Childhood Acute Disseminated Encephalomyelitis Research Articles

Life-Threatening MOG Antibody-Associated Hemorrhagic ADEM With Elevated CSF IL-6.

Acute disseminated encephalomyelitis (ADEM) is one characteristic manifestation of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). A previously healthy man presented with retro-orbital headache and urinary retention 14 days after Tdap vaccination. Brain and spine MRI suggested a CNS demyelinating process. Despite treatment with IV steroids, he deteriorated, manifesting hemiparesis and later impaired consciousness, requiring intubation. A repeat brain MRI demonstrated new bilateral supratentorial lesions associated with venous sinus thrombosis, hemorrhage, and midline shift. Anti-MOG antibody was present at a high titer. CSF IL-6 protein was >2,000 times above the upper limits of normal. He improved after plasma exchange, then began monthly treatment alone with anti-IL-6 receptor antibody, tocilizumab, and has remained stable. This case highlights how adult-onset MOGAD, like childhood ADEM, can rapidly become life-threatening. The markedly elevated CSF IL-6 observed here supports consideration for evaluating CSF cytokines more broadly in patients with acute MOGAD.

A rare case of bilateral optic neuritis and acute disseminated encephalomyelitis post mycoplasma pneumoniae infection

A case of a 4-year-old boy who developed acute disseminated encephalomyelitis (ADEM) and optic neuritis (ON) following Mycoplasma pneumoniae infection is reported. His symptoms, including excessive sleepiness, frontal headache, bilateral vision impairment, retro-auricular pain and unbalanced gait, were resolved after methylprednisolone pulse therapy, intravenous immunoglobulin (IVIG) and ciprofloxacin. Cerebrospinal fluid myelin basic protein (MBP) and Mycoplasma serology IgM were detected in our patient. This is the first report of a child with ADEM and ON associated with mastoditis caused by M. pneumoniae infection. Combined immunomodulatory therapy (pulse steroids and immunoglobulin) with anti- mycoplasma microbial therapy resulted in favorable visual recovery. Bilateral isolated optic neuritis as the first presenting feature in childhood ADEM is rare and requires proper evaluation and early therapeutic management. This case highlights the need for physician awareness of the association of mycoplasma infection with optic neuritis and ADEM.

MOGAD: How It Differs From and Resembles Other Neuroinflammatory Disorders.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct CNS inflammatory disease with symptoms and imaging findings that overlap other neuroinflammatory disorders. We highlight the imaging characteristics of MOGAD and contrast them with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Intracranial features that suggest MOGAD include childhood acute disseminated encephalomyelitis pattern with diffuse signal abnormality in the cortical gray matter, subcortical white matter, deep white matter, and deep gray matter on T2-weighted and FLAIR images; few bilateral T2-hyperintense fluffy and poorly demarcated lesions; pontine or thalamic involvement (or both); and cerebellar peduncle lesions in children. Intraorbitally, one sees edematous, enlarged, tortuous optic nerve or nerves; bilateral long-segment T2 hyperintensity of anterior segments of the optic nerve; sparing of the optic chiasm and retrochiasmatic pathways; and perioptic nerve sheath and surrounding orbital fat enhancement. Spinal involvement is seen as longitudinally extensive transverse myelitis with a sagittal T2-hyperintense intramedullary spinal line, the axial "H" spinal cord sign (central cord gray matter T2 hyperintensity), and conus medullaris involvement. Early accurate diagnosis of MOGAD is important because prognosis and treatment differ from those for NMOSD and MS.

