ADEM

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Acute Disseminated Encephalomyelitis. Inflammatory, nonvasculitic, demyelinating, immune mediated, monophasic and polysymptomatic disease of the central nervous system Post infectious encephalomyelitis, Post vaccination encephalomyelitis. . 5

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ADEM

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1. ADEM Dr Rajesh Kumar MD (PGI), DM (Neonatology) PGI, Chandigarh, India Rani Children Hospital, Ranchi

2. Acute Disseminated Encephalomyelitis Inflammatory, nonvasculitic, demyelinating, immune mediated, monophasic and polysymptomatic disease of the central nervous system Post infectious encephalomyelitis, Post vaccination encephalomyelitis

3. 5 ½ years FCH, had pain abdomen, fever 7 days back Had dystonia, aphasia, seizure one episode Developed fever next day On examination: no neurodeficit CT: MRI

8. 8 years old FCH Sudden onset of loss of vision Headache Afebrile MRI: normal Eye: B/L Pappilitis Treated with 3 days IV methylpred, good recovery

9. Post infectious CNS illness Acute cerebellar syndrome: 1 in 1000 Sensorineural deafness after mumps Sydenham’s chorea Inflammatory lesion at single site: optic neuritis, transverse myelitis Disseminated inflammatory CNS disease: ADEM, MDEM, MS

10. History Why should we know now Increase in vaccinations Post ADEM may have long term disability Highly effective treatment is available now

11. ADEM: Pathology

12. Pathology Resembles pathology of experimental allergic encephalomyelitis (EAE). Prominence of perivenular round cell inflammation (found in many encephalitis) Patchy demyelination with preservation of axon cylinders and the prominence of microglial cells in the inflammatory exudate (these are not found in encephalitis. )

14. Epidemiology Incidence: 0.8 per 100,000, F>M 80% of childhood cases occur < 10 years, even at 4 months 2 weeks post infection (range: 2-20 days) (antigenic triggering) Post exanthematous fever ADEM : 100:100,000 after measles in one series Post vaccine: meales, MMR, Rubella, influnzae, rabies, Jap B encephalitis measles vaccination–associated ADEM is about 10 to 20 per 100 000 Vaccine assoiated ADEM upto 3 months post vaccination: WHO guidline

15. Spectrum of demyelinating disease Optic neuritis ---- ADEM ------- MS Division between these processes is indistinct Other boundaries of ADEM merge indistinctly with a wide variety of inflammatory encephalitic and vasculitic illnesses as well as monosymptomatic postinfectious illnesses that should remain distinct from ADEM, such as acute cerebellar ataxia (ACA). A further indistinct boundary is shared by ADEM and Guillain-Barré syndrome and is manifested in cases of Miller-Fisher syndrome and encephalomyeloradiculoneuropathy (EMRN).

