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Recurrence of Acute Disseminated Encephalomyelitis at the Previously Affected Brain Site
Oren Cohen, MD;
Bettina Steiner-Birmanns, MD;
Iftah Biran, MD;
Oded Abramsky, MD, PhD;
Sylvia Honigman, MD;
Israel Steiner, MD
Arch Neurol. 2001;58:797-801.
ABSTRACT
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Background Acute disseminated encephalomyelitis (ADEM) is a usually monophasic
demyelinating disorder of the central nervous system. Recurrences pose a diagnostic
challenge because they can be overlooked or suggest an alternative diagnosis.
Objective To examine the frequency, nature, and outcome of recurrent ADEM.
Design Review of the medical records of patients diagnosed in our institution
as having ADEM between January 1, 1983, and May 31, 1998. Recurrences were
defined as appearance of new symptoms and signs at least 1 month after the
previous episode.
Results Five (24%) of 21 patients with ADEM developed recurrent disease episodes.
In all, diagnosis was confirmed by brain biopsy. One patient had 4 disease
episodes, 2 had 3, and the other 2 each had 2. Recurrence appeared 1.5 to
32 months after initial presentation and involved the same brain territory
in 6 of 9 recurrences in 3 of 5 patients. In 2 patients, recurrences included
neuropsychiatric signs. A good response to corticosteroid therapy was observed
in 10 of 13 of treated ADEM attacks: in 3 of the 4 treated initial events
and in 7 of 9 recurrences.
Conclusions Recurrent ADEM may be more prevalent than previously recognized. Patients
who relapse tend to have more than 1 recurrence that usually involves, clinically
and radiologically, a brain territory that was affected before and can simulate
a space-occupying lesion that requires histologic diagnosis. Neuropsychiatric
features may be the main presentation of a relapse. Since recurrent ADEM is
a corticosteroid-responsive condition, awareness and early diagnosis are mandatory.
INTRODUCTION
ACUTE disseminated encephalomyelitis (ADEM) is a demyelinating disorder
of the central nervous system that is usually monophasic.1
Relapses are rare, and patients with recurrent episodes are eventually diagnosed
as having multiple sclerosis (MS). Features of ADEM are quite well delineated.
The disease can appear after infection or vaccination; is associated with
fever, convulsions, drowsiness, meningeal findings, and multifocal signs1, 2; and may take a fulminant or even a
fatal course. Unlike MS, in which magnetic resonance (MR) imaging usually
demonstrates multiple white matter lesions with predilection for periventricular
and pericallosal areas without mass effect, the ADEM lesions tend to be large,
confluent, and asymmetric; can involve gray matter areas such as the cortex,
basal ganglia, and thalamus; may have a mass effect; and usually enhance massively
with gadolinium.3, 4 Pleocytosis
and elevated protein levels are characteristic of the cerebrospinal fluid
(CSF) in ADEM.1 However, it is often difficult,
both at presentation and in retrospect, to differentiate between hyperacute
and/or malignant forms of MS and other fulminant central nervous system demyelinating
diseases such as ADEM.5, 6
Recurrent or relapsing ADEM may present such a difficulty in definition
and is a much less well-characterized entity. We were faced with this reality
when we recently encountered 2 patients with ADEM who had multiple relapses
and presented a diagnostic and therapeutic challenge. This prompted us to
examine the frequency, nature, and outcome of the recurrent disease in patients
diagnosed in our institution as having ADEM.
PATIENTS AND METHODS
Between January 1, 1983, and May 31, 1998, ADEM was diagnosed in 21
patients at Hadassah University Hospital, Jerusalem, Israel. The diagnosis
was based on the clinical context, the clinical signs and course of the disease,
and imaging and laboratory findings. In 7 patients, brain biopsy specimens
showed demyelination, mononuclear perivascular infiltration, loosening of
the white matter, and macrophages containing myelin debris, establishing the
diagnosis of ADEM. In all patients, a possible infectious cause (such as syphilis
and Lyme disease) was ruled out and an immunogram was negative for a systemic
immune-mediated condition. Three patients with ADEM (1 with recurrent disease)
underwent brain angiography, and cerebral vasculitis was excluded.
