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RARE CLINICAL CASE OF GLIOBLASTOMAMULTIFORME, MULTIPLE SCLEROSIS ANDEPILEPSY: CLINICAL, MRI AND 18F-FDG PETSTUDY

Ivan N. Dimitrov1, Ara G. Kaprelyan2, Radoslav Georgiev3, Borislav D. Ivanov4,Yavor Enchev.5, Tony Avramov5, Margarita V. Grudkova2, Nadezhda S. Deleva2

1) Department of Nursing, Sliven Affiliate, Medical University - Varna, Bulgaria2) Department of Neurology, Medical University - Varna, Bulgaria3) Department of Imaging Diagnostics and Radiotherapy, Medical University -Varna, Bulgaria4) Department of Clinical Medical Sciences, Faculty of Dental Medicine, MedicalUniversity - Varna, Bulgaria5) Department of Neurosurgery and Otolaryngology, Medical University - Varna,Bulgaria

Journal of IMAB - Annual Proceeding (Scientific Papers) 2015, vol. 21, issue 4Journal of IMABISSN: 1312-773Xhttp://www.journal-imab-bg.org

ABSTRACTBackground: The clinical features of multiple scle-

rosis during a relapse may raise the suspicion of a braintumor as a possible differential diagnosis. Regardless of thehigh informative value of neuroimaging, some clinical casesremain challenging for neurologists, neurosurgeons and ra-diologists. Associations of brain tumors and relapsing-re-mitting multiple sclerosis have been described in the litera-ture. Epilepsy, being common in brain tumors, is not amongthe most frequent and typical manifestations of multiplesclerosis, but both disorders appear together more com-monly than by chance.

Objective: To present and discuss the diagnosticchallenges in a case of coexisting epilepsy, multiple scle-rosis, and glioblastoma multiforme.

Method: Case report.Results: We present a 38-year-old patient with re-

lapsing-remitting multiple sclerosis manifesting clinically along period after a successfully treated epilepsy in child-hood and adolescence. After reappearance of generalizedtonic-clonic seizures and imaging evidence of a tumefactivelesion, the differential diagnosis between a new relapse andan initial manifestation of a brain was discussed. Glioblas-toma multiforme was found intraoperatively.

Conclusion: Our case study demonstrates that thelikelihood of parallel development of different pathologi-cal processes, such as demyelinating and neoplastic, in thesame patient, should not be underestimated. We emphasizethe critical importance of biopsy for the resolution of simi-lar diagnostic dilemmas. Yet, obtaining consent for biopsyis not always a leading point in the communication with pa-tients and their relatives. All efforts made for an accuratediagnosis are important, as properly chosen therapeutic op-tions influence the prognosis.

Keywords: 18F-FDG PET, Biopsy, Epilepsy,Glioblastoma, Multiple sclerosis

BACKGROUNDClinical manifestations of multiple sclerosis (MS)

during a relapse have often provoked discussions about thedifferential diagnosis of brain malignancy. Nowadays, inspite of the availability of multiple neuroimaging tech-niques, there are still clinical cases which challenge neu-rologists qualified in the domain of demyelinating diseases,neurosurgeons, and radiologists.

Publications in the literature describing solitary,well demarcated space occupying demyelinating lesions, re-quiring a broad differential diagnosis, have increased in re-cent years. The term of “tumefactive multiple sclerosis” hasbeen introduced. It describes the constellation of atypicalneuroimaging characteristics of MS lesions, such as: singlespace occupying lesion, size larger than 2 cm, mass effect,edema and/or ring enhancement, etc [1, 2]. Other defini-tions, including “tumefactive demyelinating lesions”, “de-myelinating pseudotumor”, “tumor-like demyelinating le-sions”, “giant plaques” are related to clinical cases wherelarge, aggressive demyelinating lesions can be seen in pa-tients with, but also without confirmed MS.

Among the frequently encountered neurologicalmanifestations in a number of cases of MS with lateralizedsymptoms and MRI picture of giant plaques reminding abrain tumor with perifocal edema, are global/nominativeaphasia, spastic hemiparesis, epileptic seizures, syndromeof intracranial hypertension. Such manifestations are rarelyseen during a relapse in usual MS patients [1-3].