MITOCHONDRIAL DYSFUNCTION AND HYPOGAMMAGLOBULINEMIA RESULTING IN LACTIC ACIDOSIS AND RECURRENT BACTERIAL INFECTIONS

Introduction Defective mitochondrial function has been reported to cause T cell suppression and disruption of B cell isotype class switching and differentiation. We describe a patient with a mitochondrial DNA mutation and hypogammaglobulinemia. Case Description A 24-year-old Caucasian male with a history of acute disseminated encephalomyelitis in childhood presented with progressive myeloneuropathy, episodic rhabdomyolysis and lactic acidosis, and recurrent bacterial infections, including bacteremia. His IgG was 584mg/dl (700-1600 mg/dl) with post-vaccination protective titers to 6 of 23 Streptococcus pneumonia serotypes. His presentation was concerning for X-linked adrenoleukodystrophy (X-ALD), a genetic defect in the transport of very long-chain fatty acids (VLCFAs) across the peroxisomal membrane. Whole exome sequencing revealed a missense mutation (c.274G>A, amino acid change p.Gly92Arg) in the ALD protein. VLCFAs profile is abnormal in 99.9% of males with X-ALD, and his was normal. Mitochondrial gene sequencing was due to recurrent lactic acidosis, and showed a missense mutation (m.8552 T>C) at ATP6/ATP8 gene overlapping region. A muscle biopsy showed increased immature type IIC muscle fibers, suggestive for mitochondrial disorder. He was started on intravenous immunoglobulin, with subsequent resolution of fevers and bacteremia. However, he continues to have episodes of lactic acidosis. Discussion This clinical presentation suggests a possible link between mitochondrial function and humoral immunity. This patient has mutations in ATP synthase and ALD protein, which functions as a transporter to bind and hydrolyze ATP. These novel mutations are not well categorized. Functional studies may be helpful in understanding the consequence of these mutations and the effect of mitochondrial dysfunction on the immune system.

Childhood acute disseminated encephalomyelitis: an Egyptian pilot study.

Describing the variable clinical features, laboratory findings, neuroimaging findings, and treatments given to children who presented with ADEM and following them up both clinically and radiologically. 21 patients were recruited: 14 new cases, and 7 old ones presenting over the preceding 5years (retrospective review of existing data). 11 males and 10 females, with a mean age of 4.4years±2.7 SD, were included. All new patients were subject to full history, examination and a panel of investigations including MRI of the brain. Treatment was given in the form of pulsed methyl prednisolone or intravenous immunoglobulin (IVIG), followed by clinical and radiological follow-up every 3months as needed. 11 cases occurred in spring, 8 post vaccine, of which 5 were after oral polio vaccine (OPV). MRI was done for all 21 patients and was abnormal in all of them, CT was done in only 10 patients as was normal in 9. Hyponatremia was seen in 11 patients. All patients who received corticosteroids showed prompt improvement. 6 out of 10 patients who received IVIG first failed treatment. Of the 17 treated patients, 10 had no sequelae and 10 had total lesion resolution on MRI at 3months, versus 1 and 0 patients, respectively, in the untreated group. We found a disproportionately large number of post vaccination cases, especially after OPV. The association of ADEM with hyponatremia needs further study. MRI is central to diagnosis. Outcome is much better with treatment with steroids being far superior to IVIG. Excess use of IVIG should be discouraged.

Childhood acute disseminated encephalomyelitis: An Egyptian pilot study

Childhood acute disseminated encephalomyelitis: An Egyptian pilot study

Long-Term Neuropsychological Outcomes of Childhood Onset Acute Disseminated Encephalomyelitis (ADEM): a Meta-Analysis.

The long-term neurocognitive prognosis of childhood onset acute disseminated encephalomyelitis (ADEM) is unclear. This review and quantitative synthesis of the available literature examined whether there are long-term impacts of childhood ADEM on neurocognitive functioning. A search of online databases (MEDLINE, EMBASE, EBSCO CINAHL, PsycINFO and the Cochrane Database of Systematic Reviews) from their inception to October 2015 and reference lists identified 13 papers eligible for inclusion in the systematic review; seven of these were eligible for inclusion in meta-analyses. The systematic review indicated that, at a group level there is a positive long-term neuropsychological outcome from childhood onset ADEM. However, despite the apparent absence of long-term negative impacts of ADEM at a group level, at an individual level impairments in the areas of IQ, attention, executive functioning, processing speed, learning and memory, visuospatial skills and internalising symptoms were found in up to 43% of patients when aggregated across the studies. No significant negative effect of ADEM for any of the neuropsychological domains examined was found in meta-analyses. However, the effects for Processing Speed (r mean=-0.296 (CI 95%=-0.605-0.013)) and Internalising symptoms (r mean=0.242 (CI 95%=-0.014-0.564)) approached significance (p=0.06), suggesting a trend towards ADEM leading to long-term reduced processing speed and elevated internalising symptoms. Together, our findings suggest that despite a generally positive neurocognitive outcome post childhood ADEM there are a subset of individuals who can suffer from ongoing specific cognitive impairments. Clinical implications and research priorities are discussed.

