Tumefactive demyelinating lesions: a case report and literature review

Abstract

Tumefactive multiple sclerosis (TMS) is a rare and diagnostically challenging variant of demyelinating disease that frequently mimics neoplastic, infectious, or vascular brain lesions. Its variable presentation often leads to diagnostic uncertainty and delayed treatment. We describe a case of a 46-year-old woman who presented with subacute neurological deficits and a large, contrast-enhancing lesion on MRI, initially suspected to be a high-grade glioma. Cerebrospinal fluid studies and advanced MRI sequences, including diffusion-weighted imaging (DWI), MR spectroscopy (MRS),were inconclusive.Histopathological examination following brain biopsy confirmed the diagnosis of TMS. The patient was treated with high-dose intravenous corticosteroids, followed by plasma exchange for steroid-refractory symptoms, resulting in partial neurological and radiological improvement. This case highlights the diagnostic complexities of TMS, emphasizing the importance of integrating advanced neuroimaging, multidisciplinary clinical assessment, and histopathological confirmation. We review recent literature on the epidemiology, radiological features, immunopathology, and evolving therapeutic approaches to TMS. Advances in MRI techniques and increased clinical awareness have improved detection, but challenges remain, especially in low-resource settings. TMS should be considered in the differential diagnosis of solitary, tumor-like brain lesions, particularly in young adults with prior demyelinating events. Early recognition and collaborative management are essential to avoid unnecessary surgical interventions and optimize patient outcomes.

Introduction

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system (CNS), representing a significant global health burden and affecting approximately 2.8 million people worldwide [1]. Classically, MS is characterized by multiple demyelinating lesions disseminated in space and time. However, a less common and diagnostically challenging variant—tumefactive multiple sclerosis (TMS)—has been identified. TMS is defined by the presence of large (>2 cm), space-occupying demyelinating lesions that produce mass effect, perilesional edema, and variable contrast enhancement patterns, often mimicking brain tumors or abscesses on imaging [2].

Tumefactive multiple sclerosis (TMS) is considered a rare entity, accounting for approximately 1 to 3 cases per 1,000 patients with multiple sclerosis [3]. Its clinical presentation can be highly variable: it may occur as a clinically isolated syndrome (CIS), as part of relapsing-remitting MS (RRMS), or less commonly as an atypical initial manifestation of a more aggressive disease course [4]. Unlike classical MS plaques, TMS lesions often provoke acute, focal neurological deficits—such as hemiparesis, aphasia, or seizures—depending on the lesion’s location. The diagnostic complexity of TMS stems from its frequently non-specific, and occasionally normal, cerebrospinal fluid (CSF) findings, as well as its radiological resemblance to neoplastic or infectious processes [5].

When evaluating the radiological features of TMS on magnetic resonance imaging (MRI), several non-pathognomonic but suggestive signs may be observed. These include open-ring enhancement, relative sparing of cortical gray matter, absence of restricted diffusion, and a degree of mass effect that is typically mild to moderate in relation to lesion size [6]. In cases where the clinical picture remains ambiguous or the response to corticosteroids is suboptimal, brain biopsy may be necessary to establish a definitive diagnosis. Histopathological analysis typically reveals dense macrophage infiltration, relative preservation of axons, and marked myelin loss—features that help differentiate tumefactive demyelination from neoplastic processes [7].

Despite advancements in MRI technology and immunological testing, TMS continues to be frequently misdiagnosed—particularly in low-resource settings where essential diagnostic tools such as advanced neuroimmunology panels, serial imaging, and brain biopsy are often unavailable [8]. Additionally, cases with delayed progression from isolated optic neuritis or initially normal MRI findings introduce further complexity to clinical decision-making, often obscuring the underlying demyelinating process [8].