In clinical practice, the dilemma of brain tumor ordemyelinating lesion emerges when focal neurological defi-cit appears abruptly and does not suggest more than a sin-gle location of the pathologic process, and also when somecharacteristic symptoms of brain tumors are imitated. It istherefore recommended to consider a pseudo tumor mani-festation of MS in young patients with rapidly occurringunilateral hemiparesis and raised intracranial pressure [4].

Tavee et al. [2] have presented an unusual case ofa 25-year-old woman with sudden spastic hemiparesis and

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an episode with a fall and loss of consciousness. On MRIthey found a lesion in the left posterior frontal region, 5.0× 3.5 × 3.5 cm in size, causing mass effect, showing a het-erogeneous increase of signal intensity on T2 and FLAIR,and hypointensity on T1. The findings were interpreted ascystic astrocytoma, but focal fields of demyelination werefound on biopsy. Differential diagnostic challenges in simi-lar cases are also related to the fact that contrast enhance-ment and brain edema may fade away after application ofcorticosteroids, the standard treatment of MS relapses [5].

Biopsy of giant pseudo tumor demyelinating le-sions does not yet have an alternative. In a retrospectiveanalysis of biopsy confirmed inflammatory demyelinatingdisease of the central nervous system in 168 patients, 61%having a first clinical event, 29% with relapsing-remitting,and 4% with progressive clinical course, Lucchinetti et al.[6] underline the diagnostic challenges in cases with atypi-cal clinical and radiological characteristics. Actually, innearly 10% of patients with MS, no multiple lesions arefound on MRI. Demyelinating diseases affecting the cor-pus callosum may even present on neuroimaging as a but-terfly glioma [2]. According to Navarro et al. [3], thespectroscopic picture of inflammation with cell destructionand replacement does not contribute to the differentiationbetween demyelinating disease and high grade glioma.

On the other hand, the possibility that two proc-esses, demyelinating and neoplastic, can develop togetherat the same time, should not be underestimated.

Association of brain tumors with multiple scle-rosis

The association of brain tumors such as meningi-omas, oligodendrogliomas, astrocytomas, glioblastomas,diffuse gliomas, primary CNS lymphomas, and ependymo-mas of the spinal cord, with relapsing-remitting MS, hasbeen known from a series of case descriptions. Usually, aninitial clinical and neuroimaging based suspicion of aneoplastic process emerges, which can later be proven bymeans of biopsy. Patients are most likely to have a consecu-tive relapse with worsening or initial symptoms with evi-dence of a single lesion [7-9].

The development of two parallel processes, demy-elinating and neoplastic, in patients with MS, can also besuspected in patients with secondary progressive MS whosecondition worsens, and who do not respond to corticoster-oid treatment. A careful evaluation of symptoms and MRIfindings is recommended even when the clinical picture andthe diagnosis are well documented, as well as in cases withlong history of the disease [10-12].

If large, contrast enhancing brain lesions are foundin older patients with relapsing-remitting course of MS andsteroid resistant visual disturbances, primary CNS lym-phoma should be considered [13, 14].

Concerning the parallel development of multiplesclerosis and later of a primary CNS lymphoma in the samepatient, lymphoma can be discussed as a possible compli-cation of chronic immunosuppression with corticosteroids,immunosuppressants and beta-interferon, leading to animmunocompromised state. The demyelinating disease, pre-

ceding the lymphoma, may on the other hand be subject toa neoplastic transformation [15, 16].

Epilepsy in brain tumors and multiple sclerosisEpileptic seizures are a well-known manifestation

of brain tumors [17, 18]. Though they are not among themost frequent and typical symptoms of MS, results of popu-lation-based studies show that MS and epilepsy occur to-gether more commonly than by chance [19]. Occurrence ofseizures during the clinical course of MS may be associ-ated with early-onset and increased disease severity [20].It is believed that subcortical plaques and their strategic lo-cation underlie seizure activity in patients with MS and epi-lepsy [21]. According to Nicholas et al., grey matter lesionsin the temporal lobe in MS underlie a loss of inhibitory in-terneuron’s in the cortex and these changes could togetherwith concurrent infection enhance susceptibility to seizures[22].

