Demyelinating lesions resembling cerebral tumours have been described since the 1970s and 1980s, and differential diagnosis in these cases required a brain biopsy.3,4 In 1993, Kepes reported on 31 patients, 24 with solitary lesions and seven with multifocal lesions.5 These lesions resembled tumours, abscesses, neurocysticercosis cysts, gliomas, or metastasis. All patients underwent cerebral biopsy. This type of demyelinating disease was called tumour-like or swollen demyelination because of its appearance on MRI images. Kepes initially interpreted these lesions as an intermediate disorder between MS and ADEM. Some authors now classify them as MS variants, since clinical symptoms and radiological findings of Charcot MS appear in some cases. Lesions in other cases, however, are isolated, follow a monophasic course, and resolve completely. As a result, experts are not in full agreement as to the nature of the disease. The 31 patients included in the study by Kepes5 can be considered ‘index cases’, and we therefore propose calling them ‘Kepes FTDL’, in honour of this leading neuropathologist who died in February 2010.6 Lucchinetti et al.7 subsequently described the largest series of which we are aware: 168 patients with histopathologically confirmed demyelinating lesions larger than 2cm.

Histological studies of these lesions showed chronic perivascular inflammatory infiltrates, macrophages containing myelin degradation products, reactive astrocytes, demyelinating lesions with clearly defined margins, and relative axon preservation (Fig. 1). An acute demyelinating process can mimic a malignant glioma, which can contain pleomorphic astrocytes including Creutzfeldt cells. The pathological patterns of demyelinating disorders include features that made them difficult to distinguish from gliomas,8 such as pleomorphic astrocytes, hypercellularity, necrosis, mitotic figures, and cyst-like changes. These pleomorphic astrocytes, including multinucleated or Creutzfeldt cells, may be highly noticeable in active plaques, especially near the edge. They tend to display a homogeneous distribution pattern opposite to that seen in gliomas, in which cells tend to agglomerate. In contrast with neoplastic astrocytes, reactive astrocytes are not characterised by a hyperchromatic nucleus. Meanwhile, macrophages may be mistaken for astrocytes or oligodendroglia and are also indicative of infiltrative tumour growth. Diagnosis therefore requires immunohistochemical stains that affect macrophages (anti-HAM 56 or CD68, for example), together with myelin staining to evidence the demyelinating process (Fig. 1).

Figure 1.

A 38-year-old man with symptoms of headache and vertigo. MRI revealed multiple right frontal and temporal lesions, lesions on basal ganglia, periventricular lesions, lesions on corpus callosum, and optic radiation. Central hyperintensity with a cyst-like appearance and gadolinium-enhanced rim was observed on T2-weighted images. Results from the neurological examination were normal. Biopsy was evaluated by Dr Kepes (Kansas) and Dr Toro (Bogotá): (a) H&E stain showing a vessel surrounded by leukocytes, surrounded in turn by foamy macrophages. (b) Small benign gemistocytic astrocytes. (c) Bielschowsky silver stain that shows areas of myelin loss and a significant number of preserved axons. (d) Weil and Weigert stain showing almost total myelin loss. Findings were compatible with demyelinating disease. The patient was monitored for 15 years, and displayed an excellent response to interferon treatment.

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Biological and clinical findings from these patients differ from those of patients with acute fulminant multiple sclerosis (Marburg type)9 and Schilder disease.10–12 The report describes clear differences in the course of the disease. Most patients in the Kepes et al. series presented a monophasic course, but lesions may also be recurrent.5 The clinical course of monophasic lesions may be caused by the relative axonal integrity present here, in contrast with the pronounced axonal loss that occurs in chronic MS. In the series by Lucchinetti et al. 70% of the patients developed recurrent lesions.7 Definitive diagnosis of MS according to McDonald criteria was assigned after a median follow-up of 3.9 years, and median time to second exacerbation of 4.8 years.

Diagnosis of this type of demyelinating lesion initially required a brain biopsy but thanks to the advances in CT and MRI techniques, biopsies are becoming less frequent. We now describe the neuroimaging sequences that are useful for diagnosing this type of lesions.

Simple CT is useful in differential diagnosis of gliomas when compared to MRI results, since the rim observed in contrast-enhanced T1-weighted sequences is isointense, unlike the hypodense ring observed on CT in demyelinating lesions. This rim is sometimes not discernible by CT imaging but appears in T2 and contrast-enhanced T1 MR images.13 Contrast-enhanced CT sometimes shows an incomplete rim similar to that observed using MRI, as described below.14

Conventional MRI sequences show large single or multifocal lesions usually evidencing no mass effect, no cortical involvement, and little oedema. Oedema, together with incomplete rim on gadolinium-enhanced T1-weighted MRI sequences, has a P value of <.05.13 Contrast-enhanced areas indicate active demyelinating lesions affecting the white matter. In the case of tumour-like lesions or abscesses, the rim is generally complete.15 Detecting other typical MS demyelinating lesions in the brain or cervical spinal cord may also aid differential diagnosis.14 Another technique is dynamic T2*-weighted gradient-echo imaging, which is performed during IV administration of the contrast agent. These images show vessel-like structures running from the centre of the lesion towards a subependymal vein that is usually dilated.16 The diagnostic accuracy of CT plus MR imaging is 97%, compared to 73.0% for MR imaging alone (P=.001).13

