Monofocal acute inflammatory demyelination (MAID): a unique disorder simulating brain neoplasm.

ABSTRACT

Background. Monofocal acute inflammatory demyelinating (MAID) lesions present as large masses that mimic brain tumors. The natural history and nosologic classification are not well defined.

Methods. Five patients with MAID from our files and 4 from the literature are presented. We defined MAID as a mass-like lesion, >4 cm in diameter. Demyelination was pathologically proven in all patients.

Results. Headaches and motor deficits were the most common presenting symptoms. Language problems and motor deficits were the most common findings on physical examination. After a median follow-up of 44 months, none of our 5 patients had multiple sclerosis. In similar cases, additional lesions indicative of multiple sclerosis developed within an average of 8 months.

Conclusions. It may be difficult to distinguish MAID from brain tumor. It may be that MAID represents a unique form of isolated demyelinating disease, or it may represent transition to multiple sclerosis.

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MONOFOCAL acute inflammatory demyelination (MAID) is a rare and unique central nervous system (CNS) demyelinating disorder affecting the cerebral hemispheres. Magnetic resonance imaging (MRI) shows a single, large, monofocal, contrast-enhancing lesion with associated edema and mass effect. A brain tumor is the usual initial clinical and radiologic diagnostic impression in these patients, whose presenting symptoms include acute onset of hemiplegia, hemisensory complaints, seizures, aphasia, visual field deficits, and, rarely, an alteration in the level of consciousness. These symptoms are atypical for multiple sclerosis (MS) (1,2); however, brain biopsy shows typical findings of demyelination.

Common examples of other monofocal demyelinating processes include acute transverse myelitis and isolated optic neuritis. In both of these forms of demyelinating disease, as well as in some instances of MAID, multiple sclerosis may subsequently develop; however, each of these forms of demyelination may remain an isolated event, without other demyelinating lesions developing to indicate multiple sclerosis, despite long follow-up periods. Multiple sclerosis, the prototypical CNS inflammatory demyelinating disease, is a multifocal illness, typically showing a relapsing-remitting temporal profile. Rarer forms of CNS demyelinating disease include those occurring as monophasic autoimmune disorders, often triggered by an infectious illness or vaccination (eg, acute disseminated encephalomyelitis [ADEM] and acute hemorrhagic leukoencephalitis). Other CNS demyelinating diseases occur as a consequence of infection of the CNS (eg, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, and progr essive rubella panencephalitis).

Monofocal acute inflammatory demyelination often presents clinical dilemmas that may lead to incorrect or delayed diagnosis and treatment. Care must be taken not to assume that these patients have a neoplastic process. Brain biopsy may be necessary to establish the demyelinating character of these mass lesions. Pathologic interpretation of frozen sections obtained at the time of biopsy may not be sufficiently characteristic to distinguish MAID from a primary brain tumor, and definitive diagnosis should await the results of appropriate histopathologic examination. These lesions may reveal hypercellularity and the presence of atypical reactive astrocytes with mitotic figures, which may be observed in these demyelinating lesions and be mistaken for an astrocytic neoplasm. (3) Significant inflammatory infiltrates are not always present. (4) Special stains that show myelin loss and relative preservation of axons are required to make the correct diagnosis. (3)

To clarify the clinical, diagnostic, therapeutic, prognostic, and nosologic implications of a MAID diagnosis, 9 patients, collected from the authors' files and the English medical literature, are presented.

PATIENTS AND METHODS

Monofocal acute inflammatory demyelination is defined by neuroradiologic criteria as an acute, large lesion of the CNS caused by demyelination. For this report, a diameter of >4 cm was chosen to exclude the typical multiple sclerosis plaques. The MRI is suggestive of a mass lesion because of edema, contrast enhancement, and shift of adjacent structures. (5-7) Records of 5 patients with biopsy-proven MAID from the files of the neurology departments at Lahey Clinic Medical Center in Burlington, Mass, and the University of Kentucky in Lexington were reviewed. Other relevant cases reported since 1966 were selected from the neurology literature by searching the National Library of Medicine (Washington, DC) Medlar database. Key words used in the search included diagnosis, radiography, multiple sclerosis, mass lesion, acute disseminated encephalomyelitis, acute postinfectious encephalomyelitis, and postvaccinial encephalomyelitis. Only the English language reports were reviewed for this study. Patients younger than age 18 years, those with previous CNS symptoms, those with multiple lesions on MRI, and those not documented as having had brain MRI were excluded from this analysis. Those patients with pathologically proven Balo's disease, in which the MRI showed the typical concentric lamellar demyelination, (8-11) or Marburg's disease with single (12) or multiple demyelinating lesions (13,14) were also excluded, as were those cases reported in reviews (7,15,16) of patients with MAID presented only in a tabular form.