CASE REPORTWe present a case of development of a brain tumor

in a patient with relapsing-remitting MS, clinically mani-fested and confirmed years after successfully treated epi-lepsy in her childhood and adolescence.

The patient is a 38-year-old woman whose multi-ple sclerosis presented for the first time in 2010 with weak-ness and pain in her right leg, dizziness and walking insta-bility. The second and third relapses, in November 2010 andMay 2011 respectively, presented with worsening of thesymptoms, together with appearance of double vision. Thepatient was treated with corticosteroids and her conditionimproved. MRI findings in October 2011 were in line withdiagnosis of MS (Fig.1.).

In December 2011 the patient was hospitalizedagain due to weakness and numbness of the right extremi-ties and unstable gait. Physical exam was unremarkable.Neurologic exam showed right internuclearophthalmoparesis, paresis of the right lower extremity,hyperreflexia more pronounced on the right, bilateral Bab-inski and Chaddock signs, and cerebellar Romberg test.EDSS was 2.5. Laboratory tests were normal. Another ster-oid course led to improvement and the patient was dis-charged.

A year later, in 2012, another hospitalization wasperformed because of leg weakness, numbness of the leftside of the body and the left extremities. EDSS was 4.0 be-cause of more pronounced pyramidal and coordinationsymptoms. Again, steroids were applied and the patient wasdischarged with relative improvement.

In March 2013 she had a generalized tonic-clonicseizure. She was hospitalized and computed tomographywas performed in emergency. Suspicion of a space occu-pying lesion in the right temporal region was raised. Newfindings from the neurologic exam were impaired spatialorientation, slower thinking and speech. MRI was per-formed (Fig.2.).

The right temporal lesion seen on CT was con-firmed, 27 x 23.5 mm in size, with mild surrounding edemaand mass effect, showing insignificant, non-homogeneous

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contrast enhancement. The lesion had restricted diffusionand increased perfusion. It was interpreted as a possibletumor-like MS lesion or, less likely, a low-grade glioma.MRI follow-up in 3 months was recommended.

PET of the brain was performed, showing an areaof increased activity, 15 mm in size, in the right temporallobe (Fig.3.).

After fusion of PET and MRI images, the area wasfound to project in the ventral medial third of the MRI le-sion and towards the temporal horn of the lateral ventricle(Fig.4.).

The lesion was interpreted as strongly suspiciousfor malignancy, most likely a high-grade glioma or lym-phoma. Biopsy was recommended but the patient and herrelatives refused the procedure. The patient was dischargedafter antiepileptic treatment was prescribed.

Two months later she presented again, this timewith weakness and numbness of the extremities, more pro-nounced on the left, impaired speech and swallowing. Fol-low-up MRI was performed which showed evidence of in-creased size of the tumor-like lesion compared to the pre-vious assessment. New lesions were visualized in the rightparietal region and around the ventricles, with vast edemaand uneven but significant contrast enhancement. Again, theinterpretation was difficult, with tumefactive MS and gliomabeing the most feasible options. In the meantime, the gen-eral and neurologic condition of the patient had worsened.EDSS was 6.0.

Another MRI was done in June 2013. A large, dif-fuse, multi-centric tumor formation was visualized in theright temporal and parietal region, with pronounced masseffect and edema. Two confluent lesions were seen in theinterior part of the temporal lobe, 13.5 and 27 mm in size,respectively. A third lesion, 33 mm in size, was situated inthe right parasagittal region. Compression and midline shiftwere noted. The structure of the formation was describedas heterogeneous, with hemorrhagic and necrotic areas, sig-nificantly increasing its signal intensity after application ofgadolinium contrast. This time the lesion was interpreted asmost probably anaplastic high-grade glioma. The patientwas transferred to a neurosurgery clinic where she was op-erated on. The histological diagnosis of glioblastoma wasfinally established.