The medical files of all patients with ADEM were reviewed for symptoms;
clinical, laboratory, and imaging findings; response to treatment; and disease
relapses. In accord with the diagnostic criteria,7 recurrence was defined as the development of new symptoms
and signs, lasting more than 24 hours and separated by a minimum of 1 month
from the previous episode.
RESULTS
CHARACTERISTICS OF PATIENTS WITH ADEM
During the study period, 21 patients with ADEM (14 females and 7 males,
aged 5-77 years; mean age, 37 years) were hospitalized at the Hadassah University
Hospital. A history of previous febrile illness (8 patients) or vaccination
(1 patient) was evident in 9 (43%) of the 21 patients.
Presenting symptoms were nausea and vomiting (6 patients), headache
(5 patients), fatigue (4 patients), limb weakness (5 patients), gait disturbance
(4 patients), and diplopia (2 patients). The common signs at presentation
were drowsiness or confusion (7 patients), hemiparesis (7 patients), fever
(5 patients), paraparesis (4 patients), urinary retention (3 patients), and
ataxia (3 patients).
Magnetic resonance images were available for 13 patients at presentation.
In 4, large confluent lesions were evident. In an additional 4, a large solitary
lesion was seen, and in 5, multiple small hyperintense T2 lesions were identified.
Results of CSF examination were available in 14 patients. Three had mild to
moderate pleocytosis (0.02 x 109/L to 0.50 x 109/L), 5 had elevated protein levels (ranging from 0.75 to 2.20 g/L;
reference range, <0.65 g/L), and in 8 the CSF was normal. Oligoclonal bands
were present in 3. In 2 patients without CSF oligoclonal bands, a repeated
assay was also negative. In 8 of 21 patients, brain biopsy was performed.
In 7 it showed diffuse demyelination and perivascular mononuclear infiltration,
loosening of white matter, and foamy macrophages, confirming or establishing
the clinical diagnosis of ADEM. In 1 the biopsy results were inconclusive.
Eight of the 21 patients had new signs and symptoms that occurred more
than 1 month after a previous episode. Two of these 8 patients were finally
diagnosed as having clinically definite laboratory-supported MS according
to the criteria of Poser et al7 and 1 developed
a combined central and peripheral white matter disease resulting from a systemic
autoimmune disease. In the other 5 patients (24% of this group), the diagnosis
of recurrent ADEM could be established.
CHARACTERISTICS OF PATIENTS WITH RECURRENT ADEM
The patients with recurrent ADEM were 2 men and 3 women with an age
range of 30 to 77 years (mean, 51 years). One patient had 4 episodes of neurologic
disorder, 2 had 3, and 2 had 2 episodes each. None of the patients with recurrent
ADEM had a history of infection or immunization.
An illustrative case was that of a 30-year-old man who was admitted
after 1 week of headache, fever, and drowsiness. His medical history included
trauma to the right eye 8 years before his admission, with resultant ophthalmoplegia,
blindness, and sympathetic ophthalmia, treated with prednisone. Results of
general examination on admission were unremarkable except for temperature
of 40°C. On neurologic examination, he was alert and conscious. He had
right-eye blindness and right medial rectus palsy. Left-sided hemiparesis
and hyperreflexia were noted. Plantar responses were flexor, and results of
sensory and cerebellar tests were normal. Erythrocyte sedimentation rate,
complete blood cell count, results of blood biochemistry studies, and electroencephalogram
were normal. Lumbar puncture showed an elevated protein level (1.02 g/L) with
normal glucose level and no oligoclonal bands. The MR image demonstrated a
large hyperintense T2 lesion involving the right basal ganglia and thalamus,
causing moderate pressure on the lateral ventricle (Figure 1A). Biopsy of the lesion showed nonspecific inflammatory
changes.
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Figure 1. Magnetic resonance imaging studies.
A, At presentation, there is a large confluent lesion of the right basal ganglia
and thalamus. B, After corticosteroid treatment, there is a decrease in lesion
size and postbiopsy changes. C, At the fourth recurrence, in addition to the
old lesion and postbiopsy changes in the right hemisphere, there are new lesions
at the left thalamus and internal capsule.
