RECENT ADVANCES IN ADEM

RECENT ADVANCES IN ADEM DR. SUMIT KAMBLEDEPT. OF NEUROLOGYGMC, KOTA

Is a demyelinating disease of the central nervous system that typically presents as a monophasic disorder associated with multifocal neurologic symptoms and encephalopathy.Usually follows an infection or vaccination.Is characterised by multifocal white matter lesions on neuroimaging.Monophasic disease. Uncommonly ADEM can relapse.

EPIDEMIOLOGYAnnual incidence of ADEM is 0.40.8 per 100,000 Commonly affects children and young adults, probably related to the high frequency of exanthematous and other infections and vaccination in this age group.No gender predominance.Mortality and major neurological sequelae of ADEM after varicella and rubella infections are much lower in comparison with ADEM after measles infection.

Postinfectious-preceded by a viral or bacterial infection, usually in the form of a nonspecific upper respiratory infection. Antecedent infection could be identified in 72 -77 % of patients. most cases present in winter and spring.

Postvaccinial- Less than 5 percent of all ADEM cases follow immunization.

PRECEDING INFECTIOUS ILLNESSESA. InfectionsB. Vaccines Viral Measles, Mumps. Influenza A or B. Hepatitis A or B. Herpes simplex. Varicella, rubella. Epstein-Barr Cytomegalovirus. HIV.Others Mycoplasma pneumoniae. Chlamydia. Legionella. Campylobacter. Streptococcus.Rabies. Diphtheria, tetanus, pertussis. Smallpox. Measles. Japanese B encephalitis. Polio. Hepatitis B. Influenza.

Risk of occurrence of ADEM is 20 times lower after vaccination than ADEM after natural measles virus infection.ADEM found after measles is associated with mortality rates as high as 25% and 25%40% of survivors were left with permanent neurological sequelae.

International Pediatric MS Study GroupConsensus DefinitionsMonophasic ADEM First clinical event with a presumed inflammatory or demyelinating cause, with acute or subacute onset that affects multifocal areas of the CNS; Clinical presentation must be polysymptomatic and must include encephalopathy, which is defined as one or more of the following:Behavioral change occurs, e.g., confusion, excessive irritability.Alteration in consciousness occurs, e.g., lethargy, coma. Event should be followed by improvement, clinically, on MRI, or both, but there may be residual deficits.

Patient has no history of a clinical episode with features of a prior demyelinating event.No other etiologies can explain the event.New or fluctuating symptoms, signs, or MRI findings occurring within 3 months of the inciting ADEM event are considered part of the acute event.Neuroimaging shows focal or multifocal lesion(s), predominantly involving white matter, without radiologic evidence of previous destructive white matter changes.

Brain MRI, with FLAIR or T2-weighted images, reveals large (>1 to 2 cm) lesions that are multifocal, hyperintense, and located in the supratentorial or infratentorial white matter regions; gray matter, especially basal ganglia and thalamus, is frequently involved.In rare cases, brain MR images show a large single lesion (1 to 2 cm), predominantly affecting white matter.Spinal cord MRI may show confluent intramedullary lesion(s) with variable enhancement, in addition to abnormal brain MRI findings specified previously.

Recurrent ADEMNew event of ADEM occurs with recurrence of the initial symptoms and signs 3 or more months after the first ADEM event without involvement of new clinical areas by history, examination, or neuroimaging.Event does not occur while on steroids and occurs at least 1 month after completing therapy.MRI shows no new lesions; original lesions may have enlarged.No better explanation exists.

Multiphasic ADEM ADEM is followed by a new clinical event also meeting criteria for ADEM, but involving new anatomic areas of the CNS as confirmed by history, neurologic examination, and neuroimaging. Subsequent event must occur (1) at least 3 months after the onset of the initial ADEM event and (2) at least 1 month after completing steroid therapy.Subsequent event must include a polysymptomatic presentation, including encephalopathy, with neurologic symptoms or signs that differ from the initial event (mental status changes may not differ from the initial event). Brain MRI must show new areas of involvement but also demonstrate complete or partial resolution of those lesions associated with the first ADEM event.

Acute disseminated encephalomyelitis and related disordersAcute disseminated encephalomyelitis Postinfectious. Postvaccinial.Acute haemorrhagic leucoencephalitisRestricted form of acute, inflammatory demyelinating diseases Transverse myelitis. Optic neuritis. Cerebellitis. Brain stem encephalitis.Multiphasic form of acute disseminated encephalomyelitis and multiple sclerosis

PATHOLOGYPathological hallmark - areas of perivenous demyelination and infiltration of lymphocytes and macrophages.Other changes - hyperaemia, endothelial swelling, and vessel wall invasion by inflammatory cells, perivascular oedema, and haemorrhage.Present in the small blood vessels of both white and grey matter.Postinfectious encephalomyelitis typically involves the white matter, lesions in grey matter can also been seen.

Pathological features of acute demyelinating disordersFeatureADEMAcutemultiplesclerosisAcutehaemorrhagicleucoencephalitisNeuromy-elitisopticaPerivascular infiltratesLymphocytesMacrophages or monocytesPolymorphsEosinophils ++

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++ ++ -- ++ ++ ++ ++Perivascular haemorrhage -- -- ++ --Necrotising venules -- -- ++ +Perivascular demyelination ++ ++Axonal damage ++ ++

PATHOPHYSIOLOGYADEM results from a transient autoimmune response against myelin or other autoantigens, possibly, via molecular mimicry or by non-specific activation of an autoreactive T cell clone.Genetic susceptibility explains why encephalomyelitic complications develop in only a small minority of patients.Human leucocyte antigen class II genes have the most significant influence.

Immunopathological events leading to ADEM can be divided into two major phases-

1.Initial T cell priming and activation2.Subsequent recruitment and effector phase

Acute haemorrhagic leucoencephalitis is a more severe and frequently fatal hyperacute variant of ADEM.Most important distinguishing feature of acute haemorrhagic leucoencephalitis from ADEM is necrotising vasculitis of venules. Perivascular infiltrates consist mainly of polymorphonuclear cells. Perivascular haemorrhages are also common

CLINICAL FEATURESSystemic symptoms - fever, malaise, myalgias, headache, nausea, and vomiting often precede the neurological symptoms.Begin 421 days after the inciting event.Encephalopathy- ranging from lethargy to coma.Focal and multifocal neurological signs like hemiparesis, cranial nerve palsies, and paraparesis. Other commonly reported findings include meningismus, ataxia, and varied movement disorders.Seizure may occur in severe cases, especially in the acute haemorrhagic form of ADEM.Optic neuritis is often bilateral (23%) and transverse myelopathy is often complete

43% of have peripheral nervous system (PNS) involvement, which is usually demyelinating and subclinical.Most adult patients present clinically in a fashion similar to that of children, except that there is a relatively infrequent occurrence of headache, fever and meningismus, and a higher frequency of sensory deficits. Optic neuritis is also infrequent in adult ADEM.Restricted forms : ON, Transverse myelitis, Cerebellitis, Brain stem encephalitis.

Recovery can begin within days . Mortality varies between 10% and 30%, with complete recovery in 50%.Poor prognosis is correlated with severity and abruptness of onset of the clinical syndrome.Measles virus associated ADEM may carry a worse prognosis than vaccine associated disease.

Acute disseminated encephalomyelitis: Clinical syndromes

LABORATORY FEATURESCerebrospinal fluid-

Increased pressure, lymphocytic pleocytosis (as much as 1000/mm3, sometimes polymorphonuclear leucocytosis initially), and raised protein (usually