In this report, we present the case of a young woman with a remote history of recurrent optic neuritis and initially normal brain imaging, who later developed a large demyelinating lesion with tumor-like features. The lesion showed no clinical improvement with high-dose corticosteroids, necessitating a brain biopsy that confirmed a demyelinating pseudotumor. Remarkable radiological regression was subsequently achieved through plasma exchange. In parallel, we provide a comprehensive literature review of tumefactive demyelinating lesions, with a focus on diagnostic strategies, treatment modalities, and outcomes. This case reinforces the importance of maintaining a high index of suspicion for TMS in atypical brain lesions and highlights the need for nuanced diagnostic algorithms in ambiguous presentations.

Methodology

A structured literature review was conducted to support the discussion of this case. Searches were performed across PubMed, Scopus, and Web of Science databases for English-language articles published up to April 2025. The search terms included combinations of: “tumefactive multiple sclerosis,” “tumefactive demyelinating lesion,” “demyelinating pseudotumor,” “imaging,” “biopsy,” and “treatment.”Articles were screened by title and abstract for relevance to the diagnosis, pathology, imaging features, and management of tumefactive multiple sclerosis (TMS). Case reports, cohort studies, and review articles providing clinical, radiological, or therapeutic insight into TMS were included. Exclusion criteria were non-English publications, pediatric-only series, and studies focused primarily on other demyelinating diseases such as neuromyelitis optica spectrum disorder (NMOSD) or acute disseminated encephalomyelitis (ADEM).

The search process yielded 65 initial records, of which 36 met relevance criteria after duplicate removal. Reference lists of key reviews were manually examined to identify additional studies of interest. Data were extracted on patient characteristics, MRI and MR spectroscopy findings, cerebrospinal fluid profiles, histopathological results, and treatment outcomes. The methodology adhered to narrative review principles, emphasizing interpretative synthesis rather than quantitative meta-analysis.

Case presentation

A 46-year-old woman with a prior diagnosis of recurrent retrobulbar optic neuritis (RBON) presented in March 2025 with acute-onset neurological symptoms. Her history dates back to 2013, when she first experienced painful vision loss in the left eye. Brain MRI at the time was reportedly normal, and she improved significantly with intravenous dexamethasone.

Approximately 7–8 months after her first attack in 2013, she developed new symptoms of blurred vision in the contralateral (right) eye, again preceded by ocular pain. Brain MRI remained normal (images not currently available), and cerebrospinal fluid (CSF) analysis revealed a normal IgG index, negative oligoclonal bands (OCB), and negative anti-aquaporin-4 (AQP4) antibodies. She was again diagnosed with RBON of unclear etiology. Despite the severity of the relapse, she experienced near-complete visual recovery, although partial optic nerve atrophy persisted.

In March 2025, she presented with new neurological deficits, starting with weakness in the left hand that progressed within 24 h to include paresis of the left lower limb and dysarthria. Clinical examination reported the following : Mental status: Alert, fully oriented, and cognitively intact.

Speech: Moderate dysarthria, characterized by slurred articulation and slowed speech output.

Cranial nerves: Partial pallor of the left optic disc was noted on fundoscopy; other cranial nerves were unremarkable.

Motor strength (MRC scale):

Left upper limb: 2/5 (severe weakness; movement possible only with gravity eliminated).

Left lower limb: 1/5 (near-complete paralysis; minimal voluntary movement).

Right upper and lower limbs: 5/5 (normal strength).

Muscle tone: Mild spasticity in the left upper and lower limbs.

Deep tendon reflexes: Hyperreflexia in the left upper and lower limbs; positive Babinski sign on the left.

Sensory examination: Mild reduction in light touch and pinprick sensation in the left upper and lower limbs.

Coordination: Finger-to-nose testing with the left hand was impaired due to severe weakness; normal on the right.

Gait: Ambulation was not possible due to left lower limb paralysis.

Other findings: No evidence of seizures, brainstem, or cerebellar signs.

Brain MRI with contrast Fig. 1, magnetic resonance angiography (MRA), and both cervical and thoracic spine MRI were performed. She underwent a lumbar puncture and was treated with a 5-day course of high-dose intravenous methylprednisolone (Solu-Medrol), but no clear clinical improvement was observed.