Influenza A(H1N1)pdm09 Infection With Simultaneous Comorbidity of Severe Pneumonia and Acute Disseminated Encephalomyelitis: A Case Report.

The 2009 H1N1 pandemic strain of influenza A(H1N1)pdm09 was first detected in Mexico and the United States in the spring of 2009 and, thereafter, spread to across the world. In Japan, the number of patients affected by the virus increased dramatically since September 2009.1 The clinical profile of (H1N1)pdm09 infection varies from asymptomatic or mild to severe cases, resulting in severe respiratory failure, encephalitis or encephalopathy, and death in the worst scenario.2 Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder of the central nervous system following a viral infection or vaccination. The pathogenesis of ADEM is proposed to be autoimmune mechanisms triggered by infectious agents or vaccines. Childhood ADEM occurs more often after infection, and its prognosis is considered to be generally favorable.3 There are several reports of severe pneumonia caused by (H1N1)pdm09 infection, while there are only 7 pediatric case reports of ADEM following (H1N1)pdm09 until recently: none of these cases were complicated by pneumonia.4-6 Here we describe the case of 5-year-old boy who developed ADEM secondary to (H1N1)pdm09 severe pneumonia. To the best of our knowledge, this is the first case report of a pediatric patient with both comorbidities.

Acute Disseminated Encephalomyelitis Onset: Evaluation Based on Vaccine Adverse Events Reporting Systems

ObjectiveTo evaluate epidemiological features of post vaccine acute disseminated encephalomyelitis (ADEM) by considering data from different pharmacovigilance surveillance systems.MethodsThe Vaccine Adverse Event Reporting System (VAERS) database and the EudraVigilance post-authorisation module (EVPM) were searched to identify post vaccine ADEM cases. Epidemiological features including sex and related vaccines were analysed.ResultsWe retrieved 205 and 236 ADEM cases from the EVPM and VAERS databases, respectively, of which 404 were considered for epidemiological analysis following verification and causality assessment. Half of the patients had less than 18 years and with a slight male predominance. The time interval from vaccination to ADEM onset was 2-30 days in 61% of the cases. Vaccine against seasonal flu and human papilloma virus vaccine were those most frequently associated with ADEM, accounting for almost 30% of the total cases. Mean number of reports per year between 2005 and 2012 in VAERS database was 40±21.7, decreasing after 2010 mainly because of a reduction of reports associated with human papilloma virus and Diphtheria, Pertussis, Tetanus, Polio and Haemophilus Influentiae type B vaccines.ConclusionsThis study has a high epidemiological power as it is based on information on adverse events having occurred in over one billion people. It suffers from lack of rigorous case verification due to the weakness intrinsic to the surveillance databases used. At variance with previous reports on a prevalence of ADEM in childhood we demonstrate that it may occur at any age when post vaccination. This study also shows that the diminishing trend in post vaccine ADEM reporting related to Diphtheria, Pertussis, Tetanus, Polio and Haemophilus Influentiae type B and human papilloma virus vaccine groups is most likely due to a decline in vaccine coverage indicative of a reduced attention to this adverse drug reaction.

