Tumefactive Acute Disseminated Encephalomyelitis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.279688
Source of Support: None, Conflict of Interest: None
Keywords: Acute disseminated encephalomyelitis, demyelination, differential, multiple sclerosis, tumefactive
Key Messages: Demyelinating disease of the brain and spinal cord may present with tumefactive or pseudotumoral lesions upon neuroimaging. Neuroimaging may reveal distributed hyperintensities throughout the white matter of the brain and spinal cord. These lesions may occasionally be tumefactive giving the faux appearance of malignant tumors. Acute presentation in the context of recent viral infection or vaccination, absence of oligoclonal bands in the cerebrospinal fluid, monophasic disease course, and persistent absence of recurrence, compositely favor a diagnosis of acute disseminated encephalomyelitis over neoplasia and an initial attack of multiple sclerosis. Corticosteroid remains the main stay of therapy. The neuroimaging pattern and the distinguishing clinical features of acute disseminated encephalomyelitis sharpens the diagnostic armamentarium and therapeutic capacity of the treating neurosurgeon or neurologist.
Primary acquired demyelinating diseases of the central nervous system are broadly categorized into acute disseminated encephalomyelitis (ADEM) and its hemorrhagic variant (acute hemorrhagic leukoencephalitis, also known as Weston-Hurst variant); multiple sclerosis and its variants (Marburg variant, balo-concentric variant, and Schilder's disease); and neuromyelitis optica. Tumefactive demyelination is a phenomenon originally described for multiple sclerosis, with characteristically solitary lesions >2 cm in diameter, exhibiting the appearance of CNS tumors.
While originally and most commonly described for multiple sclerosis, tumefactive demyelination has additionally been reported, though with exceeding rarity, in nine cases of ADEM within the past decade.,,,, ADEM occurs with an incidence of approximately 0.8 per 100,000 individuals per year and affects infants and adults. Incidence following vaccination is 0.2 in 100,000. Pathophysiology of ADEM involves autoimmune demyelination and is likely attributable to T-cell hypersensitivity, though remains to be thoroughly understood.,,
We searched the PubMed database for cases of acute disseminated encephalomyelitis with tumefactive demyelination.
Nine cases of tumefactive ADEM have been reported in the literature across five reports. Four of these cases were not attributed to a specific etiology, whereas the remaining patients developed tumefactive ADEM in the context of HIV (n = 3), H1N1 influenza virus infection (n = 1), and following the HPV vaccination (n = 1). Presentations included headache, vertigo, altered mental status, focal neurologic deficits (weakness, visual field cuts, and aphasia), and seizures. Diagnosis was made on clinicoradiological grounds in most patients and confirmed with biopsy in a few individuals. Most patients responded well to treatment with corticosteroids, though one patient expired. Tumefactive ADEM was monophasic in most patients, but a multiphasic course was described in two of three HIV patients with tumefactive ADEM.
Tumefactive ADEM cases with undetermined etiology
Pradhan and colleagues reported on a series of three patients with tumefactive ADEM. The first patient was a 35-year-old lady who originally presented with left-sided paresthesias and mild weakness (UE and LE 4/5). Magnetic resonance imaging (MRI) revealed a lesion predominantly in the right frontal lobe, extending across the corpus callosum into the left frontal lobe, exhibiting the appearance of a butterfly glioma. Corticosteroids effected clinical improvement. Interestingly, a biopsy revealed active demyelination, with evidence of glial and foam cell infiltration. The patient had near complete resolution of her lesion at 3 year follow-up and remained without recurrence at 6-year follow-up, though continued to experience neuropathic pain. The diagnosis of tumefactive ADEM was strongly supported, given response to corticosteroids, demyelination on biopsy, and absence of recurrence on long-term follow-up.