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Treatment with intravenous methylprednisolone sodium succinate was associated
with marked improvement of the hemiparesis and the drowsiness. An MR image
obtained 2 months later demonstrated a significant decrease in lesion size
(Figure 1B), but after an additional
4 months he again developed headache, fever, and left-sided weakness. On examination,
mild left hemiparesis was found and a computed tomographic scan showed enlargement
of the lesion in the right thalamus and basal ganglia. Lumbar puncture was
traumatic and therefore inconclusive. A second brain biopsy was performed
and disclosed inflammatory and demyelinative changes. Treatment with intravenous
methylprednisolone was initiated, with marked improvement of the patient's
symptoms and signs.
Seven months after the first episode, and during a gradual decrease
of the corticosteroid dosage, the patient again developed marked (3+/5 on
the Medical Research Council scale) left hemiparesis. An MR image showed postbiopsy
changes and an increase in the right hemispheric lesion, with extension into
the pons and midbrain. A third biopsy specimen and review of the second biopsy
specimen showed loosening of the white matter, marked demyelination, foamy
macrophages, and perivascular mononuclear infiltration, compatible with ADEM
(Figure 2). The patient was again
treated with high-dose intravenous corticosteroids, which were tapered down
because of depression and suicidal thoughts and were maintained at a very
low dose for about 1.5 years. However, about 30 months after the first episode,
he developed fever, drowsiness, and gait disturbance, and on examination he
was somnolent with mild left hemiparesis with hyperreflexia and right cerebellar
syndrome. An MR image showed, in addition to the right hemispheric lesion,
new lesions at the left thalamus and internal capsule and in the mesencephalon
and upper pons (Figure 1C). The
patient was again treated with corticosteroids, with a good response.
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Figure 2. Brain biopsy specimens showing
a mononuclear perivascular infiltration, demyelination, loosening of the white
matter, and foamy macrophage compatible with acute disseminated encephalomyelitis
(hematoxylin-eosin, original magnification x200).
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Initial Episode
Two patients had fever and 2 complained of headache (Table 1). Drowsiness or acute confusion was evident in 3 and hemiparesis
was also present in 3 patients. In 4 patients, MR images or computed tomographic
scans showed a large solitary lesion, and in 1 patient, multiple hyperintense
T2 foci were seen. Cerebrospinal fluid was obtained from 4 patients and showed
elevated protein level in 1 (patient 1) and oligoclonal bands in another (patient
3). In 1 patient (patient 5), initial diagnosis was a possible cerebrovascular
event, and therefore correct diagnosis and therapy were delayed until the
second disease episode 5 months later. Brain biopsy eventually established
the diagnosis of ADEM in all 5 patients. Four of the 5 patients were treated
with corticosteroids, and 3 of them markedly improved. In 2, this was accompanied
by radiologic improvement.
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Table 1. Clinical and Laboratory Features of the First Episode in 5
Patients With Recurrent Acute Disseminated Encephalomyelitis
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Recurrences
The time range to recurrence was 1.5 to 32 months (mean, 13 months)
(Table 2). The clinical presentation
at recurrence involved, at least in part, the same central nervous system
territory that was affected during the initial episode in 6 of 9 recurrences.
In the remaining 3, the new symptoms and signs were attributed to a different
brain territory. Two patients had neuropsychiatric symptoms at recurrence,
which were attributed to parenchymatous brain involvement. Three patients
had new radiologic abnormalities at recurrence. Brain biopsy was performed
again in 4 of the 9 relapses. In all, the histologic findings were compatible
with ADEM. All patients were treated with corticosteroids. Four patients had
good clinical improvement, while 1 had only a mild response. A good response
to corticosteroids was evident in 7 of 9 recurrences. The 3 patients with
more than 1 relapse, who had responded to treatment at the first relapse,
also responded in subsequent relapses.
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Table 2. Clinical and Laboratory Features of Recurrent Demyelinating
Episodes in 5 Patients With Recurrent ADEM*
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COMPARISON BETWEEN PATIENTS WITH AND WITHOUT RECURRENCES
Comparison between the 16 patients with ADEM who had no disease relapse
and the 5 patients with recurrent ADEM is summarized in Table 3. The only difference between patients with a single ADEM
episode and those who relapsed was the presence of a previous febrile illness,
a finding that was not statistically significant.
