Tumefactive demyelinating lesions in multiple sclerosis

Meredith Frederick (Dr. Frederick of Oregon Health & Science University has no relevant financial relationships to disclose.)
Michelle Cameron MD (Dr. Cameron of Oregon Health & Sciences University has no relevant financial relationships to disclose.)
Anthony T Reder MD, editor. (Dr. Reder of the University of Chicago served on advisory boards and as a consultant for Bayer, Biogen Idec, Caremark Rx, Genentech, Genzyme, Novartis, Questcor/Malinkrodt, Serono, and Teva-Marion.)
Originally released June 25, 2010; last updated December 22, 2016; expires December 22, 2019

This article includes discussion of tumefactive multiple sclerosis, tumor-like multiple sclerosis, pseudotumoral multiple sclerosis, and tumefactive demyelinating lesions. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Multiple sclerosis presenting with clinical and radiographic features similar to a brain tumor is referred to as tumefactive multiple sclerosis. This often poses a diagnostic challenge for the neurologist, neurosurgeon, radiologist, and pathologist. In this article, Drs. Meredith Frederick and Michelle Cameron of the Oregon Health and Science University Department of Neurology discuss the spectrum of central nervous system inflammatory demyelinating disease that can have a tumefactive clinical or radiographic presentation, including the Marburg variant of multiple sclerosis and Balo concentric sclerosis. Acute disseminated encephalomyelitis, acute hemorrhage leukoencephalitis, and neuromyelitis optica can also have tumefactive presentations, but are beyond the scope of this article.

Key points

 

• Tumefactive demyelinating lesions can be caused by a number of diseases, including multiple sclerosis. It is important to recognize that use of the terms tumefactive demyelinating lesions and tumefactive multiple sclerosis in the literature is not standardized and can cause confusion.

 

• A spectrum of disorders causes inflammatory demyelination of the central nervous system; the disorders are collectively referred to as CNS idiopathic inflammatory demyelinating diseases.

 

• Any type of CNS idiopathic inflammatory demyelinating disease may present clinically and radiographically as a tumefactive lesion.

 

• Multiple sclerosis is the most common CNS idiopathic inflammatory demyelinating disease.

 

• Pathological features of multiple sclerosis lesions include focal demyelination, variable inflammation, gliosis, and relative axonal preservation.

 

• Two thirds of patients who present with tumefactive demyelinating lesions subsequently develop multiple sclerosis, with a relapsing-remitting disease course.

 

MRI features associated with tumefactive demyelination include multifocal lesions with at least a single dominant lesion larger than 2.0 cm, variable presence of mass effect or edema, and ring enhancement.

 

• High-dose intravenous corticosteroids are the first line management for tumefactive relapses.

 

• Aggressive supportive management in the acute phase is crucial because the predicted long-term outcome of many patients is good.

Historical note and terminology

Multiple sclerosis is a chronic CNS idiopathic inflammatory demyelinating disease characterized by multiple lesions disseminated in time and space. Multiple sclerosis is the most common CNS idiopathic inflammatory demyelinating disease across all age groups. Typical multiple sclerosis lesions involve the white matter, with a predilection for the periventricular areas, cerebellum, brainstem, spinal cord, and optic nerves. Lesions typically range in size from a few millimeters to a centimeter in diameter (Paty et al 1988). Multiple sclerosis is diagnosed on the basis of demonstrating multiple lesions disseminated in time and space clinically or radiographically (McDonald et al 2001; Polman et al 2010). Occasionally, patients are found to have large CNS demyelinating lesions that appear tumor-like. These are known as tumefactive demyelinating lesions.

The terms tumefactive demyelinating lesions and tumefactive multiple sclerosis are often used interchangeably, although these terms are not synonymous. A tumefactive demyelinating lesion is any CNS demyelinating lesion that appears tumor-like. Tumefactive demyelinating lesions can be caused by a variety of disorders, including, but not limited to, multiple sclerosis. The term tumefactive multiple sclerosis usually refers to multiple sclerosis with tumor-like lesions, but this term is sometimes used to refer to both typical multiple sclerosis and the rare multiple sclerosis variants that can cause tumefactive lesions, including Marburg acute multiple sclerosis, Balo concentric sclerosis, and Schilder disease. This article focuses on tumefactive multiple sclerosis and the variants of multiple sclerosis that present with tumefactive lesions:

 

• Tumefactive multiple sclerosis
• Marburg acute multiple sclerosis
• Balo concentric sclerosis
Schilder disease

Acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalomyelitis, and neuromyelitis optica can also have tumefactive presentations but are beyond the scope of this article.

Tumefactive multiple sclerosis. Although this term is not used uniformly and consistently in the literature, it typically refers to demyelinating brain lesions 2 cm or larger in size, often with features of edema and mass effect. Radiographic features may include a solitary large lesion or multiple lesions with variable contrast enhancement. These lesions may occur in prototypic multiple sclerosis, as part of a monophasic illness, or in the acute fulminant variants of CNS idiopathic inflammatory demyelinating diseases described below. In the largest study of patients with biopsy-proven tumefactive demyelinating lesions that included 168 patients (Lucchinetti et al 2008), the majority had multiple sclerosis. When tumefactive lesions occur in prototypic multiple sclerosis, it is most often at initial presentation, although there are increasing reports of tumefactive lesions in the setting of use or withdrawal of some of the newer disease-modifying therapies for multiple sclerosis, most notably fingolimod (Hardy and Chataway 2013; Pilz et al 2013).