The second patient was a 37-year old female presenting with expressive aphasia contemporaneously with altered mental status over the course of several days. MRI revealed a T1 hypointense and T2 hyperintense left posterior frontal lesion, with minimal peripheral contrast enhancement, without mass effect, midline shift, or restricted diffusion. Magnetic resonance spectroscopy (MRS) revealed increased choline and decreased creatinine and N-acetyl aspartate peaks. The patient exhibited gradual spontaneous convalescence and was subsequently started on a steroid taper. The patient's expressive speech deficits completely resolved at 2-month follow-up, with contemporaneous radiographic resolution of her frontal lesion. Given clinicoradiological improvement with steroids and non-recurrence, the diagnosis of tumefactive ADEM was supported.
The third patient was a 33-year-old, who presented with acute headache, vertigo, and altered mental status, having just recently convalesced from an upper respiratory tract infection. Neurologic examination was remarkable for generalized hyperreflexia. MRI revealed a T2/FLAIR hyperintense, T1 hypointense, minimally enhancing left occipital lobe lesion causing obliteration of the left occipital horn, with minimal mass effect and no restricted diffusion. Magnetic resonance angiography and venography were negative for vascular disease. A presumptive diagnosis of tumefactive ADEM prompted initiation of high-dose intravenous methylprednisolone therapy followed by an 8 week steroid taper. The patient's altered mental status improved rapidly and follow-up imaging at 3 months revealed complete resolution of the patient's lesion.
Koshihara and colleagues reported on a 51-year-old lady who presented with headache, gradually worsening aphasia, and hemiparesis, without a recent history of vaccination or known infection. MRI revealed multifocal non-enhancing lesions in the subcortical white matter of the left temporal and parietal lobes, along with confluent areas representing demyelination in the periphery of the brainstem. Cerebrospinal fluid (CSF) examination demonstrated atypical lymphocytes and absence of oligoclonal bands. Single photon emission computed tomography (SPECT) revealed left temporoparietal hypoperfusion. Electroencephalography (EEG) showed focal slow wave activities over the right frontotemporal convexity. The patient's language deficits evolved to a global aphasia following admission. Right hemiparesis was evident and the patient developed focal motor seizures with involvement of the face.
Left temporal biopsy revealed findings overlapping between ADEM and early stage multiple sclerosis, including meningeal infiltration by B and T lymphocytes, subpial and perivenular demyelination (characteristic of ADEM), and areas of plaque-like confluent demyelinative foci (characteristic of multiple sclerosis). Treatment with high-dose intravenous methylprednisolone was followed by a prednisolone taper and effected an excellent clinical and radiological response. Although the patient had returned to her neurological baseline by 2-month follow-up, she had persistence of mild word finding difficulties and no recurrence on 6 year follow-up.
Tumefactive ADEM in patients with HIV
In addition to precipitation by vaccination or infection, ADEM may also occur in immunocompromised patients. Naidoo and colleagues reported on a series of seven HIV-infected patients who developed atypical ADEM. Four of these patients had an uncharacteristically multiphasic illness, distinct from the typical monophasic disease course experienced by otherwise immunocompetent patients. Three patients exhibited tumefactive lesions, which while not uncommon in the acute demyelination of multiple sclerosis, is very uncommon in ADEM, with only a few case reports of this. Thus, tumefactive ADEM accounted for greater than two-fifths of cases in this series. Two of the patients had corpus callosum lesions. Atypical course (cases with multiple recurrences, tumefactive lesions) is attributed by the authors to moderate T-cell immunosuppression (CD4 200-500).
Tumefactive ADEM in a patient with H1N1 influenza virus
In April of 2009, an outbreak of H1N1 influenza occurred in Mexico, causing high mortality in young patients, frequently effecting pneumonia and acute respiratory distress syndrome. The H1N1 influenza virus has been described to cause a variety of neurological sequelae in afflicted patients.,,
Chan and colleagues described a 21-year-old female, who had a history of diplegic cerebral palsy and epilepsy who presented with acute fever, cough, and respiratory distress. After unremarkable chest roentgenography and testing negative for both influenza A and B, the patient was treated with amoxicillin/clavulanic acid and developed a complicated disease course. She developed generalized tonic clonic seizures, followed by oximetry desaturation requiring intubation and intensive care. Computed tomography of the brain revealed multiple patchy hypodensities in the gray-white matter junction, as well as the white matter of the frontal, parietal, and temporal lobes bilaterally.