Fig. 1.

A Sagittal T1-weighted image showing a large hypointense lesion in the right frontoparietal lobe, with mild mass effect and compression of the adjacent sulci. B Axial T2-weighted sequence reveals a well-demarcated hyperintense lesion suggestive of vasogenic edema and demyelination. C Axial FLAIR image demonstrates extensive perilesional hyperintensity and incomplete ring-like appearance, features commonly associated with tumefactive demyelinating lesions

By April 2025, her clinical condition had stabilized with partial improvement in speech and slight improvement in upper limb function, but continued motor deficit in the lower limb. Follow-up brain MRI with contrast showed a doubling in the size of the cerebral lesion compared to previous imaging. Repeat spine MRI and a full infectious, fungal, and autoimmune panel were unremarkable.

A stereotactic brain biopsy was performed. Histopathological analysis with immunohistochemical staining confirmed a diagnosis of demyelinating pseudotumor—a hallmark of tumefactive multiple sclerosis. The patient was then treated with five sessions of plasma exchange (PLEX) over 10 days.

One month later, repeat brain MRI with magnetic resonance spectroscopy (MRS) Fig. 2 demonstrated a regression in lesion size from 8 cm to approximately 5 cm Fig. 3, correlating with partial clinical improvement reported as: Neurological Examination One Month (After Plasma Exchange):

Fig. 2.

MR spectroscopy showed decreased NAA and mildly elevated choline peaks. Quantitatively, NAA/Cr = 0.72, Cho/NAA = 1.90 and Cho/Cr = 1.38, consistent with low-grade inflammatory demyelination rather than neoplastic process

Fig. 3.

TMS Post-Treatment MRI (A). Coronal T2W: Demonstrates marked reduction in lesion hyperintensity and perilesional edema (B). Coronal T1W Contrast: Shows resolution of ring enhancement and restoration of surrounding parenchymal architecture (C). Axial T1W Contrast: Highlights improved lesion margins and decreased mass effect

Mental status: Normal.

Speech: Marked improvement, with only mild residual dysarthria.

Cranial nerves: Stable optic atrophy, no new deficits.

Motor strength (MRC scale):

Left upper limb: 4/5 (mild weakness; able to resist moderate force).

Left lower limb: 3/5 (improved; able to move limb against gravity but not against resistance).

Right upper and lower limbs: 5/5 (normal).

Muscle tone: Persistent mild spasticity in the left-sided limbs.

Deep tendon reflexes: Mildly brisk in the left upper and lower limbs; Babinski sign weakly positive on the left.

Sensory examination: Significant improvement; only mild residual reduction in light touch in the left lower limb.

Coordination: Improved finger-to-nose testing with the left hand; normal on the right.

Gait: Ambulation possible with assistance, though a pronounced limp remains due to persistent left lower limb weakness.

Other findings: No new neurological deficits or complications.

1000 mg of intravenous Rituximab was administered as a maintenance therapy post PLEX, followed by a second dose two weeks later, the patient is undergoing check ups every three to six months and.

she is prescribed a dose of 1000 mg rituximab every six months.

Discussion

Tumefactive multiple sclerosis (TMS) constitutes a significant diagnostic challenge due to its close radiological resemblance to neoplastic, infectious, and vascular etiologies. This is largely attributable to its mass-like clinical and imaging presentation, which often leads to misclassification as a space-occupying lesion [4]. In our case, the extended interval between the patient’s initial symptom and the biopsy-confirmed diagnosis—spanning over 12 years—highlights the highly variable and unpredictable natural history of demyelinating disorders. Classically, TMS is defined by large, contrast-enhancing lesions measuring greater than 2 cm in diameter. These lesions may occur de novo or in patients with a preexisting diagnosis of multiple sclerosis [9]. Our patient’s prolonged asymptomatic period following bilateral optic neuritis, alongside previously normal MRI and CSF findings, represents a rarely documented disease trajectory that has only been described in isolated reports and small case series.