16. Pathogenesis (Two concepts) Molecular mimickery: brain vaccines Th2 lymphocytes have increased reactivity to myelin basic protein Inflammatory cascade concept: CNS infections triggering immune response, damage to BBB, brain specific antigens spills into systemic circulation and initiates immunologic process Extensive research with these animal models has led to the development of 2 current pathogenic concepts. The inflammatory cascade concept implies a direct CNS infection with a neurotropic pathogen, resulting in CNS tissue damage and systemic leakage of CNS-confined autoantigens into the systemic circulation through a disintegrated blood-brain barrier. These autoantigens, once processed in systemic lymphatic organs, will lead to tolerance breakdown and to a self-reactive and encephalitogenic T-cell response. Such activated T cells are capable of invading the CNS and perpetuating CNS inflammation even further. The molecular mimicry concept proposes a structural or partial amino-acid sequence homology between the inoculated pathogen and myelin proteins of the host.37 This structural homology is not sufficient for a pathogen to be recognized as "self," which would result in immunotolerance. Antigen-presenting cells such as B cells or dendritic cells process the pathogen at the site of inoculation, leading to T-cell activation. Activated T cells may in turn cross-activate antigen-specific B cells. Both activated T cells and B cells are quite capable of entering the CNS for routine immune surveillance. Thus, even after clearance of the pathogen, these antigen-specific cells may encounter the homologue myelin protein during their physiologic surveillance of the CNS. They may become reactivated by local antigen-presenting cells such as microglia, causing an inflammatory immune reaction against the presumed foreign antigen; thus, the initially physiological immune response leads to detrimental autoimmunity. Some of the vaccine-associated ADEM cases can be directly attributed to the contamination of the specific vaccine with CNS tissue. This contamination may explain the substantial 0.15% incidence of ADEM after immunization with a live attenuated rabies virus vaccine (Semple vaccine) in developing countries, which is propagated in cultures of rabbit or goat CNS tissue. In this regard, antibodies against myelin antigens are detectable in patients with Semple vaccine–associated ADEM.31 Newer rabies vaccines are propagated in human diploid cells and do not cause this particular adverse effect. A similar mechanism may account for ADEM observed after vaccination against Japanese B encephalitis, where certain vaccine strains are Extensive research with these animal models has led to the development of 2 current pathogenic concepts. The inflammatory cascade concept implies a direct CNS infection with a neurotropic pathogen, resulting in CNS tissue damage and systemic leakage of CNS-confined autoantigens into the systemic circulation through a disintegrated blood-brain barrier. These autoantigens, once processed in systemic lymphatic organs, will lead to tolerance breakdown and to a self-reactive and encephalitogenic T-cell response. Such activated T cells are capable of invading the CNS and perpetuating CNS inflammation even further. The molecular mimicry concept proposes a structural or partial amino-acid sequence homology between the inoculated pathogen and myelin proteins of the host.37 This structural homology is not sufficient for a pathogen to be recognized as "self," which would result in immunotolerance. Antigen-presenting cells such as B cells or dendritic cells process the pathogen at the site of inoculation, leading to T-cell activation. Activated T cells may in turn cross-activate antigen-specific B cells. Both activated T cells and B cells are quite capable of entering the CNS for routine immune surveillance. Thus, even after clearance of the pathogen, these antigen-specific cells may encounter the homologue myelin protein during their physiologic surveillance of the CNS. They may become reactivated by local antigen-presenting cells such as microglia, causing an inflammatory immune reaction against the presumed foreign antigen; thus, the initially physiological immune response leads to detrimental autoimmunity. Some of the vaccine-associated ADEM cases can be directly attributed to the contamination of the specific vaccine with CNS tissue. This contamination may explain the substantial 0.15% incidence of ADEM after immunization with a live attenuated rabies virus vaccine (Semple vaccine) in developing countries, which is propagated in cultures of rabbit or goat CNS tissue. In this regard, antibodies against myelin antigens are detectable in patients with Semple vaccine–associated ADEM.31 Newer rabies vaccines are propagated in human diploid cells and do not cause this particular adverse effect. A similar mechanism may account for ADEM observed after vaccination against Japanese B encephalitis, where certain vaccine strains are

18. Clinical features Prodromal illness ? asymptomatic period ? acute neurological presentation Neurological onset is abrupt (>95% cases) Mental changes are common (>85% cases) Convulsive seizure in >25% cases Optic Neuritis, Cranial nerve abnormality Long tract signs in >85% cases

19. ADEM: Clinical Syndromes Mild encephalopathy, sometimes associated with long tract signs Severe encephalopathy with bilateral paresis, often associated with brainstem signs, particularly the lower cranial nerves Predominantly brainstem presentation with features suggesting Fisher syndrome in some cases or Bickerstaff brainstem encephalitis in other cases Hemiparesis, ipsilateral long tract signs, with or without seizure Predominantly ataxic, differing from the predominantly axial/gait ACA in that ADEM-associated ataxia is often associated with nystagmus, extremity ataxia, and long tract signs EMRN (mixed upper and lower motor neuron signs)