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Table 3. Comparison Between Patients With and Without Recurrences*
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COMMENT
Although recurrent ADEM was initially documented more than 50 years
ago,8 the disease is still widely regarded
as a monophasic disorder.1 There are only several
anecdotal case reports of relapsing ADEM9, 10, 11, 12
and 3 series (Table 4),13, 14, 15 which are not based
on pathological confirmation and, except for 1 series,15
do not contain MR imaging data.
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Table 4. Clinical Features of Patients With Recurrent ADEM*
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We observed recurrent episodes in 24% of our patients with ADEM. Such
a recurrence rate is somewhat higher than that described by Miller and Evans13 and much higher than reported before.1
Patients who relapsed tended to have more than 1 recurrence. Three of 5 patients
with recurrent ADEM had 3 or more disease episodes.
Neuropsychiatric features were the main presenting symptoms at recurrence
in 2 of our patients. Since psychiatric and/or cognitive symptoms may be overlooked
and regarded as a mental reaction to the disease, or as a pharmacologic side
effect, the treating physicians should be aware that depression or even psychosis
may herald a recurrent ADEM episode.
Recurrences tend to involve, clinically and radiologically, a brain
territory that was affected before. Thus, 6 of 9 recorded recurrences consisted
of new symptoms and signs emanating from brain regions that showed signs of
disease involvement during a previous episode. This feature, also reported
in other series,13, 14 is of special
clinical significance because recurrence at the same brain region might be
overlooked. More important, local clinical and radiologic recurrence challenges
the initial diagnosis and may call for a second brain biopsy.
This observation has clinical implications and theoretical meaning for
the following reasons: (1) Our experience suggests that patients with a histologically
confirmed diagnosis of ADEM who have a relapse that is confined to the initial
brain territory may be spared a second surgical procedure aimed at obtaining
brain tissue. (2) In these cases, an empirical therapeutic trial is indicated.
(3) The mechanism responsible for such a recurrence is intriguing. It may
be speculated that, even after a complete clinical and radiologic remission,
there is still either a "locus of minor resistance" vulnerable to further
disease relapse, even a long time after the first episode, or a residual area
of subclinical disease activity that gives rise to a new relapse.
The occurrence of large focal tumorlike demyelinating brain lesions
has been documented before.16 However, these
cases, borderline or intermediate between ADEM and MS, were monophasic. The
occurrence of such a relapse, clinically and radiologically simulating a brain
tumor in 3 of our 5 patients with histologically confirmed ADEM, implies that
not only MS,17 but also ADEM, may have a tumorlike
form.
Our experience suggests that recurrent ADEM is a corticosteroid-responsive
condition. Patients were treated with intravenous methylprednisolone acetate
(1000, 500, 250, 200, and 100 mg for 2 days each), and a good or very good
response was observed in 7 of 9 recurrences. A good response was also noticed
in other series,14 and a long-term corticosteroid-dependent
course was also reported.12 It is important
to emphasize, however, that some of the patients with recurrent ADEM in the
series by Miller and Evans13 improved or recovered
spontaneously, although the relatively high rate of recurrences in their series
can be attributed to the lack of treatment. These data justify a therapeutic
protocol with corticosteroids in patients with recurrent ADEM.
In conclusion, recurrent ADEM is more common than previously regarded
and may occur in a significant proportion of patients with ADEM. It tends
to affect the same brain territory and thus may be overlooked or challenge
the initial diagnosis. Correct diagnosis is mandatory, as this condition seems
to be amenable to therapy in most patients.
AUTHOR INFORMATION
Accepted for publication October 25, 2000.
From the Department of Neurology and The Agnes Ginges Center for Human
Neurogenetics, Hadassah University Hospital and the Hebrew University Medical
School, Jerusalem, Israel (Drs Cohen, Steiner-Birmanns, Biran, Abramsky, and
Steiner); and the Department of Neurology, Carmel Medical Center, Haifa, Israel
(Dr Honigman).
Corresponding author: Israel Steiner, MD, Department of Neurology,
Hadassah University Hospital, PO Box 12000, Ein Karem, Jerusalem 91120, Israel
(e-mail: isteiner{at}md2.huji.ac.il).
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