DISCUSSIONThe present case requires discussion in several as-

pects. Above all, it demonstrates the development of a newlesion in a patient with relapsing-remitting MS, which needsto be determined as either demyelinating or neoplastic incharacter. Usually the first possible hypothesis in such casesis that a giant demyelinating lesion has developed in thecourse of a consecutive relapse. Though this is the morelikely situation, we should not underestimate the recommen-dation that the association of MS with gliomas must be con-sidered in all cases of mass lesions appearing in patientswith MS. Neuroimaging is not always capable of determin-ing the type of pathologic process, even if complementary,

non-conventional techniques are applied. Similarly totumors, MS lesions may enhance their signal after contrast-ing with gadolinium, and because of the acute edema, masseffect can be seen in large demyelinating plaques [1, 2, 12].

In order not to underestimate the possible develop-ment of two processes, demyelinating and neoplastic, it isimportant to carefully examine the patient if new and unu-sual symptoms appear in the course of development of MS.It should be noted that in numerous cases presented in theliterature only a follow-up MRI and the appearance of sei-zures have led to a suspicion of a different process. Our casealso raises the question about the diagnostic contribution ofthe appearance or reappearance of epileptic seizures (in caseof history of epilepsy in the past) to the differential diag-nosis between a consecutive relapse of MS and an initialmanifestation of a brain tumor. In studies of prevalence, in-cluding a metaanalysis of 29 published series of patientswith epileptic seizures and MS, it has been found that sei-zures affect 2.3% to 4.25% of MS patients, 3 to 6 timesmore than the general population. In most studies epilepticseizures are not among the initial symptoms [21, 23, 24].

The glial tumor found intraoperatively and provenon biopsy allows our case to be added to the rarely de-scribed association of MS with brain tumors. The associa-tion of MS with gliomas, though rare, requires special at-tention because the appearance of new complaints andsymptoms is usually attributed to a relapse and consecu-tively no neuroimaging is performed. At the same time,when a new focal mass lesion is visualized, it is most com-monly interpreted as a pseudotumor plaque. In a clinicalcase of a 37-year-old man diagnosed with MS, describedby de la Lama et al. [12], the patient had a large lesion inthe right frontal lobe, interpreted initially as a pseudotumorplaque. Two years later simple partial seizures appearedwhich were treated with valproate, but later became resist-ant to treatment. Then, on follow-up imaging, the lesion wasfound to be enlarged and heterogeneous in structure. It waslater determined histologically as oligodendroglioma. Bi-opsy obtained by means of neuronavigation can be ex-tremely useful in such cases [25] as it would help solvingdiagnostic dilemmas. It has to be noted though that beforebiopsy is performed, the patient and/or his relatives mustprovide informed consent. Unfortunately, like in our case,they are often reluctant.

CONCLUSIONOur case study demonstrates that the likelihood of

parallel development of different pathological processes,such as demyelinating and neoplastic, in the same patient,should not be underestimated. We emphasize the critical im-portance of biopsy for the resolution of similar diagnosticdilemmas. Yet, obtaining consent for biopsy is not alwaysa leading point in the communication with patients and theirrelatives. All efforts made for an accurate diagnosis are im-portant, as properly chosen therapeutic options influence theshort- and long-term prognosis.

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Fig. 1. AxT2 MRI showing demyelinating lesions Fig. 2. AxT2 MRI showing a right temporal and pa-rietal tumor formation

Fig. 3. 18F-FDG PET (CT fusion images): hypermetabolism in the lesion

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Please cite this article as: Dimitrov IN, Kaprelyan AG, Georgiev R, Ivanov BD, Enchev Y, Avramov T, Grudkova MV,Deleva NS. Rare Clinical Case of Glioblastoma Multiforme, Multiple Sclerosis and Epilepsy: Clinical, MRI and 18F-FDG PET Study. J of IMAB. 2015 Oct-Dec;21(4):908-913.

Received: 01/09/2015; Published online: 13/11/2015