Cognitive and Behavioral Outcomes in Individuals With a History of Acute Disseminated Encephalomyelitis (ADEM)

We describe cognitive and behavioral outcomes in 12 males and 7 females diagnosed with acute disseminated encephalomyelitis (ADEM) in childhood. Age at assessment ranged from 6 to 23 years and all participants were at least 2 years post-ADEM presentation (mean 5.4 years). Performance was compared with 18 control subjects. Three of 19 ADEM patients met criteria for cognitive impairment, defined as performance falling ≤1.5 SD on at least three tests. Age at ADEM-onset was not associated with outcome. Despite the transient nature of the illness and absence of persistent physical disability, cognitive sequelae occur in some individuals following childhood ADEM.

Severe acute disseminated encephalomyelitis: a paediatric intensive care population-based study

There is a paucity of literature on the epidemiology of severe acute disseminated encephalomyelitis (ADEM). We describe a Paediatric Intensive Care Unit (PICU) population-based study to determine the epidemiology and clinical characteristics of children with ADEM requiring PICU admission or resulting in death. Anonymized data from the Paediatric Intensive Care Audit Network (PICANet) were obtained for all children under 16 years with a diagnosis of ADEM admitted to 25 PICUs in England and Wales (2004–2008). The Office for National Statistics (ONS) mortality database was also searched. In total, 27 PICANet cases (13 females:14 males; median age 4.8 years) were ascertained and all were alive on discharge. In addition, three cases were identified from the ONS mortality database. Of the 27 PICANet cases, clinical features included; seizures (n = 5); upper airway respiratory obstruction/stridor (n = 2); unspecified encephalopathy (n = 27); and polyfocal neurological deficits (n = 6). The median duration of ventilation was 3 days. Inotropic support was required in 4/27 patients, and one patient had invasive intracranial pressure monitoring. None received plasmapheresis. We conclude that the incidence of childhood ADEM admitted to the PICU in England and Wales is approximated at 0.5 per million children/year, thus representing approximately one quarter of children admitted with ADEM (denominator: 2009 Canadian surveillance data).

Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis

To study the longitudinal dynamics of anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases. We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry. Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels. The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination.

Acute disseminated encephalomyelitis: A 10-year cohort study in Thai children

Childhood acute disseminated encephalomyelitis (ADEM) is a demyelinating disease with variable clinical courses and outcomes. Its evolution to multiple sclerosis in Asian children is yet to be determined. Medical records, investigation results and magnetic resonance imaging of brain of Thai children aged less than 15 years with initial diagnosis of ADEM at a referral university hospital in Thailand from January 1997 to December 2006 were reviewed. Clinical course and the outcome were finalized by telephone interview, self-report questionnaire, and/or neurological examination by December 2008. Modified Rankin Score was applied for determination of disability. MRI findings were categorized along with the locations and number of areas of abnormalities shown by T2-weight and FLAIR. 16 patients consisting of 5 boys and 11 girls (age-range 1–14 years, mean 6.9 ± 3.6 years, median 6 years) were identified. Nine patients had cranial nerve dysfunctions including one child with optic neuropathy. One patient died with confirmed pathological diagnosis of ADEM. Among the remaining 15, who were followed from 2 to 10 years (mean 5.8 years), 13 and 3 patients were classified into monophasic ADEM and multiple sclerosis, respectively. Ten of 13 with final diagnosis of ADEM had complete recovery. There was no association between number of lesions or location in the initial MRI and the outcome and final diagnosis. ADEM in Thai children had similar clinical presentation and outcome to previous studies in Western countries. ADEM can occasionally evolve to multiple sclerosis in Thai children as being shown in previous reports from other Asian countries.

