      • Lebrun C.
      • Debouverie M.
      • Vermersch P.
      • et al.
      Cancer risk and impact of disease-modifying treatments in patients with multiple sclerosis.
      ) or no difference from the general population (
      • Midgard R.
      • Glattre E.
      • Grønning M.
      • Riise T.
      • Edland A.
      • Nyland H.
      Multiple sclerosis and cancer in Norway. A retrospective cohort study.
      ,
      • Sumelahti M.-L.
      • Pukkala E.
      • Hakama M.
      Cancer incidence in multiple sclerosis: a 35-year follow-up.
      ). The general trend and meta-analysis showed even a diminished risk of cancer in MS population (
      • Handel A.E.
      • Ramagopalan S.V.
      Multiple sclerosis and risk of cancer: a meta-analysis.
      ).
      The prevalence of brain tumour in MS has been reported to be increased in some studies (
      • Kingwell E.
      • Bajdik C.
      • Phillips N.
      • et al.
      Cancer risk in multiple sclerosis: findings from British Columbia, Canada.
      ,
      • Sumelahti M.-L.
      • Pukkala E.
      • Hakama M.
      Cancer incidence in multiple sclerosis: a 35-year follow-up.
      ,
      • Fois A.F.
      • Wotton C.J.
      • Yeates D.
      • Turner M.R.
      • Goldacre M.J.
      Cancer in patients with motor neuron disease, multiple sclerosis and Parkinson's disease: record linkage studies.
      ), but not in others (
      • Møller H.
      • Kneller R.W.
      • Boice J.D.
      • Olsen J.H.
      Cancer incidence following hospitalization for multiple sclerosis in Denmark.
      ,
      • Kingwell E.
      • Bajdik C.
      • Phillips N.
      • et al.
      Cancer risk in multiple sclerosis: findings from British Columbia, Canada.
      ,
      • Lebrun C.
      • Debouverie M.
      • Vermersch P.
      • et al.
      Cancer risk and impact of disease-modifying treatments in patients with multiple sclerosis.
      ,
      • Midgard R.
      • Glattre E.
      • Grønning M.
      • Riise T.
      • Edland A.
      • Nyland H.
      Multiple sclerosis and cancer in Norway. A retrospective cohort study.
      ,
      • Nielsen N.M.
      • Rostgaard K.
      • Rasmussen S.
      • et al.
      Cancer risk among patients with multiple sclerosis: a population-based register study.
      ). The elevated risk for brain cancer was most evident soon after disease onset of MS, suggesting a surveillance bias given that patients were being investigated for another condition and brain tumours were found unexpectedly.
      Let us now return to the cases and see which represented TDLs or tumours.

      12. Follow-up of cases

      12.1 Follow up of Case A

      She developed progressive weakness in her right upper extremity, twitching and tingling in her right cheek and hand, and facial paresis. She had no symptom or sign of Increased ICP. She was admitted in hospital and underwent surgical resection. Her pathological diagnosis confirmed as a high grade Astrocytoma (Glioblastoma multiforme-GBM –Fig. A3). She underwent radio-chemotherapy with only partial improvement and was left with severe aphasia and right-sided hemiparesis (Fig. A4).
      Figure thumbnail gr9
      Fig. A4Brain MRI and CT after Surgery and Radiotherapy.

      12.2 Follow up of Case B

      He was prescribed a 5-day course of IV methylprednisolone experienced nearly complete clinical improvement with only minor asymmetrical hyperreflexia as the only residual sigh. His CSF examination showed +OCB and increased IgG Index typical for MS.
      His MRI after steroid therapy demonstrated evolution of some of the lesions (Fig. B2). The left corona radiata lesion cystic portion has evolved. The other lesions make the diagnosis compatible with MS. He was diagnosed as ‘Tumefactive’ MS and disease modifying therapy was suggested. He left the country and further follow up was not available.
      Figure thumbnail gr10
      Fig. B2Evolution of the lesions on IVMP.

      12.3 Follow up of Case C

      He underwent a streotactic brain biopsy which confirmed “anaplastic astrocytoma”. He was given chemo-radiotherapy, but he died due to tumour recurrence after 3 years (Fig. C3).
      Figure thumbnail gr11
      Fig. C3Follow up MRI of Case 3.

      12.4 Follow up of Case D

      She experienced gradual near complete recovery of her neurological deficits over the following months with complete recovery after 3 years. Her follow up imaging also showed significant lesion resolution (Fig. D2). Her CSF re-exam after 3 years was again unremarkable. She has not had another episode in her long term follow-up after 9 years.
      Figure thumbnail gr12
      Fig. D2Follow up of MRI case D.

      12.5 Follow up of Case E

      She underwent a C-Spine MRI and CSF examination. Cervical cord MRI showed a hyperintense T2 lesion involving the dorsal aspect of the spinal cord at C2 and C3, suggestive of a demyelinating process. Her CSF examination showed +OCB and increased IgG index, typical for MS. She was treated with a course of IV methylprednisolone with significant but partial improvement of her left hemiparesis (Fig. E2). 2 years later, she only had her left sided mild spastic hemiparesis as a sequela of her first presentation. In her follow up MRI, the previous T2 lesion in centrum semiovale demonstrated interval decrease in size, but 3 new interval lesions were identified. After 4 years, she developed a mild visual blurring – a possible new MS relapse – and she was treated with a disease modifying therapy for her RRMS and had no new clinical events, but her follow up MRI after 4 years, showed new lesions including a new TDL.

      13. Conclusions

      We presented here some challenging cases hoping to illustrate the dilemma in the diagnosis of TDLs vs brain tumour. Although early clinical presentation, imaging findings or other ancillary tests can help favour one diagnosis over the other, sometimes only follow-up visits or ultimately pathological diagnosis of biopsies can clarify the final diagnosis. In our series, TDLs in long-term MS patients were diagnosed finally as a brain tumour, which suggests prudent vigilance in managing and evaluating any new atypical neurological deficits occurring in MS patients. We also showed that some patients with MS can have recurrent TDLs. Monitoring of clinical and imaging findings after a trial of high dose corticosteroid treatment is sometimes very helpful to reach the final diagnosis and may avoid unnecessary biopsy of lesions.

      Conflict of interest statement

      We certify that there is no conflict of interest with any financial organisation regarding the material discussed in the manuscript.

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