Recurrence of Acute Disseminated Encephalomyelitis at the Previously Affected Brain Site FREE

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 signs^{1 - 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.

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.

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 × 10⁹/L to 0.50 × 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.

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.

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.

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.

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.

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.

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 ADEM^{9 - 12} and 3 series (Table 4),^{13 - 15} which are not based on pathological confirmation and, except for 1 series,¹⁵ do not contain MR imaging data.

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.

Accepted for publication October 25, 2000.

Corresponding author: Israel Steiner, MD, Department of Neurology, Hadassah University Hospital, PO Box 12000, Ein Karem, Jerusalem 91120, Israel (e-mail: isteiner@md2.huji.ac.il).