Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis

INTRODUCTION — Acute disseminated encephalomyelitis (ADEM), also known as postinfectious encephalomyelitis, is a demyelinating disease of the central nervous system that typically presents as a monophasic disorder associated with multifocal neurologic symptoms and disability.

This topic will review the treatment and prognosis of ADEM in children. Other aspects of ADEM are discussed separately. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis".)

APPROACH TO TREATMENT — The mainstay of treatment for ADEM is high-dose intravenous glucocorticoids [1,2]. Additional options include intravenous immune globulin and plasma exchange [3,4].

Empiric antibiotic treatment — Children with ADEM typically present with fever, meningeal signs, acute encephalopathy, and evidence of inflammation in blood and cerebrospinal fluid. Thus, it is reasonable to treat with broad-spectrum antibiotics and acyclovir until an infectious etiology is excluded. (See "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Empiric therapy' and "Acute viral encephalitis in children: Treatment and prevention", section on 'Empiric acyclovir'.)

However, once ADEM is considered the most likely diagnosis, immunotherapy (most often intravenous high-dose glucocorticoids) should be started if it is not already being given.

Initial immunotherapy — For children with ADEM, we recommend immunotherapy using either high-dose glucocorticoids, intravenous immune globulin (IVIG), or plasma exchange. We suggest initial therapy with glucocorticoids rather than IVIG or plasma exchange, in line with most of limited published evidence and clinical experience. Glucocorticoids may be started at the time of the patient's presentation and can be used concurrently with antibiotics and acyclovir in consultation with an infectious disease specialist. Antibiotics and acyclovir can be discontinued when infection has been ruled out through medical judgement and/or test results. (See 'Empiric antibiotic treatment' above and 'Glucocorticoids' below.)

Assessing response to initial therapy — Children with ADEM should be evaluated daily to determine whether they are improving with immune-modulating therapy. Clinical parameters can be used to monitor response. Resolution or clinically meaningful improvement of altered mental status (eg, coma, encephalopathy) and associated neurologic deficits (eg, cerebellar ataxia, hemiparesis, cranial neuropathies) suggests a good response to immunotherapy, whereas the lack of meaningful improvement or continued neurologic deterioration implies a poor response.

While an immediate response is not expected, improvement should be evident within a few days of starting immunotherapy, in line with the usual five-day course of high-dose intravenous methylprednisolone treatment. Ongoing deterioration or the absence of meaningful improvement at five to seven days after starting treatment should signal the need for further treatment with a different immunotherapy, as discussed in the following section.

Inadequate response to acute therapy — In our clinical experience, most patients do not require a second therapy. However, for children who do not have clinically significant improvement after five days of intravenous glucocorticoids (eg, methylprednisolone), we treat with IVIG (2 g/kg given in divided doses over three days); plasma exchange (a total of six exchanges, one every other day) is an alternative that is most often used for patients with fulminant forms of ADEM and profound encephalopathy (eg, coma) who need intensive care unit management. For most children, we prefer IVIG over plasma exchange because of relative safety and ease of administration; it is also more widely available. (See 'Intravenous immune globulin' below.)

For children with ADEM who have longitudinally extensive transverse myelitis and an inadequate response to initial glucocorticoid therapy, it is reasonable to treat with plasma exchange rather than IVIG. (See 'Plasma exchange' below.)

Inadequate response to a second therapy — Children who have a poor response to initial treatment with intravenous methylprednisolone and no meaningful improvement within one week after completing a second-line therapy (either IVIG or plasma exchange) should receive the alternate treatment (ie, IVIG after plasma exchange or vice versa). Plasma exchange halts any potential ongoing benefit of IVIG by removing it from the circulation, but the absence of a clinical response to IVIG raises concerns for poor prognosis and justifies the compromise entailed with using plasma exchange shortly after IVIG.

Some experts additionally treat such patients with ongoing weekly intravenous methylprednisolone (30 mg/kg per dose) in the hope of improving their outcome.

Management of malignant edema — In some rare cases, fulminant ADEM or acute hemorrhagic leukoencephalitis (AHL) may progress to develop malignant, space-occupying brain edema with increased intracranial pressure and brain tissue shifts or herniation [5]. This process can lead to neurologic deterioration with signs that typically include decreased arousal, pupillary changes, and worsening of motor responses. These neurologic signs are indicators of the need to intervene urgently with measures to treat brain edema.