Clinical study of childhood acute disseminated encephalomyelitis, multiple sclerosis, and acute transverse myelitis in Fukuoka Prefecture, Japan

Acute disseminated encephalomyelitis (ADEM) has recently been studied in several countries owing to the development and wide spread use of imaging technology, but few epidemiological studies of childhood ADEM have been undertaken in Asian countries. To perform a comprehensive survey of ADEM and related diseases in Japanese children, we conducted a multicenter, population-based study on childhood ADEM, multiple sclerosis, and acute isolated transverse myelitis in Fukuoka Prefecture, Japan. We identified 26 children with ADEM, 8 with multiple sclerosis, and 4 with acute transverse myelitis during 5 years between September 1998 and August 2003. The incidence of childhood ADEM under the age of 15 years was 0.64 per 100,000 person-years, mean age at onset was 5.7 years, and male–female ratio was 2.3:1. The prevalence of childhood multiple sclerosis was 1.3 per 100,000 persons. The mean age at onset of multiple sclerosis, 9.3 years, was significantly higher than that of ADEM. Nineteen (73%) and four (15%) patients with ADEM experienced antecedent infectious illnesses and vaccinations, respectively, within 1 month before the onset. Clinical and radiological findings of ADEM revealed that the frequency of seizures, mean white blood cell counts in cerebrospinal fluid, and the frequency of subcortical lesions in Fukuoka study, seemed to be higher than those in previous non-Asian studies. These findings suggest that there are ethnic or geographical differences in the incidence and clinical features of ADEM, and that there might be potent genetic or environmental risk factors for ADEM distinct from those for multiple sclerosis.

Childhood Acute Disseminated Encephalomyelitis Presenting as Foix-Chavany-Marie Syndrome

A 10-year-old boy presented with anarthria and bilateral central faciolinguovelopharyngeomasticatory paralysis with "automatic voluntary dissociation" suggestive of Foix-Chavany-Marie syndrome or anterior opercular syndrome following a nonspecific upper respiratory infection. Brain magnetic resonance imaging revealed bilateral subcortical perisylvian demyelination in addition to multiple subcortical white-matter demyelination. The clinicoradiologic picture suggested acute disseminated encephalomyelitis. The child recovered completely following intravenous methylprednisolone and intravenous immunoglobulin therapy. This is the first report of anterior opercular syndrome in childhood acute disseminated encephalomyelitis.

Neuroimaging features of acute disseminated encephalomyelitis in childhood

Acute and disseminated demyelination of the central nervous system in children may have many causes. This study reports a retrospective cohort of 10 consecutive pediatric cases (5 to 17 years; mean [S.D.] 12.1 [4.3] years) with a presenting diagnosis of acute disseminated encephalomyelitis and the clinical and radiologic follow-up. The evolution of magnetic resonance imaging abnormalities was determined from serial studies in nine patients with a mean (S.D.) follow-up of 334.2 (312.8) days. Resolution of magnetic resonance imaging T(2) prolongation (i.e., demyelination) within 6 months of presentation was associated most commonly with a final clinical diagnosis of acute disseminated encephalomyelitis (including the multiphasic form), but failed to meet statistical significance (Fisher's exact test; P = 0.083). Incomplete resolution of the magnetic resonance imaging signal abnormalities yielded a statistically significant association (Fisher's exact test; P = 0.048) with an abnormal neurologic outcome. In summary, we conclude that early resolution of magnetic resonance imaging signal abnormalities or recurrent demyelination within 6 months of an acute and disseminated demyelinating event suggests the diagnosis of acute disseminated encephalomyelitis in children, although this association failed to meet statistical significance. However, a statistically significant association between complete resolution of magnetic resonance imaging signal abnormalities and a normal neurologic outcome was observed.

Adult acute disseminated encephalomyelitis associated with poststreptococcal infection

Acute disseminated encephalomyelitis (ADEM) is a monophasic illness that is thought to develop from antigenic mimicry with antibodies having cross-reactivity to host epitopes in the nervous system. The disorder typically follows an exanthematous or recent viral infection. In contrast, complications from bacterial poststreptococcal infections more commonly give rise to disorders in the pediatric population including Sydenham's chorea, pediatric autoimmune neuropsychiatric disorders, and ADEM. We present the novel case of documented streptococcal pharyngitis and elevated antideoxyribonuclease B (ADNB) titers in an adult giving rise to ADEM. Furthermore, the absence of basal ganglia abnormalities on MRI and the degree of leukocytosis in the CSF distinguish the adult form of ADEM from childhood ADEM and adult viral demyelinating diseases.

