IgG4-related disease: neurologic manifestations
Nov. 29, 2022
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When multiple sclerosis or its variants present with clinical and radiographic features of a brain tumor, this is referred to as tumefactive multiple sclerosis or tumefactive demyelinating lesions. Tumefactive demyelinating lesions often pose a diagnostic challenge. In this article, the authors discuss the spectrum of central nervous system inflammatory demyelinating disease that can have a tumefactive clinical or radiographic presentation, including Marburg acute multiple sclerosis, Balo concentric sclerosis, and Schilder disease. Tumefactive demyelinating lesions occurring in association with autoimmune diseases (eg, Sjogren disease, lupus erythematosus, neuromyelitis optica, MOG-antibody associated disease), infectious diseases (eg, HIV), malignancy (eg, renal cell carcinoma), related to drugs (eg, tacrolimus, fingolimod), and postinfectious conditions (eg, acute disseminated encephalomyelitis, acute hemorrhage leukoencephalitis) are not included. This updated review adds information from recent retrospective reviews, case series, and epidemiological studies.
• 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.
• 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.
• Pathological features of tumefactive demyelinating 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.
• 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 generally good.
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 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 (57). Multiple sclerosis is diagnosed on the basis of demonstrating multiple CNS lesions disseminated in time and space clinically or radiographically, with more recent updates including cerebrospinal fluid analysis (49; 61; 77). 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. Whether these entities are variants of multiple sclerosis, as they have historically been identified, or discrete pathophysiologic entities remains controversial. This article focuses on workup of tumefactive multiple sclerosis and the variants of multiple sclerosis that present with tumefactive lesions:
• Marburg acute multiple sclerosis
Tumefactive demyelination can also occur in other conditions including autoimmune diseases (eg, Sjogren disease, lupus erythematosus, neuromyelitis optica, associated with aquaporin 4 (AQP4) antibody, acute disseminated encephalomyelitis (ADEM), and myelin oligodendrocyte glycoprotein [MOG] antibody-associated disease), infectious diseases (eg, HIV), malignancy (eg, renal cell carcinoma), related to drugs (eg, fingolimod, tacrolimus), and postinfectious conditions (eg, acute disseminated encephalomyelitis, acute hemorrhage leukoencephalitis). These are beyond the scope of this article.
Tumefactive demyelinating lesions. 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. By MRI these can appear as a solitary large lesion or multiple lesions with variable contrast enhancement. These lesions may occur in prototypic multiple sclerosis, other causes of demyelination associated with infection, postinfection or autoimmune causes, 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 (44), the majority were determined to have multiple sclerosis. When tumefactive lesions occur in prototypic multiple sclerosis, it is most often at initial presentation.
Disease-modifying therapy-associated tumefactive demyelination. There are growing numbers of reports of tumefactive demyelination in association with multiple sclerosis disease-modifying therapies, including alemtuzumab, natalizumab, and fingolimod. At least 20 cases of tumefactive demyelination associated with fingolimod have been reported (13; 31; 26; 59; 28; 78). These events have been reported to occur directly after drug initiation, 13 months into treatment (78), and shortly after discontinuation of fingolimod (65; 24). Although a causal link has not been proven, the association is striking. A few of these cases occurred in the setting of transitioning a patient from natalizumab to fingolimod (13; 31). There is 1 published case with biopsy of the tumefactive lesion, which showed typical pathologic changes associated with demyelination in multiple sclerosis (28). As has been reported by other authors—and we are in agreement—this likely represents a unique phenomenon and is not simply emergence of underlying highly active multiple sclerosis (28). Several disease-modifying therapies for multiple sclerosis, including interferon-beta and natalizumab, worsen neuromyelitis optica and cause tumefactive demyelinating lesions in patients with neuromyelitis optica (79). As tumefactive demyelination occurs more commonly as the first demyelinating event and tumefactive lesions have not been reported in association with glatiramer acetate, it is reasonable to hypothesize that an immunologic phenomenon occurring as a result of fingolimod treatment triggers these tumefactive lesions (28).
A single case of tumefactive demyelination associated with natalizumab has been reported in a patient with multiple sclerosis in the setting of discontinuation and early restarting of the medication (08). The patient in this case discontinued natalizumab, then had a relapse of multiple sclerosis without tumefactive lesions, prompting 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 1 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 partially 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 (08).
A case of tumefactive demyelinating lesions have been reported 4 months after initiation of alemtuzumab for relapsing multiple sclerosis (06). Alemtuzumab is thought to prevent multiple sclerosis relapses by targeting CD52, causing rapid and prolonged depletion of lymphocytes. In the patient reported, there was early and disproportionate B-cell reconstitution with little increase in T-lymphocytes leading to dynamic alteration in T/B-lymphocyte ratio. Tumefactive demyelination has also been reported in a case of neuromyelitis optica after the third cycle of annual alemtuzumab infusions (04). Interferon beta can cause exacerbation of demyelination and tumefactive demyelinating lesions in neuromyelitis optica and within the first 6 to 12 months of therapy increases peripheral newly produced B-cells while decreasing T-lymphocytes (87).
One case of tumefactive demyelination has been reported with ocrelizumab in a patient with severe, fulminant disease who developed a tumefactive lesion prior to their third infusion (51). The patient’s pre-infusion CD19 was approximately 0.7%, suggesting only limited reconstitution of B cells. Whether that reconstitution was enough to lead to the exaggerated immune response is unclear. A brain biopsy was consistent with active demyelinating disease. A case of multiple severe tumefactive lesions with onset within 2 days of initiation of rituximab initiation has also been reported (50).
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 (80; 76; 73). There is 1 case report with a favorable response to high-dose cyclophosphamide (55). An additional patient eventually reached long-term disease stability, although with significant disability, after treatment with corticosteroids, cyclophosphamide, plasma exchange, and interferon-beta (80).
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 (05). 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 (34; 27). MRI is characterized by lesions with alternating concentric hyperintense and hypointense rings that may enhance with gadolinium (54). 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.
A retrospective study of 8 patients with lesions typical of Balo concentric sclerosis proposed further subcategorization based on radiological characteristics and response to treatment (81). They identified a group of patients with/without coexisting nonspecific white matter lesions who responded poorly to intravenous methylprednisolone but responded well to cyclophosphamide, a group with typical multiple sclerosis lesions and good response to intravenous methylprednisolone, and a third group with typical multiple sclerosis lesions and a poor response to intravenous methylprednisolone.
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 (25), and the other had multiple sclerosis (37). Balo-like lesions have also been described in patients with progressive multifocal leukoencephalopathy (47), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (15), and a patient with active hepatitis C and CSF positive for human herpes virus 6 (23).
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). As such, very long-chain fatty acid testing must be considered in the evaluation of suspected cases. Schilder disease typically causes large, bilateral, roughly symmetrical demyelinating lesions with progressive enlargement that ultimately interfere with motor function, speech, personality, hearing, and vision and autonomic functions. In 1986, Poser and colleagues proposed criteria for this diagnosis (62). It may be difficult to distinguish Schilder disease from acute or subacute fulminant multiple sclerosis.
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