Multiple sclerosis disease-modifying therapy-associated tumefactive demyelination. There are growing numbers of reports of tumefactive demyelination in association with fingolimod and a single report in association with natalizumab. At least 20 cases of tumefactive demyelination associated with fingolimod have been reported (Centonze et al 2012; Jander et al 2012; Hardy and Chataway 2013; Pilz et al 2013; Hellmann et al 2014; Totaro et al 2016). These events have occurred directly after drug initiation, 13 months into treatment, and shortly after discontinuation of fingolimod (Totaro et al 2016). Although a causal link has not been proven, the association is striking. A few of these cases occurred as patients were transitioned from natalizumab to fingolimod (Centonze et al 2012; Jander et al 2012). One published case with biopsy of the tumefactive lesion showed typical pathologic changes associated with demyelination in multiple sclerosis (Hellmann et al 2014). The authors of this article are in agreement with the authors of these studies that this likely represents a unique phenomenon and is not simply emergence of underlying highly active multiple sclerosis (Hellmann et al 2014). Because tumefactive demyelination occurs more commonly as the first demyelinating event and tumefactive lesions have not been reported in association with interferons or glatiramer acetate, it is reasonable to hypothesize that there is an immunologic phenomenon occurring as a result of fingolimod treatment that triggers these tumefactive lesions (Hellmann et al 2014). It is possible that immune cells that have been educated in the lymph nodes are released into the circulation after fingolimod is withdrawn.

A single reported case of tumefactive demyelination occurred soon after natalizumab was restarted after prior discontinuation of the medication (Beume et al 2015). This patient discontinued natalizumab, then had a relapse of multiple sclerosis without tumefactive lesions, which prompted the providers to restart natalizumab. After restarting, she had a severe inflammatory relapse with tumefactive lesions. This case is notable because of the severity of the tumefactive disease activity, leading to stupor and quadriparesis. Biopsy of one of the tumefactive lesions showed demyelination and inflammation dominated by B cells. There are other reports of high-rebound disease activity without tumefactive lesions with discontinuation of natalizumab, but this may reflect more active disease in patients selected for treatment with natalizumab. The case presented by Beume and colleagues suggests the possibility of modification of the immune response by restarting natalizumab, leading to malignant disease activity.

Marburg acute multiple sclerosis. This is an acute, fulminant, monophasic CNS idiopathic inflammatory demyelinating disease characterized by large hemispheric cerebral lesions and rapid progression to death within months to 1 year from onset. Marburg acute multiple sclerosis was first described by Otto Marburg in 1906. He described a 30-year-old woman presenting with confusion, headache, vomiting, ataxia, and left hemiparesis, rapidly progressing to death within 1 month. Autopsy revealed widespread destructive inflammatory demyelination. The clinical diagnosis of Marburg acute multiple sclerosis is often made in retrospect because it is difficult to predict the course and outcome at the onset of symptoms. Cases described in the literature typically show little or no response to treatment, including with high-dose corticosteroids, intravenous immunoglobulins, plasma exchange, azathioprine, cyclophosphamide, and mitoxantrone (Turatti et al 2010; Talab and Kundrata 2011; Suzuki et al 2013). There is one case report with a favorable response to high-dose cyclophosphamide (Nozaki and Abou-Fayssal 2010). An additional patient eventually reached long-term disease stability, although with significant disability, after treatment with corticosteroids, cyclophosphamide, plasma exchange, and interferon-beta (Turatti et al 2010).

Balo concentric sclerosis. This acute CNS idiopathic inflammatory demyelinating disease is pathologically and radiographically characterized by a unique pattern of concentric demyelination. Josef Balo from Hungary first characterized the pathology of this disease in 1928 (Balo 1928). Balo described a 23-year-old gentleman presenting with progressive right hemiparesis and numbness. Patients with Balo concentric sclerosis have traditionally been thought to have an acute fulminant presentation with rapid progression to death within 1 year, similar to Marburg acute multiple sclerosis; however, some people with Balo-like lesions detected on MRI have favorable outcomes (Karaarslan et al 2001; Hardy and Miller 2014). MRI is characterized by lesions with alternating concentric hyperintense and hypointense rings that may enhance with gadolinium (Ng et al 1999). Lesions range in size from 1 centimeter to large sections of a cerebral hemisphere. Their distinctive appearance allows them to be distinguished from lesions in other CNS tumefactive disorders. The diagnosis of Balo concentric sclerosis is typically made based on MRI or autopsy findings demonstrating the pathologic hallmark of concentric demyelination.

Concentric CNS lesions can also rarely occur in other demyelinating disorders. Two case reports of patients with Balo-like brainstem lesions have been described. One patient had neuromyelitis optica (Graber et al 2009), and the other had multiple sclerosis (Kishimoto et al 2008). Balo-like lesions have also been described in patients with progressive multifocal leukoencephalopathy (Markiewicz et al 1977), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (Chitnis and Hollmann 2012), and a patient with active hepatitis C and CSF positive for human herpes virus 6 (Ferreira et al 2011).

Schilder disease (myelinoclastic diffuse sclerosis). This very rare CNS idiopathic inflammatory demyelinating disease was initially described by Paul Schilder in 1912. It is a progressive, degenerative, demyelinating disorder of the CNS that usually begins in childhood or young adulthood (mostly males between the ages of 7 and 12). A number of patients initially diagnosed with Schilder disease were subsequently found to have other CNS disorders, including metabolic and hereditary leukodystrophies (eg, adrenoleukodystrophy = Addison-Schilder disease). Schilder disease typically causes bilateral, large hemispheric demyelinating lesions with progressively larger lesions that interfere with motor function, speech, personality, hearing, and vision and, ultimately, autonomic functions. In 1986, Poser and colleagues proposed criteria for this diagnosis (Poser et al 1986). It is difficult to distinguish Schilder disease from acute or subacute fulminant multiple sclerosis.

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