Neuropsychological outcome after acute disseminated encephalomyelitis: Impact of age at illness onset

Recovery from acute disseminated encephalomyelitis in childhood appears relatively uneventful, at least when looking at functional recovery parameters such as neurologic outcome. However, neuropsychology literature suggests that relatively transient illnesses affecting the central nervous system are associated with cognitive and social sequelae, particularly when the illness occurs during the preschool years. This study investigated the impact of timing of acute disseminated encephalomyelitis on intellectual, educational, and social functioning in children. Nineteen children (10 with acute disseminated encephalomyelitis before the age of 5 years), who had been admitted to the Royal Children's Hospital, Melbourne Australia, in the past 6 years underwent a brief neuropsychologic assessment. Performance was compared with 19 control subjects, stratified for age and socioeconomic status with the acute disseminated encephalomyelitis group. Children who sustained their illness before 5 years of age were particularly vulnerable to impairments in both cognitive and social domains. In particular, a higher incidence of severe behavioral and emotional problems was reported by parents of children who had experienced acute disseminated encephalomyelitis before 5 years of age. This finding suggests that there may be long-term complications in early childhood. A multidisciplinary approach to management post-illness is warranted in this age group.

Acute disseminated encephalomyelitis in children: outcome and prognosis.

Acute disseminated encephalomyelitis (ADEM) is the most common demyelinating disorder of childhood. Its clinical features, prognosis and treatment vary in different reports. To examine a series of children with ADEM for clinical findings, course, recurrences, and possible variables affecting outcome. Multicentric data collected from 7 tertiary referral centers were registered and evaluated in a central database in 1990 - 2001 for clinical, laboratory, and MRI features. Course and prognosis were assessed in patients with at least 12 months' follow-up. Forty-six patients were evaluated. Median age at onset was 8 years, M/F ratio, 1.7/1. Most common symptoms and signs pertained to the motor system and consciousness. Of 39 children with 12 months' follow-up, 71 % recovered completely. Thirteen (33 %) children had relapses. Patients who had more than one relapse (n = 4) presented with new symptoms at each attack. Treatment with high-dose methylprednisolone was associated with complete recovery, and tapering over more than 3 weeks, with a lower rate of relapses. MRI lesions could persist even in asymptomatic patients; in particular, periventricular lesions tended to disappear later than others. Complete clinical recovery is common and serious complications are rare in childhood ADEM, but the rate of relapses is considerable. Clinical picture at first relapse may help to identify patients likely to experience multiple relapses. The timing and duration of steroid treatment affects outcome.

Multiple sclerosis vs acute disseminated encephalomyelitis in childhood

The initial presenting clinical and laboratory findings of either acute disseminated encephalomyelitis or the first attack of multiple sclerosis in the pediatric population were compared and contrasted. A retrospective review of the medical records was conducted of all children younger than 17 years who presented with either the diagnosis of acute disseminated encephalomyelitis or multiple sclerosis between 1987 and 2001. Seventeen cases of clinically definite multiple sclerosis (seven female, mean age 12.4 ± 4.5 years) and seven cases of acute disseminated encephalomyelitis (three female; mean age 8.7 ± 3.8 years) were reviewed. Systemic and nonfocal neurologic symptoms were more commonly evident in acute disseminated encephalomyelitis than in multiple sclerosis: fever (43% vs 6%), headache (57% vs 24%), fatigue (71% vs 29%), vomiting (57% vs 0%), and encephalopathy (71% vs 6%). In multiple sclerosis patients, T 2-weighted white matter magnetic resonance imaging lesions were more commonly located in the corpus callosum (64% vs 17%) and the periventricular area (91% vs 50%) compared with those in patients with acute disseminated encephalomyelitis. These results suggest that acute disseminated encephalomyelitis and multiple sclerosis can be differentiated to some degree according to clinical and radiologic data at initial presentation, which is important because the long-term prognosis for childhood multiple sclerosis appears to be less favorable.