CASE REPORTS

Case 1. A 48-year-old man in good health had mild speech difficulty for 2 weeks. He had minimal dysphasia, but neurologic examination was otherwise normal. Cranial MRI revealed a large, contrast-enhancing, left frontal mass lesion with surrounding signal abnormality (Fig 1A, 1B, and 1C). Repeated MRI 3 weeks later showed possible enlargement of the original lesion. Cerebral angiography was normal. Stereotactic brain biopsy showed loss of myelin with preserved axons, perivascular macrophage infiltrates, and reactive astrocytosis, compatible with a demyelinating process. Follow-up MRI 6 weeks after a short course of orally administered dexamethasone showed considerable improvement (Fig 1D). The patient has had no neurologic problems in the past 7 years.

Case 2. A 48-year-old woman with treated hypertension had right leg weakness in 1996. She had no previous neurologic symptoms, but her sister had had an "MS attack." Neurologic examination revealed severe right leg weakness with hyperreflexia, ankle clonus, and a questionable plantar response. An MRI of the brain showed a large, focal, gadolinium-enhancing, left frontal mass lesion, suggesting glioblastoma multiforme. Stereotactic biopsy of the lesion revealed demyelination with sparing of axons, sparse perivascular lymphocytic infiltration, numerous macrophages, and reactive astrocytes. The right leg returned to normal after the patient received a short course of methylprednisolone. Follow-up MRI 6 months later revealed almost complete resolution of the mass-like lesion. The patient has remained asymptomatic for more than 4 years.

Case 3. A 50-year-old man with hypertension had increasingly severe headaches and speech difficulties after a flu-like syndrome in early 1996. Neurologic examination revealed expressive aphasia. An MRI of the brain showed a large, left temporal, ring-enhancing mass with moderate mass effect and an 11-mm midline shift, compatible with a glioma. Biopsy showed typical findings of demyelination. Headaches resolved promptly with dexamethasone therapy, and within 2 months his neurologic examination was normal. Repeated MRI of the brain showed a decrease in both the size of the lesion and degree of contrast enhancement. The patient is doing well more than 5 years after onset of symptoms.

Case 4. A 62-year-old man reported difficulty recognizing faces, reading, and seeing to his left in December 1996. Neurologic examination showed a dense left homonymous hemianopia. An MRI of the brain revealed a large, right occipitoparietal lesion. Cerebrospinal fluid contained 128 mg/dL of protein, with elevated immunoglobulin C (IgG) at 10.1 mg/dL and elevated IgG synthesis at 8.2 mg/dL. Three months after onset of symptoms, MRI of the brain showed gadolinium enhancement with extension of the edema. Needle biopsy revealed demyelination. No clinical improvement followed dexamethasone therapy, but the MRI 5 months later showed mild improvement. The patient's neurologic condition and MRI abnormality have remained stable for more than 5 years.