Magnetic resonance imaging (MRI) remains the primary diagnostic modality for identifying tumefactive multiple sclerosis. Although several radiological features—such as ring-enhancing lesions, sparing of cortical gray matter, and mild to moderate mass effect relative to lesion size—may favor a demyelinating etiology, none of these findings are pathognomonic [10]. In our patient, the lesion demonstrated rapid growth despite corticosteroid treatment, accompanied by worsening mass effect and persistent clinical deficits. These findings necessitated consideration of alternative diagnoses, including high-grade glioma and primary CNS lymphoma. It is noteworthy that this diagnostic dilemma is frequently reported in the TMS literature. In one large series, approximately 30% of patients with tumefactive demyelinating lesions underwent brain biopsy due to a strong clinical suspicion of malignancy, despite imaging features suggestive of demyelination. Our case aligns with these observations, illustrating that radiologic suspicion of TMS—particularly in the context of steroid non-responsiveness and lesion progression—should prompt early histopathological confirmation to avoid misdiagnosis and inappropriate treatment.

Cerebrospinal fluid (CSF) analysis frequently yields inconclusive results in patients with tumefactive multiple sclerosis. Oligoclonal bands and elevated IgG index—considered hallmarks of classical MS—are less consistently detected in TMS, with reported rates ranging from 30% to 50% across studies [5]. In our patient, serial CSF analyses over a 12-year period consistently returned normal results, including negative anti-aquaporin-4 (AQP4) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies which were tested retrospectively. These non-specific findings are consistent with prior literature and further complicate diagnostic certainty, particularly in low-resource settings where access to advanced neuroimmunologic assays may be limited. In this context, the combination of inconclusive laboratory findings, non-definitive radiological appearance, and lack of clinical improvement was the primary rationale for proceeding with brain biopsy to establish a definitive diagnosis [9].

Due to the ambiguity behind radiological and laboratory findings, histopathological examination stands as the gold standard for confirming TMS when clinical features are inconclusive. In our case, biopsy revealed a demyelinating pseudotumor, characterized by perivascular lymphocytic infiltration, myelin loss with relative axonal preservation, and foamy macrophage accumulation [11]. These findings are consistent with active demyelination and critical in excluding neoplastic, infectious, or granulomatous pathologies. The decision to biopsy, though invasive, was ultimately diagnostic and prevented inappropriate oncologic or surgical interventions.

Therapeutically, TMS is initially managed with high-dose intravenous corticosteroids, but steroid-refractory cases are not uncommon. In such settings, plasma exchange (PLEX) has demonstrated clinical efficacy, particularly in acute demyelinating syndromes unresponsive to steroids [12]. Keegan and colleagues reported a 44% response rate to PLEX in patients with severe CNS demyelination, and our patient’s course further supports this [13]. Following five sessions of PLEX, she experienced both radiological regression of the lesion and partial neurological improvement. The observed lesion reduction from 8 cm to approximately 5 cm one month post-treatment illustrates the potential role of PLEX in mitigating inflammatory burden when conventional therapy fails.

This case also raises important considerations about diagnostic pathways in low-resource environments. Limited access to serial MRI, advanced immunological assays, or rapid histopathological assessment often delays diagnosis or leads to mismanagement. In such contexts, interdisciplinary collaboration and heightened awareness of TMS as a differential diagnosis for intracranial mass lesions are essential [11]. Ultimately, our case adds to the growing recognition that TMS, while rare, should be actively considered in young adults with tumor-like brain lesions—particularly when imaging characteristics and clinical history suggest prior demyelinating events.