Bronchoalveolar lavage was positive for H1N1 influenza. The patient was treated with oseltamivir and piperacillin-tazobactam but remained comatose. On physical exam, the patient had an absent response to deep pain, exhibited wandering eyes with tonic pupils, and sluggish pupillary light reactivity. Oculocephalic reflexes were not elicitable. Limbs were hypotonic and areflexic. Inflammatory markers were elevated and the influenza A virus titers increased significantly over 10 days (from 10:1 to 640:1). EEG revealed alpha coma pattern along with intermittent generalized slow waves. Periodic lateralizing epileptiform discharges with a frequency of 1 cycle/s were recorded over the right frontocentral region lasting 4 to 5 s. The patient had high CSF opening pressure but no oligoclonal bands and a negative Gram stain. MRI of the brain and cervicothoracic spine revealed multiple lesions, with the largest ~3 cm in diameter, throughout the cerebral white matter, medulla, and spinal cord, with the cervical cord most extensively involved and lesions herein extended rostrally into the medulla [Figure 1]. The lesions were hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging. A diagnosis of tumefactive ADEM was favored and no biopsy was performed. The patient was treated with methylprednisolone and intravenous immunoglobulin without neurological improvement.
Tumefactive ADEM following HPV vaccination
Mendoza Plasencia and colleagues reported on a 17-year-old lady who had recently received her first dose of the HPV Gardasil vaccine 2 months prior and the second dose 15 days prior to presenting with visual deficits. Examination revealed homonymous hemianopsia. Viral serologies were negative and a full panel of autoimmune antibodies revealed positivity for antinuclear antibody at a titer of 80:1. CSF was negative for oligoclonal bands. MRI revealed minimally peripherally-enhancing tumefactive lesions in the occipitotemporal and parietal posterosuperior regions. The patient was treated with high dose intravenous methylprednisolone followed by a prednisone taper, effecting rapid resolution of neurologic deficits and radiographic resolution at 2 month follow-up.
There had been one previous case of ADEM in a 15-year-old following her second dose of Gardasil. The diagnosis was presumed and confirmed clinically, by imaging, rapid resolution, and a monophasic course; no biopsy was performed. Thus, only two cases of ADEM following Gardasil vaccine administration have been reported in the literature.
Although no neurological deficits were reported when the HPV vaccine was originally marketed, since then, there have been reports of the vaccine precipitating Guillain-barre syndrome (Vaccine Adverse Event Reporting System, CDC), optic neuritis, and multifocal myelitis with spinal and cerebral symptoms. Neurological deficits secondary to HPV vaccination have responded well to treatment with methylprednisolone.
The spectrum of clinical presentations for ADEM includes focal neurologic deficits, optic neuritis, seizures, and/or altered mental status. It is characteristically a monophasic illness, with recurrence occurring in only 5–10% of patients, with excellent response to treatment with corticosteroids, and full clinicoradiologic resolution in the majority of patients. A diagnosis of tumefactive ADEM is supported by imaging findings characteristic of acute demyelinating disease and confirmed with biopsy (see below).
The differential diagnosis for tumefactive ADEM includes CNS lymphomas and other neoplasias, systemic lupus erythematosus, CNS vasculitis, multiple sclerosis, and vascular, toxic, or infectious leukoencephalopathies. ADEM presents acutely, whereas the other diagnoses present subacutely or, more commonly, as chronic conditions. Although multiple sclerosis may be distinguished from ADEM by the presence of lesions disseminated in time and the presence of oligoclonal bands in CSF, the distinction between a first attack of multiple sclerosis and ADEM may be difficult to make on clinical grounds alone, especially during the early course.