Case 5. A 21-year-old woman had 2 brief generalized seizures preceded by right facial tingling in April 1998. In the postictal state, she had a mild expressive aphasia, mild right hemiparesis, and diminished sensation over the right side of the face. An MRI of the brain showed a large, left frontal, partially ring-enhancing, cystic lesion abutting the cortex (Fig 2). Cerebrospinal fluid analysis and evoked potential testing (visual, brain stem auditory, and somatosensory) were normal. Frozen section pathology at the time of brain biopsy suggested a malignant process. Further histopathologic evaluation revealed pervascular lymphocytic cuffing, scattered reactive astrocytosis, and profound myelin loss at the margins. The parenchyma showed tightly packed, lipid-filled macrophages, giving rise to an appearance of hypercellularity. Soon after the operation, the right arm weakness worsened. Repeated MRI revealed a large, gadolinium-enhancing, edematous, circumferential lesion in previously uninvolved brain adjacent to the surgical bed. Despite treatment with parenteral and oral corticosteroids, she had frequent focal seizures involving speech and the right-side extremities during the next 2 months. Cranial MRI showed an expansion of the lesion and surrounding edema. Analysis of the CSF showed 1 white blood cell/[mm.sup.3], normal IgG synthesis rate, normal IgG index, and no oligoclonal bands. Myelin basic protein level was 1.6 ng/mL (normal, 0.0 to 2.3 ng/mL). Treatment with methylprednisolone, 500 mg administered intravenously every 12 hours over 3 days, and intravenous immunoglobulin (IVIG), 400 mg/kg administered over 5 days, resulted in clinical and MRI findings returning to baseline levels over the span of 1 month. Symptomatic worsening followed attempts to discontinue the monthly IVIG until April 1999 (9 months after initiation), when treatment with IVIG and prednisone was discontinued. Repeated physical examination and cranial MM through October 2001 revealed no new findings suggestive of multiple sclerosis. She exhibits mild speech hesitancy and mild right central facial and upper extremity paresis.

RESULTS

We found a total of 9 patients, including 5 from our files (cases 1-5), who fulfilled the MAID selection criteria. (4, 17) Average age at presentation was 37.2 years (median, 31 years; range, 21 to 62 years; SD, 14.9 years). Five of the 9 patients were men. Neurologic symptoms at presentation were headaches in 3 of the 9 patients (33%), motor deficits in 3 (33%), language difficulties in 2 (22%), sensory deficits in 2 (22%), visual field deficits in 2 (22%), psychiatric manifestations in 2 (22%), confusion/memory deficits in 1 (11%), and monocular visual deficits in 1 (11%). Two patients (22%) had generalized seizures as the presenting symptom (1 was of partial origin). Except for the 2 patients who presented solely with seizures, patients had more than one symptom at presentation (Table).

Neurologic examination showed language deficits, the most common finding, in 5 patients (56%), motor deficits in 4 (44%), and visual deficits in 2 (22%). Spinal fluid examination was obtained in 4 patients. Mild lymphocytic pleocytosis was noted in the CSF of 2 patients (cases 7 and 9), increased protein and IgG in 1 patient (case 4), oligoclonal bands in one patient (case 9), and no abnormalities in another patient (case 5). Cranial MRI showed a single, >4 cm mass associated with perilesional edema, contrast enhancement, and sometimes a shift of the contiguous cerebral tissue. Each of these 9 patients had biopsy-proven demyelination, with relative preservation of axons and variable degrees of macrophage infiltration and reactive gliosis.

Our 5 patients with MAID (cases 1-5) have been observed for a mean duration of more than 50 months (median, 44 months; range, 30 to 86 months; SD, 21.1 months) without the appearance of additional neurologic or neuroimaging abnormalities suggestive of multifocal disease. Complete remission was observed in 3 of these patients with MAID. Two patients (cases 4 and 5) had residual neurologic deficits, but no clinical or neuroimaging features suggestive of continued active focal disease. The 4 remaining patients with MAID reported in the literature (cases 6-9) were observed for a shorter time than our patients (mean, 8 months; median, 6 months; range, 1 to 24 months). Eventually, other neurologic symptoms, deficits, and neuroimaging changes developed in each individual to fulfill criteria for a diagnosis of multiple sclerosis. (18, 19)

DISCUSSION

The clinical diagnosis of inflammatory demyelinating disease in a patient without a history of CNS symptoms and with neuroradiologic evidence of a focal mass process requires brain biopsy. Each of the 9 patients with MAID in this report had acute monofocal symptoms and deficits at presentation, without previous neurologic complaints. The clinical onset and the presence of a single, large, mass-like lesion, with enhancement and sometimes shift of adjacent structures on MRI studies, were more in keeping with malignant brain tumor or abscess than a demyelinating process. While lesions with open ring enhancement (incomplete ring with no contrast enhancement in the area abutting the cortical gray matter) on MRI of the brain have been posited to be suggestive of demyelinating lesions, no characteristic patterns of peripheral enhancement were observed in our series. (20) Magnetic resonance spectroscopy, (21) perfusion MRI, (21) and magnetization transfer imaging (21,22) have been suggested as potentially useful tech niques to help differentiate between MAIDs and brain tumor.