Epidemiology and clinical spectrum

van der Velden et al. described tumefactive multiple sclerosis (TMS) in the 1979 as large demyelinating lesions that have neoplasm like-features. Initially termed “pseudotumoral demyelinating lesions” [14], these entities had clinical and radiological resemblance to gliomas, lymphomas, and abscesses which constituted a diagnostic challenge. Prior to the widespread use of MRI, many cases were misdiagnosed and inappropriately managed surgically [15]. However, neuropathological evidence accumulating over the year clarified TMS to be a phenotypic variant of MS rather than an isolated entity [16]. 2005 mcdonald criteria revisions and following refinements aided the merge of TMS into the broader MS diagnostic framework, particularly diagnosing atypical radiological patterns, now TMS is acknowledged radiologically and clinically as an isolated syndrome when appropriate while underscoring its integration into MS nosology [17, 18].

Tumefactive demyelinating lesions (TDLs) represent a rare and distinct variant of the multiple sclerosis (MS) spectrum, typically presenting as solitary lesions exceeding 2 cm in diameter and exhibiting incomplete ring enhancement [4, 19]. The true incidence of tumefactive multiple sclerosis (TMS) is likely underestimated due to misdiagnosis and limited access to advanced imaging modalities [2]. Recent meta-analyses report that TMS accounts for approximately 0.1–0.3% of MS presentations [20]. Female predominancy is clearly noted with a peak onset between the second and fourth decades of life [2]. Some studies suggest a higher frequency of TMS among Asian and Latin American populations, although this may reflect referral or reporting bias. It is important to note that a multicenter retrospective study from Europe and North America found that 25% of patients initially diagnosed with TMS went on to develop relapsing remitting MS within five years, while other had monophasic courses, highlighting phenotypic heterogeneity [21]. Broader MRI access and greater clinician awareness and improved differentiation from neoplasms are the main causes behind increased detection rate in recent years.

Pathophysiology and immunopathology

The pathology of TMS is not merely a scaled-up version of typical MS plaques. Instead, it demonstrates a unique immunopathological profile, often featuring confluent demyelination, prominent macrophage infiltration, and perivascular lymphocytic cuffs, with substantial astrocytic and axonal preservation in early lesions [22]. Type II immunopattern (antibody/complement-mediated demyelination) is commonly reported in biopsy samples. Studies using cerebrospinal fluid (CSF) and post-mortem tissue suggest that local synthesis of oligoclonal IgG bands, upregulation of MHC class II expression, and astrocyte-derived chemokines (like CXCL13) contribute to lesion expansion and mass effect [23, 24]. Interestingly, some reports describe a higher rate of apoptotic oligodendrocytes in TMS compared to conventional MS, implicating additional non-immune mechanisms like excitotoxicity or oxidative stress [23]. The interplay between innate and adaptive immunity, particularly in lesion evolution and resolution, remains an active area of investigation(Fig. 4).

Fig. 4.

Comparative radiological and clinical features of tumefactive multiple sclerosis (TMS) versus common differential diagnoses including acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorder (NMOSD), and neoplastic/infectious lesions. The table highlights key distinctions in presentation, imaging patterns, enhancement, antibody markers, and associated features aiding in accurate diagnosis

Radiological differentiation

Classically, TMS lesions display incomplete or open-ring gadolinium enhancement and reduced mass effect compared with their size, features that help distinguish them from high-grade gliomas.Standard MRI sequences (T1, T2, FLAIR) are essential but insufficient alone. Advanced techniques include:

-MR Spectroscopy (MRS):

In proton MRS they are characterized by lac increase, depending on the degree of inflammatory reaction, and by increased Cho/Cre ratios due to acute myelin break down, but usually not so intense as in neoplastic lesions [25, 26], ↓ NAA, ↑ choline, and occasionally ↑ lactate distinguish demyelination from neoplasm. However, overlap remains, particularly in high-grade gliomas [27, 28].

-Perfusion-Weighted Imaging (PWI):

TMS generally shows decreased relative cerebral blood volume (rCBV), contrasting with elevated rCBV in neoplastic lesions due to angiogenesis [29].

-Diffusion Tensor Imaging (DTI):

Offers insights into white matter integrity and lesion tract disruption, potentially identifying demyelinating patterns early [29].

-Susceptibility-Weighted Imaging (SWI):

Can detect iron-laden macrophages and venous anatomy, which may differ in neoplasms [30].