There are two distinctions to make when presented with a lesion whose differential includes tumefactive acute demyelinating disease. The first is to distinguish between tumefactive acute demyelinating disease and tumor. The second is to distinguish between tumefactive multiple sclerosis, for which this lesion was originally and is most commonly described, and tumefactive ADEM, of which there have only been a few cases. To guide initial therapy, only the former distinction is critical, as any acute demyelinating disease will respond readily to high-dose intravenous corticosteroids, whether the etiology is multiple sclerosis or ADEM. The latter distinction, however, becomes important in terms of the patient's long-term prognosis and predicting likelihood of recurrent attacks. ADEM is typically a monophasic illness following a vaccination or infection, with a latency of 2 to 30 days., However, recurrences have been reported, but these are typically limited to a single recurrence.
Tumefactive ADEM versus tumefactive multiple sclerosis
The clinical presentations of tumefactive multiple sclerosis and tumefactive ADEM exhibit overlap and include focal neurologic deficits, seizures, and symptoms attributable to cortical dysfunction. Although altered mental status and/or encephalopathy favor a diagnosis of ADEM, these may also occur in a first attack of multiple sclerosis.,, Patients with either tumefactive ADEM or tumefactive multiple sclerosis respond well to corticosteroids and this is not a differentiating feature. Among patients presenting with tumefactive multiple sclerosis, approximately 70% will relapse. Thus, the absence of relapse more strongly supports a diagnosis of ADEM, and the greater duration the patient remains without recurrence, the more likely the diagnosis represents an attack of ADEM and not MS, though, ADEM occasionally recurs.
The distinction between tumefactive ADEM and tumefactive MS (or ADEM versus MS, in general) can be made more definitively by biopsy during the first attack, though this is not always definitive, with mixed histopathologic findings of both entities often confounding the diagnosis. Biopsy reveals confluent areas of demyelination, but does not distinguish typical from tumefactive multiple sclerosis plaques; perivenular demyelination is characteristic and favors a diagnosis of ADEM (see below).
Tumefactive acute demyelinating disease versus neoplasia
Magnetic resonance imaging and spectroscopy may successfully differentiate between tumefactive demyelinating disease from brain tumors, obviating the need to perform biopsy (see below). Alternatively, in the proper clinical context, a presumptive diagnosis can be made on clinical grounds and the response to a therapeutic trial of steroids used to support, ascertain, or confirm tumefactive acute demyelinating disease. However, resolution of symptoms in CNS tumors can also be effected by treatment with corticosteroids, especially in tumors predominantly causing symptoms by virtue of vasogenic edema. Thus, thorough review of the clinical history, disease progression, and response to therapy is crucial if a diagnosis of tumefactive acute demyelinating disease is to be pursued as principal and leading in the differential, without a biopsy. Pradhan and colleagues were able to support a diagnosis of tumefactive ADEM without a biopsy in two of their three patients. The rapid response to corticosteroid treatment, complete lesion resolution, and non-recurrence were critical elements in supporting and, over time, confirming the diagnosis of tumefactive ADEM.
MRI features favoring a diagnosis of tumefactive demyelinating disease include a solitary white matter lesion that is irregular, typically causing diminutive mass effect, vasogenic edema, and/or midline shift. Tumefactive demyelinating lesions usually involve the supratentorial white matter, though involvement of the infratentorial white matter and/or spinal cord and extension to involve gray matter may also occur. Cortical and/or subcortical involvement with periventricular sparing favors a diagnosis of ADEM over multiple sclerosis.,,,,, Moreover, a curious pattern of open ring enhancement is observed in ADEM, with the ring toward the white matter and the ring opening facing the gray matter. The enhancing portion represents the leading edge of active demyelination. The non-enhancing core represents the transition from acute to chronic inflammation.
Tumefactive demyelinating lesions characteristically exhibit low cerebral blood volume on perfusion studies and venules can be seen traversing the lesion on T2-weighted sequences.,, Although the presence of other lesions in the white matter typically favors demyelinating disease, multicentric glioma and gliomatosis cerebri can present in similar fashion. In contrast, CNS tumors tend to be heterogenous lesions with central necrosis and heterogeneous enhancement, often involve the gray-white matter junction and/or gray matter, and may cause significant mass effect, vasogenic edema, and/or midline shift.