From a clinical standpoint, the 9 patients in this series may be divided into 2 groups. In the first group (cases 1-5), a monophasic clinical course was coupled with a single, large, biopsy-proven, demyelinating lesion. Two patients (cases 1 and 4) showed transient early expansion of the initial lesion on MRI before improving. One patient (case 5) had recurrent worsening symptoms and signs from the expansion of MAID over the course of 6 months before improving. The clinical status of 3 patients (cases 1, 2, and 3) improved shortly after initiation of corticosteroid therapy. Eventually, their conditions improved (cases 1, 2, 3, and 5) or remained stable (case 4). No additional neurologic deficits or MRI lesions have developed. All 5 patients in this group have been observed clinically and with MRIs for periods ranging from 30 to 86 months without the development of new symptoms or lesions.

In the second group of 4 patients (cases 6-9) found on review of the literature, the initial clinical presentation was nonspecific but suggested a focal intracranial lesion. Magnetic resonance imaging studies had the typical features of a large mass lesion, suggestive of a brain tumor. Brain biopsy in each showed acute demyelination; however, in contrast to our 5 patients, they had multiple sclerosis within 2 years of initial presentation. (18,19)

Patients without previous neurologic symptoms who exhibit a large focal cerebral lesion may sometimes have accompanying MRI foci suggestive of demyelination. (7,15) The probability of finding a single, large, demyelinating plaque in multiple sclerosis is low, (5) despite a report (6) of a frequency approximating 5%. Rarely, a second episode of MAID may occur. We observed 2 distinct episodes of MAID separated by 15 years in a patient (not presented here because MRI was not available at onset of symptoms).

The precise nosologic classification of patients with MAID in the spectrum of acute demyelinating diseases remains uncertain. Some patients with MAID have a monophasic course without later development of symptoms, signs, or MRI findings of a separate demyelinating process elsewhere in the CNS. The condition of these patients usually improves, and abnormalities seen on MRI resolve. Pathologic studies of patients with MAID show features consistent with multiple sclerosis. (16) It is likely that, in this context, MAID is a singular form of a demyelinating disorder that currently defies more precise definition. It appears to be more akin to ADEM, a monophasic, albeit multifocal, illness, than to multiple sclerosis, a multifocal and multiphasic illness. (16) These patients may have a singular, less aggressive form fruste of ADEM. Another similar case of ADEM, presenting as a single mass lesion without further neurologic deficits during an 18-month follow-up period, has been reported. (23)

In some patients with MAID, classic multiple sclerosis evolves soon after diagnosis, with the appearance of new lesions disseminated in space, and clinical exacerbations and remissions over time. These patients with MAID likely represent an unusual presentation of multiple sclerosis. (16,23) Similarly, some patients with isolated non-MAID CNS demyelinating syndromes, such as optic neuritis or transverse myelitis, may later have classic clinical multiple sclerosis. (24) Furthermore, a MAID-like illness may also occur in patients who already have a diagnosis of multiple sclerosis. (25,26)

We believe that MAID may be a unique form of acute, monofocal, cerebral demyelinating disease that clinically and neuroradiologically mimics a malignant brain tumor. In our 5 patients, signs of a diffuse demyelinating CNS process suggestive of multiple sclerosis have not developed, despite long follow-up periods. Although pathologic studies do not permit a nosologic differentiation from the lesions of multiple sclerosis, clinically these patients may represent a rare form fruste of demyelinating disease with a milder course. It is possible that some patients with MAID, such as those with other isolated demyelinating CNS syndromes, may have different immunologic characteristics that prevent multiple sclerosis from developing or have a different pathogenetic mechanism altogether, as recently suggested for some patients with multiple sclerosis (27,28)

TABLE.