Standard medical therapy for worsening edema involves close monitoring for neurologic complications; and interventions to reduce intracerebral pressure such as elevation of the head of the bed, osmotic therapy, brief periods of hyperventilation as needed, and hemicraniectomy for patients with life-threatening cerebral edema [6,7]. (See "Evaluation and management of elevated intracranial pressure in adults".)

Treatment for relapsing disease — For patients with relapse of disease, we suggest intravenous glucocorticoids for acute management. There should be careful review of the initial diagnosis for such patients to determine if their relapse represents multiphasic ADEM (see 'Relapses' below) or another demyelinating syndrome such as myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease, multiple sclerosis, or neuromyelitis optica spectrum disorder. (See "Differential diagnosis of acute central nervous system demyelination in children" and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Differential diagnosis' and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis" and "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis".)

If an alternative diagnosis is identified, then ongoing treatment should be specific to that disease. Many patients with a relapse of ADEM or with ADEM followed by optic neuritis will have an elevated MOG immunoglobulin G (IgG) antibody titer, and this would be an indication to initiate ongoing prophylactic maintenance therapy with monthly intravenous methylprednisolone or monthly IVIG. Intravenous methylprednisolone is typically given as single a dose of 30 mg/kg each month and IVIG as a single dose of 1 gm/kg each month. The total duration of this therapy is individually determined and based upon tolerance and response, including the severity and sequela of prior attacks, recurrent attacks, the degree of persistence of MOG IgG antibody, and stability of repeat imaging studies. Most patients are treated for 12 to 24 months. Discontinuation of treatment requires ongoing close monitoring to assure true remission of disease. (See 'Relapses' below.)

IMMUNE-MODULATING THERAPIES — The effectiveness of immunotherapies (ie, glucocorticoids, intravenous immune globulin, and plasma exchange) for ADEM is supported by results from small observational studies. However, there are no randomized controlled trial data, and the optimal treatment has not been established.

Glucocorticoids — In several small observational studies, treatment of ADEM with intravenous methylprednisolone (10 to 30 mg/kg per day, maximum 1000 mg daily) or dexamethasone (1 mg/kg per day) for three to five days, followed by oral glucocorticoid taper over four to six weeks, was associated with full recovery in approximately 60 to 90 percent of patients [8-10].

In the only study that compared these two treatments for ADEM, intravenous methylprednisolone (n = 21) was associated with a modestly better outcome, as measured by the median Expanded Disability Status Scale, compared with intravenous dexamethasone (n = 25) [10]. The strength of this result is limited by small patient numbers, lack of randomization, and lack of blinded treatment or assessment.

Although the prognosis for survival and recovery of neurologic function is worse for the hyperacute hemorrhagic variants of ADEM such as acute hemorrhagic leukoencephalitis (AHL) than for typical ADEM, a few case reports suggest that early high-dose glucocorticoid treatment may be associated with good recovery in children [10,11] who have hemorrhagic variants of ADEM. (See 'Prognosis' below and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Acute hemorrhagic leukoencephalitis'.)

●Dose and duration – Although there is no consensus regarding glucocorticoid regimens, we use methylprednisolone (30 mg/kg per day, up to a maximum dose of 1000 mg per day) for five days. We use an oral prednisone taper only in children who continue to show clinical symptoms after completion of the high dose intravenous glucocorticoid treatment. The prednisone taper is typically started at a lower initial dose compared with the intravenous regimen. We begin the taper with oral prednisone 1 mg/kg per day up to a maximum of 60 mg per day and then reduce the dose by 10 mg every five days to allow for a total tapering duration of four to six weeks.

There is no convincing evidence that the use of a tapering oral glucocorticoid regimen, or its duration, influences outcome after intravenous glucocorticoid therapy. Two small observational studies reported higher relapse rates in children with ADEM who were treated with shorter (three weeks or less) compared with longer glucocorticoid tapers, but this finding was not statistically significant [8,12]. In addition, the results from one of these studies [12] were confounded by the inclusion of patients who had clinically isolated syndromes suggestive of multiple sclerosis. Such patients might have a higher relapse risk compared with those who meet all criteria for the diagnosis of ADEM.

●Adverse effects – The short-term use of high-dose glucocorticoid treatment is usually well tolerated. Potential complications include mental status changes, increased susceptibility to infection, and gastric disturbance.

Intravenous immune globulin — Data from small case series and case reports suggest that intravenous immune globulin (IVIG) is beneficial as rescue therapy in patients with ADEM who fail to respond to methylprednisolone [13-16] or as initial therapy [17]. Dosing of IVIG in these studies ranged from 1 to 2 g/kg, given either as a single dose or divided over three to five days [13-15,17].