20. Clinical presentation The age at onset ranged from 4 months to 15 years. Seventeen (85%) children had a recent infectious prodrome. Children presented most often with acute consciousness disturbance (70%) and motor deficits (55%). Seizures occurred in 10 (50%),: Acta Paediatr Taiwan. 2006 Mean age at onset was 5.3 +/- 3.9 years, with a significant male predominance. Sixty-two patients (74%) had a preceding viral illness or vaccination. Acute hemiparesis (76%), unilateral or bilateral long tract signs (85%), and changes in mental state (69%) were the most prominent presenting features: Neurology. 2002

21. Fulminant ADEM In children <3yrs Rapid evolution of a low state of function and demonstration on scans of severe edema. Transverse myelitis may begin rapidly and be associated with severe edema, usually in the cervical region

22. Physical Signs Irritability and lethargy Fever (50%),headache (45-65%) and meningism (20-30%) Development of neurologic abnormalities: minutes to 6 weeks or more. Neurological abnormality: visual disturbances and language, mental status, and psychiatric abnormalities Weakness (50-75% of cases) is more commonly discerned than sensory defects (15-20%).

23. Triad of ADEM Prodromal illness or preceding vaccination, MRI signs of demyelination, Acute presentation of neurologic symptoms

24. Lab Leukocytosis with lymphopenia, increased platelet, Mild elevation in ESR CSF may show inflammatory rsults EEG may be abnormal VEP, BERA may be abnormal

25. Neuroimaging MRI: extensive, multifocal, subcortical white matter abnormalities MRI: subcortical white matter, may be gray matter also, CT may be normal in 50% cases Convalescent MRI helpful in deffrentating with MS, new lesions in MS

26. Treatment IV methylprednisolone (20-30 mg/kg) for 3-5 days followed by oral prednisolone for 2-6 weeks Longer the course fewer the relapse IVIG, Plasmapharesis Cyclosporin , cyclophosphamide Methylpred + IVIG Controlled clinical trials that would meet the type A or type B criteria proposed by the American Academy of Neurology, Saint Paul, Minn, and the MS Council for Clinical Practice Guidelines have not yet been conducted in ADEM. At this time, intravenous high-dose corticosteroids are, based on empirical evidence (type C recommendation), widely accepted as first-line treatment.54 The aim is to abbreviate the CNS inflammatory reaction as soon as possible and to achieve an accelerated clinical improvement. A number of various other anti-inflammatory and immunosuppressant therapies may potentially also be effective. Several case studies have reported beneficial effects of plasmapheresis55 and intravenous immunoglobulin therapies.54, 56-57 Immunosuppressive agents, such as mitoxantrone or cyclophosphamide, should be considered as alternative therapies if corticosteroid treatment shows no clinical effect57-58 or if relative and absolute contraindications for corticosteroids exist. As a pragmatic and clinical practical approach, we propose the following treatment scheme. For therapeutic interventions in MS relapses, we propose an initial regime of high-dose intravenous methylprednisolone with a cumulative dose of 3 to 5 g, followed by a prolonged oral prednisolone taper of 3 to 6 weeks.3, 5, 34 Should a patient not respond adequately to corticosteroids, therapy should be escalated, preferentially with intravenous immunoglobulin (0.4 g/kg of body weight over 5 days).54, 56-57 Alternatively, or if this approach fails, we propose to consider plasmapharesis.55 In very severe cases, immunosuppression with cyclophosphamide or mitoxantrone should be attempted.57-58 In general, treatment should be initiated as early as possible and as aggressive as necessary.14 Controlled clinical trials that would meet the type A or type B criteria proposed by the American Academy of Neurology, Saint Paul, Minn, and the MS Council for Clinical Practice Guidelines have not yet been conducted in ADEM. At this time, intravenous high-dose corticosteroids are, based on empirical evidence (type C recommendation), widely accepted as first-line treatment.54 The aim is to abbreviate the CNS inflammatory reaction as soon as possible and to achieve an accelerated clinical improvement. A number of various other anti-inflammatory and immunosuppressant therapies may potentially also be effective. Several case studies have reported beneficial effects of plasmapheresis55 and intravenous immunoglobulin therapies.54, 56-57 Immunosuppressive agents, such as mitoxantrone or cyclophosphamide, should be considered as alternative therapies if corticosteroid treatment shows no clinical effect57-58 or if relative and absolute contraindications for corticosteroids exist. As a pragmatic and clinical practical approach, we propose the following treatment scheme. For therapeutic interventions in MS relapses, we propose an initial regime of high-dose intravenous methylprednisolone with a cumulative dose of 3 to 5 g, followed by a prolonged oral prednisolone taper of 3 to 6 weeks.3, 5, 34 Should a patient not respond adequately to corticosteroids, therapy should be escalated, preferentially with intravenous immunoglobulin (0.4 g/kg of body weight over 5 days).54, 56-57 Alternatively, or if this approach fails, we propose to consider plasmapharesis.55 In very severe cases, immunosuppression with cyclophosphamide or mitoxantrone should be attempted.57-58 In general, treatment should be initiated as early as possible and as aggressive as necessary.14