-Quantitative susceptibility mapping (QSM) and myelin water imaging are emerging tools with promising early data for delineating lesion composition and activity [27].

-Dynamic susceptibility contrast (DSC) is the most commonly used technique to distinguish neoplastic from non-neoplastic lesions using relative cerebral blood volume (rCBV) as an indicator of neovascularization. The TDLs have shown significantly lower rCBVs than high-grade gliomas (HGGs), with a mean rCBV of 2.11 ± 1.12 and 3.77 ± 1.65, respectively [31].

Despite these advances, biopsy remains necessary in ambiguous or rapidly progressing cases, with studies reporting histological confirmation in up to 30% of TMS diagnoses.

Therapeutic strategies

TMS possible compications such as significant mass effect and potential herniation, necessitates urgent intervention and management. The first-line treatment for TMS is classically high dose intravenous methylprednisolone (1 gram per day for 3 to 5 days) [21]. by its very well understood mechanism of supressing the proinflammatory cytokine cascade, methylprednisolone manages to reduce perilesional edema. However, some cases do not respond as well to corticosteroid treatment and have a refractory course. These cases are usually managed by plasma exchange, by removing the circulating antibodies and immune complexes that are causing the ongoing demyelination [32].

The second-line treatment is usually preserved for patients who do not show improvement to their initial therapies or who experience recurrent demyelinating activity, here immunomodulatory agents are considered. Rituximab, a monoclonal antibody targets CD20- positive B cells, which in turn reduces antigen presentation and proinflammatory cytokine release [33]. Natalizumab is also used, due to its lymphocyte migration across Blood brain barrier preventive mechanism, making it particularly useful for reducing recurrence risk [34]. Finglolimod and Siponimod, are oral agents that modulate sphingosine-1-phosphate receptors, they function by sequestering lymphocytes within lymphnodes and limiting their CNS egress.

Treatment selection is individualized based on whether the presentation represents a monophasic demyelinating event or the initial manifestation of a relapsing multiple sclerosis phenotype. Long-term decisions regarding disease-modifying therapy (DMT) are informed by follow-up MRI findings, the presence of new lesion formation, and clinical relapses.

Unique features and clinical implications of the present case

This case illustrates several uncommon aspects that expand the current understanding of tumefactive multiple sclerosis (TMS). First, the exceptionally long latency period of approximately 12 years between symptom onset and biopsy confirmation highlights the variable and sometimes indolent evolution of demyelinating pathology. Second, the case underscores the diagnostic complexity faced in resource-limited settings, where advanced biomarkers and anti-MOG testing may be unavailable, making multimodal MRI and MRS essential for diagnostic confirmation. Third, the radiologic–clinical correlation, particularly the incomplete ring enhancement and decreased relative cerebral blood volume, emphasizes the importance of integrating perfusion and spectroscopic data when differentiating TMS from neoplastic lesions. Finally, the favorable response to corticosteroid therapy and plasma exchange underscores the reversibility of demyelinating inflammation when appropriately recognized, reinforcing the need for early neuroimaging-based differentiation in ambiguous lesions.

Conclusion

Tumefactive multiple sclerosis remains a rare but important diagnostic consideration when evaluating large, atypical brain lesions. This case highlights the diagnostic complexities that arise when clinical, imaging, and laboratory findings overlap with neoplastic and infectious processes. Neuroimaging should include perfusion in these cases, as TMS shows decreased relative cerebral blood volume. Our experience emphasizes the need for a thorough, multidisciplinary approach to ensure timely and accurate diagnosis. Raising awareness of TMS, particularly in resource-limited settings, will help reduce misdiagnosis and support more effective management for future patients.

Authors’ contributions

J R : Investigation, Conceptualization.A Z: Writing – review & editing, Writing – original draftB Z: Investigation, Conceptualization, reviewing & editing.

Data availability

Not applicable (this manuscript does not report data generation or analysis).

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare no competing interests.