No studies have compared IVIG treatment with glucocorticoids or plasma exchange [3].

●Dose and duration – IVIG is typically initiated if there is no clinical improvement within seven days of completing methylprednisolone. Our preferred IVIG regimen is a total of 2 g/kg given in divided doses over three days (ie, 667 mg/kg daily for three days); other centers may divide the dose over five days (ie, 400 mg/kg daily for five days).

●Adverse effects – Adverse reactions with IVIG may include headache, nausea, fever, aseptic meningitis, rash, acute renal failure (mostly related to sucrose-containing products), and rarely hyperviscosity. Immunoglobulin A (IgA) deficiency can lead to anaphylaxis in patients treated with IVIG. These are discussed in detail separately. (See "Intravenous immune globulin: Adverse effects".)

Plasma exchange — Limited data suggest that plasma exchange is beneficial in children with ADEM who have a poor response to treatment with intravenous immunoglobulin and/or methylprednisolone [18-21]. The largest series was retrospective and reported improvement following plasma exchange in six children with ADEM who did not respond to initial treatment with glucocorticoids followed by IVIG [21].

In another retrospective study, plasma exchange demonstrated some benefit for patients with idiopathic transverse myelitis when used in combination with intravenous glucocorticoids. Therefore, it may be of particular benefit for patients with ADEM associated with myelopathy [22].

●Dose and duration – Our preferred regimen is a total of six exchanges, one every other day, with each exchange consisting of 1 to 1.5 plasma volumes. Albumin is typically used as the replacement fluid. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

●Adverse effects – The main complications of plasma exchange are hypotension, sepsis, and problems with intravenous access. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)

EXTENDED FOLLOW-UP — Follow-up magnetic resonance imaging (MRI) shows complete or partial resolution of abnormalities in the majority of ADEM cases [8,23,24]. However, residual gliosis and demyelination persist in some. Although no consensus exists, some experts suggest obtaining at least two additional MRIs after the initial MRI, over a period of at least five years from the initial episode of ADEM, to confirm the absence of new inflammatory demyelinating lesions [3].

Long-term clinical follow-up and sequential imaging by MRI are usually required to confirm the diagnosis of ADEM [3]. The development of relapses with new lesions on MRI is not compatible with a diagnosis of monophasic ADEM, and suggests that the correct diagnosis is either multiphasic ADEM, multiple sclerosis, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease, or neuromyelitis optica spectrum disorder, depending on the clinical and imaging features. (See 'Multiphasic ADEM' below and "Differential diagnosis of acute central nervous system demyelination in children" and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis".)

For patients with detectable anti-MOG antibody titers, repeat testing should be performed every six months for at least one year. Patients with persistently high titers should be closely observed clinically and have repeat imaging every 6 to 12 months. Anti-MOG antibodies, while not specific for ADEM, may have prognostic value, suggesting an increased risk for recurrent demyelinating disease other than multiple sclerosis. (See "Differential diagnosis of acute central nervous system demyelination in children", section on 'MOG antibody-associated disease'.)

PROGNOSIS

Disability — Most children with ADEM make a full recovery, usually slowly over four to six weeks, but a minority have persistent motor or cognitive impairments [25]. At follow-up, approximately 60 to 90 percent have minimal or no neurologic deficits [8-10,26-28]. One of the largest studies included 84 children from Argentina with ADEM [10]. At a mean follow-up of 6.6 years, the neurologic examination was either normal or detected minor abnormalities but no associated disability in 75 children (89 percent). Residual deficits in the remaining children included mild to severe hemiparesis, mild paraparesis, partial epilepsy, reduced visual acuity, and cognitive impairment. Additional residual deficits, described in other studies, have included behavioral problems, minor gross motor abnormalities, and persistent limb paresthesia [8,9].

The extent and site of lesions on the initial MRI do not predict the clinical outcome [10,29].

Mortality — Most studies of ADEM in children have reported no mortality [4], but other studies have found that mortality of ADEM was approximately 3 percent [30-33].

The prognosis for survival and recovery of neurologic function is worse for the hyperacute hemorrhage variants of ADEM, such as acute hemorrhagic leukoencephalitis (AHL), than for typical ADEM [3]. Brain edema and subsequent death may occur within a week of the onset of encephalopathy in these uncommon variants. However, immunotherapy may be associated with improved outcome. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Acute hemorrhagic leukoencephalitis'.)