27. Relapse within 6 months: MDEM Relapse after 6 months: MS Vaccination should be avoided within 6 months of ADEM

28. Prognosis Mortality: 10% in older studies, Now <2% Morbidity: visual, motor, autonomic, and intellectual deficits and epilepsy. Problems persist after the first few weeks of illness in only about 35% of cases, and in most of these patients, the deficits resolve within 1 year of onset. Intellectual deficits (varying from attention problems to mental retardation) and epilepsy arise most often in children whose bout of ADEM occurs before the second birthday. Visual and motor deficits and problems with bowel or bladder function may persist for varying periods of time In the past, the prognosis and long-term outcome for patients diagnosed with ADEM were considered poor. This has changed dramatically and is attributable primarily to 2 factors. First, the incidence of postinfectious measles ADEM has decreased considerably because of efficient vaccinations. Twenty-five percent of ADEM induced by measles infections may be lethal, and an additional 30% to 35% of the surviving patients do not recovery fully and suffer from persistent, disabling neurological sequelae.59 Second, the widespread and early use of high-dose steroids has shown to be beneficial, at least empirically.14, 54, 60 Nowadays, the long-term prognosis of ADEM in terms of functional and cognitive recovery is favorable (Table 2).61 In several studies, the average time period to recovery was reported to be between 1 and 6 months.4-5 However, cases with a per-acute onset or prolonged disease course were also described.3-4 The outcome was favorable in most cases, ranging between 70% and 90% if minor residual disability was considered (Table 2). However, it should be stressed that the mortality of postinfectious ADEM may still be as high as 5%. Some studies have associated an unfavorable prognosis to a sudden onset and an unusually high severity of the neurological symptoms. In the past, the prognosis and long-term outcome for patients diagnosed with ADEM were considered poor. This has changed dramatically and is attributable primarily to 2 factors. First, the incidence of postinfectious measles ADEM has decreased considerably because of efficient vaccinations. Twenty-five percent of ADEM induced by measles infections may be lethal, and an additional 30% to 35% of the surviving patients do not recovery fully and suffer from persistent, disabling neurological sequelae.59 Second, the widespread and early use of high-dose steroids has shown to be beneficial, at least empirically.14, 54, 60 Nowadays, the long-term prognosis of ADEM in terms of functional and cognitive recovery is favorable (Table 2).61 In several studies, the average time period to recovery was reported to be between 1 and 6 months.4-5 However, cases with a per-acute onset or prolonged disease course were also described.3-4 The outcome was favorable in most cases, ranging between 70% and 90% if minor residual disability was considered (Table 2). However, it should be stressed that the mortality of postinfectious ADEM may still be as high as 5%. Some studies have associated an unfavorable prognosis to a sudden onset and an unusually high severity of the neurological symptoms.

29. Follow up The long-term (10-y follow-up) risk of patients with ADEM for development of MS is 25%. Risk for MS is highest in children whose ADEM onset was (1) afebrile, (2) without mental status change, (3) without prodromal viral illness or immunization, (4) without generalized EEG slowing, (5) associated with an abnormal CSF immune profile

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