Advanced MRI techniques are equally useful in the differential diagnosis of these lesions. MR spectroscopy reveals a depressed peak for N-acetyl aspartate (NAA), which indicates neuronal death. There are also elevated choline (CHO) and lipid (LIP) peaks, which are consistent with cell membrane rupture; and elevated lactate (LAC), probably due to activated macrophages or ischaemia secondary to an acute inflammatory process.17,18 Nevertheless, these findings are highly non-specific and their validity is therefore limited, leading some authors to conclude that spectroscopy cannot be used to distinguish between neoplasm and demyelinating lesions.19 However, once the demyelinating process becomes chronic, CHO, LIP, and LAC peaks normalise and the NAA peak remains persistently low. On the contrary, in cases of neoplasm, metabolites remain altered; some authors recommend starting anti-inflammatory treatment and performing follow-up spectroscopy to distinguish between the 2 processes when the diagnosis is unclear.17 Cianfoni et al.20 also reported an interesting finding in short echo time MR spectroscopy. They observed marked elevation of glutamate and glutamine peaks, which is not typically seen in intra-axial neoplastic processes; this was thought to be secondary to an astrocyte reaction (Fig. 2).

Figure 2.

A 12-year-old girl with no relevant medical history presented acute vision loss in the right eye (RE) that was not treated. Four months later, she experienced aphasia and right hemiparesis. This figure shows some of the brain MR images that were ordered: above, axial T2-weighted images and axial Fluid Attenuation Inversion Recovery (FLAIR) images. We observe a right frontal lesion that is hyperintense in T2-weighted images and hypointense in T1-weighted images. FLAIR sequence shows adjacent vasogenic oedema and slight mass effect on the midline and ventricular system. Images suggesting vessel-like structures were obtained from the inside of the lesion. Below: brain perfusion image showing decreased enhancement and MRI spectroscopy that shows an elevated choline peak at 3.23ppm (indicative of gliolysis and remyelination processes), a decreased NAA peak at 2.05ppm (indicative of neuronal/axonal injury), and glutamate and glutamine peak of 2.4–2.5ppm. These findings were compatible with tumour-like demyelinating disease. Histopathological findings from the brain biopsy were consistent with FTDL. Doctors started a 5-day course of treatment with methylprednisolone, followed by one cycle of plasmapheresis. Clinical response was excellent. The patient completely regained her strength on the right side of the body and her ability to speak, but optic atrophy of the RE remained. After one year of follow-up, no relapses have been reported.

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Perfusion MRI techniques are also very useful in differential diagnosis of neoplastic and demyelinating processes. In neoplastic processes (both gliomas and CNS lymphomas), regional cerebral blood volume (rCBV) is markedly elevated and mean transit time (MTT) is decreased due to angiogenesis. In demyelinating lesions, however, rCBV is not elevated and may in fact be low, whereas MTT will be elevated (Fig. 2).14,16

A case of tumefactive demyelinating lesion due to tacrolimus neurotoxicity was recently reported.21 The patient had received a liver transplant for hepatocellular carcinoma. The potential mechanism for demyelination is mediated by immunity due to a supposed increase in T-cell activation. There have been numerous cases of other types of demyelination without a defined relationship, including a case of optic neuritis triggered by a Plasmodium falciparum infection.22 These reports illustrate the lack of knowledge of these diseases and the variability of probable factors eliciting demyelination.

We should stress that no results have a level of evidence sufficient for drawing up management guidelines, considering the low prevalence rates of these types of demyelination compared to MS.

There are both similarities and differences between treatment for MS and for these acute focal demyelinating lesions. As first-line treatment, an IV bolus of methylprednisolone dosed at 1g/day for 3 to 5 days should be administered. Episodes of acute CNS demyelination are considered refractory to corticosteroids if no improvement of at least one point on the extended disability status scale is observed in the 7 days after finishing steroid treatment.23 Weinshenker et al.24 propose the following criteria to start plasmapheresis: minimum duration of deficit 21 days from onset and 14 days from the onset of IV steroid therapy, or 12 days from onset if the deficit continues to worsen beyond 5 full days after starting steroid treatment. If any one of these criteria is met, plasmapheresis should be considered as second-line treatment. Some particularities of this type of therapy should be made clear. The proposed action mechanism of plasmapheresis for these diseases involves extraction of plasma and humoral factors in pathogenesis. This means that plasmapheresis could be beneficial in treating disorders mediated by the humoral system, such as ADEM, neuromyelitis optica,25,26 and MS with demyelinating pattern II as proposed by Lucchinetti27 (characterised by immunoglobulin and activated complement deposits). A small clinical trial of this therapy in 10 patients with pattern II found moderate to marked improvement;28 some authors suggest that the same type of damage is observed in Marburg type MS.29,30 Baló disease, which follows demyelination pattern III27 and whose pathogenesis does not involve humoral factors, was also treated in that clinical trial. No response to plasmapheresis treatment was reported in the six patients with that pattern.28 Three studies evaluate predictors of good response to treatment in demyelinating disorders.26,31,32 The most commonly listed factors with statistical validity are early treatment, short disease duration, preserved deep tendon reflexes, retrospective diagnosis of MS, and rim-enhancing lesion on MRI.

The next step is less clear since there have been only anecdotal reports of cases refractory to steroid treatment and plasmapheresis in which long-term treatments including interferons, cyclophosphamide,33–36 and mitoxantrone37 were administered, together with support treatment for complications typical of this severe and extensive involvement, such as intracranial hypertension.