Review of Cases

        Reference        Age (yr)/     Presenting
Case      (yr)           Sex             Features

1     Gutrecht et al     48/M       Speech difficulties

2     Gutrecht et al     48/F       Right leg weakness

3     Gutrecht et al     50/M       HA, speech difficulties


4     Gutrecht et al     62/M       Visual field and
                                    reading difficulties

5     Gutrecht et al     21/F       Partial seizure with
                                    secondary gen

6     Hunter et al (15)  24/M       Gen seizures, HA,
                                    visual loss, personality
                                    changes
7     Giang et al (16)   31/F       Left leg and arm
                                    heaviness, imbalance,
                                    legs tingling,
                                    HA, nausea
8     Giang et al (16)   27/F       Confusion, Left
                                    hemiparesis/
                                    hemianopia, vertigo

9     Giang et al (16)   24/M       Right hemisensory
                                    loss; feeling "spacey"



                                              Evoked
Case  Examination              CSF          Potentials

1     Mild dysphasia        -                 -

2     Right crural
      monoparesis
3     Expressive
      aphasia

4     Left HH              Protein, IgG
                           increased

5     Expressive           Normal           NI, SSEP,
      aphasia, Right                        VEP, BAEP
      hemiparesis
6     Visual loss (OD),
      lethargic, slow

7     Left hemiparesis;    11 L/[mm.sup.3]  NI, VEP
      Babinski


8     Dysphasia, dyslexia



9     Nonfluent aphasia,   10 L/[mm.sup.3]
      Right pronator
      drift; Right
      hemianesthesia


Case       MRI             Diagnosis             Follow up

1     Left frontal         Glioma?           78 months; normal
      enhancing mass                         examination
2     Left frontal ring-   Glioblastoma?     36 months; normal
      enhancing mass                         examination
3     Left temporal        Glioma?           48 months; normal
      ring-enhancing                         examination
      cystic lesion
4     Right occipito-      Glioma?           36 months; stable
      temporo-parietal                       deficits
      enhancing lesion
5     Left frontal         Glioma            22 months; stable
      enhancing                              deficits
      cystic mass
6     Right frontal        Butterfly glioma  ON (OD), MRI
      enhancing mass                         improvement,
      withCC extension                       Dx: MS
7     T2w high-signal      Abscess?          1 month; ON with
      lesion in same area                    abnonnal VEP, CT
                                             improved, DxM

8     Large left           Tumor             MRI improved;
      parieto-occipital                      24 months later
      lesion with                            R INO; Dx: Sx
      mass effect                            of MS
9     Left fronto-         Tumor?            3 months; new
      parictal lesion.                       deficits and
      with mass effect                       abnormalities;
                                             Dx: MS

BAEP = Brain stem auditory evoked potential, CC = corpus callosum, CSF =
cerebrospinal fluid, CT = computed tomography, DX = diagnosis, enhanc =
enhancing or enhancement, ext = extension; HA = headaches, gen =
generalized, HH = homonymous hemianopia, INO = internuclear
opthalmoplegia, MRI = magnetic resonance imaging, MS = multiple
sclerosis, NI = normal image, OD = right eye, ON = optic neuritis, SSEP
= somatosensory evoked potentials, Sx = symptoms of multiple sclerosis,
VEP = visual evoked potential.

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RELATED ARTICLE: KEY POINTS

* Large demyelinating lesions of the brain may be associated with mass effect and be indistinguishable from brain tumors on cranial magnetic resonance imaging or computed tomography.

* These demyelinating lesions may occur in isolation or may herald multiple sclerosis.

* Brain biopsy may be necessary to establish the correct diagnosis.

* A salutary response to corticosteroids may be observed but is not universal.

From the Department of Neurology, Lahey Clinic Medical Center, Burlington, Mass; the Departments of Neurology and Internal Medicine, University of Kentucky College of Medicine, Lexington; Department of Neurology, Harvard Medical School, Boston, Mass; and the Department of Diagnostic Radiology, Maine Medical Center, Portland.

Reprint requests to Joseph R. Berger, MD, University of Kentucky College of Medicine, Department of Neurology, Kentucky Clinic L-445, Lexington, KY 40536-0284.