Relapses — Most children with ADEM have monophasic disease, with no recurrent clinical episodes or demyelination with long-term follow-up. However, one or more additional demyelinating events occur in up to 36 percent [4]; seropositivity for anti-myelin oligodendrocyte glycoprotein (MOG) antibodies is associated with an increased risk for recurrent demyelinating disease other than multiple sclerosis. (See "Differential diagnosis of acute central nervous system demyelination in children", section on 'MOG antibody-associated disease'.)

Monophasic ADEM — The clinical features of ADEM typically follow a monophasic disease course, although they can fluctuate in severity and evolve in the first three months following disease onset [34]. Any new and fluctuating symptoms occurring within three months of the initial event are considered to be part of the same inciting event.

Multiphasic ADEM — Multiphasic ADEM is defined as two episodes consistent with ADEM separated by at least three months, irrespective of glucocorticoid use, but not followed by any further events [34]. The second ADEM event can involve either new or a re-emergence of prior neurologic symptoms, signs and magnetic resonance imaging (MRI) findings. By definition, both the first and second event must include a clinical presentation with encephalopathy. A second or additional attack that does not include encephalopathy and occurs three or more months after the first episode can be considered to either represent multiple sclerosis if the MRI findings meet the radiologic criteria for dissemination in space, or to represent MOG antibody-associated disease or neuromyelitis optica spectrum disorder if associated criteria are met.

ADEM followed by optic neuritis — In some children, monophasic or multiphasic ADEM is followed by single or recurrent attacks of optic neuritis [32,35,36]. This uncommon phenotype has been associated in all cases with high serum titers of anti-MOG antibodies, and represents one type of MOG antibody-associated disease.

Three or more relapses — Relapses beyond a second event are no longer consistent with ADEM, and indicate a chronic disorder such as multiple sclerosis, MOG antibody-associated disease, or neuromyelitis optica spectrum disorder [34]. The initial ADEM event is considered the first attack of the chronic disease in this regard.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

SUMMARY AND RECOMMENDATIONS

●Children with acute disseminated encephalomyelitis (ADEM) typically present with fever, meningeal signs, acute encephalopathy, and evidence of inflammation in blood and cerebrospinal fluid. Thus, it is reasonable to treat with broad-spectrum antibiotics and acyclovir until an infectious etiology is excluded. (See 'Empiric antibiotic treatment' above.)

●For children with ADEM, we recommend immunotherapy using either glucocorticoids, intravenous immune globulin (IVIG), or plasma exchange (Grade 1C). We suggest initial therapy with high-dose glucocorticoids rather than IVIG or plasma exchange (Grade 2C). Our preferred regimen is intravenous methylprednisolone (30 mg/kg per day, up to a maximum dose of 1000 mg per day) for five days, followed by a four to six week oral prednisone taper for those with residual symptoms after intravenous treatment. (See 'Initial immunotherapy' above and 'Glucocorticoids' above.)

●For children who do not have clinically significant improvement after five days of intravenous glucocorticoids (eg, methylprednisolone), we treat with IVIG (2 g/kg given in divided doses over three days); plasma exchange (a total of six exchanges, one every other day) is an alternative. (See 'Inadequate response to acute therapy' above and 'Intravenous immune globulin' above and 'Plasma exchange' above.)

●For children with a poor response to initial intravenous methylprednisolone treatment and no meaningful improvement within one week after completing IVIG therapy as a second therapy, it is reasonable to treat with plasma exchange. (See 'Inadequate response to a second therapy' above and 'Intravenous immune globulin' above and 'Plasma exchange' above.)

●Long-term follow-up is necessary to document recovery and to confirm the diagnosis of ADEM. (See 'Extended follow-up' above.)

●Most children with ADEM make a full recovery, usually slowly over four to six weeks. At follow-up, 60 to 90 percent have minimal or no neurologic deficits. Mortality of up to 3 percent has been reported in some studies. The prognosis for survival and recovery of neurologic function is worse for the hyperacute hemorrhage variants of ADEM, such as acute hemorrhagic leukoencephalitis (AHL), than for typical ADEM. (See 'Prognosis' above.)

●Most children with ADEM have monophasic disease; any new and fluctuating symptoms occurring within three months of the initial event are considered to be part of the same event. The occurrence of relapses beyond three months suggests alternative diagnoses, such as multiphasic ADEM, multiple sclerosis, ADEM plus optic neuritis, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease, or neuromyelitis optica spectrum disorder. (See 'Relapses' above.)