MRS is of great utility in distinguishing CNS neoplasia from acute demyelination. MRS typically reveals increased peaks of choline, lipid, and lactate and a decreased peak for N-acetyl aspartate. Acute demyelination is also favored by an increase in the glutamine/glutamate ratio, which is not typically manifest in gliomatous tissue. A diagnosis of brain tumor is favored by an increase in the choline peak and a decrease in the N-acetyl aspartate/creatinine ratio.
A definitive diagnosis of ADEM is established only by biopsy. Lesions may be bilateral, are typically not symmetric, and may involve the supratentorial cerebral white matter, posterior fossa (brainstem and cerebellum), or spinal cord. The myelin sheath appears to be the principal target of immune reaction in these patients. ADEM is characterized by a unique perivenular lymphocytic infiltration (composed of macrophages, lymphocytes, and plasma cells) with absence of periarteriolar inflammation. As a pathoclinical correlation, the presence of perivenular demyelination characteristically correlates with a monophasic meningoencephalitic clinical course. Among 13 patients with perivenular demyelination, three with contemporaneous plaque-like areas of demyelination relapsed. Other histopathologic features include small perivascular hemorrhages, fragmentation of axons, and leptomeningeal inflammatory cell infiltration, along with occasional subpial demyelination evident in the brainstem and/or spinal cord [Figure 2].
A diagnosis of tumefactive acute demyelination is favored over brain tumor by histopathologic preservation of axons, evidenced by the presence of neurofilaments, and loss of myelin, signified by negative Lugol's staining. Demyelination is also characterized by CD68 positivity, indicating macrophage infiltration, and Glial fibrillary acidic protein (GFAP) positivity, consequent to astrocytic proliferation. In contrast, histopathologic findings in CNS neoplasia include typical features of nuclear atypia and pleomorphism, cellular hyperproliferation, mitoses, necrosis, endothelial proliferation, and/or the presence of characteristic rosettes or pseudorosettes.
Although ADEM is distinguished histopathologically from multiple sclerosis by the presence of perivenular demyelination in the former and confluent areas of demyelination in the latter, cases with histopathologic overlap exist.,, Mixed histopathologic findings are not uncommon, with a previously reported case of hybrid MS-like and ADEM-like lesions. B and T cell leptomeningeal infiltration observed in Koshihara and colleagues' case is similar to that described previously in a patient with multiple sclerosis and cortical demyelination with secondary progressive multiple sclerosis. Meningeal inflammation has been previously reported in cases of multiple sclerosis.,,,
The treatment paradigm in patients with ADEM typically involves high-dose intravenous corticosteroids followed by a steroid taper. Treatment with corticosteroids decreases the duration of symptoms and halts progression of demyelination and worsening of clinical symptomatology., Most patients achieve a full recovery (~80%) and disease course is monophasic in 90–95% of individuals. Recurrence is rare and usually singular. More frequent recurrence suggests a diagnosis of multiple sclerosis or multiphasic disseminated encephalomyelitis. A third of patients do not respond to steroids,, and approximately, half of these individuals will improve with intravenous immunoglobulin therapy. Cyclophosphamide may be used in patients at high risk for relapse. Immunomodulators hold promise for use in the future for individuals afflicted with ADEM.
Tumefactive demyelination is an exceedingly rare phenomenon in patients with ADEM. Although the diagnosis can be made on clinical and radiological grounds alone, distinguishing it from a first attack of multiple sclerosis may be challenging. Biopsy is typically definitive and confirmatory, revealing perivenular inflammatory cell infiltration and demyelination, in contrast, to confluent plaque-like areas of demyelination in multiple sclerosis. Patients with tumefactive ADEM typically exhibit an excellent response to corticosteroids, and the disease is typically monophasic.
M.G.Z.G.: conception and design, acquisition of data, analysis and interpretation of data, drafting article, and revising critically for intellectual content; approval of final version of manuscript.
Compliance with ethical standards.
All procedures performed in the studies involving human participants were in accordance with the ethical standard committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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There are no conflicts of interest.
[Figure 1], [Figure 2]