What Is Acute Disseminated Encephalitis?

ADEM is divided into monophasic, recurrent, and polyphasic. See the diagnosis section for details.

Dong Huiqing	(Chief physician)	Department of Neurology, Xuanwu Hospital, Capital Medical University
Liu Ye	(Deputy Chief Physician)	Department of Neurology, Xuanwu Hospital, Capital Medical University

Acute disseminated encephalomyelitis (ADEM) is a type of idiopathic central nervous system demyelinating disease, which is more common in children, but can also occur at any age. According to the definition of the International Pediatric MS Study Group (IPMSSG), ADEM is an acute or subacute onset of encephalopathy (behavioural or conscious disturbance) that affects multiple areas of the central nervous system. First demyelinating disease. The typical ADEM is a uniphasic course with a good prognosis, and relapsed and polyphasic types should be distinguished from multiple sclerosis.

Western Medicine Name

Acute disseminated encephalomyelitis

English name

acute disseminated encephalomyelitis, ADEM

Affiliated Department

Internal Medicine-Neurology

Main cause

unknown reason

Multiple groups

child

Classification of Acute Disseminated Encephalomyelitis

ADEM is divided into monophasic, recurrent, and polyphasic. See the diagnosis section for details.

Causes of Acute Disseminated Encephalomyelitis

ADEM is a rare disease with an annual incidence of 0.2-0.8 / 100,000 ^[1-2] , 80% of patients occur in children under 10 years of age ^[3] , it can occur in adults, but it is rare. 70-93% of patients have a history of infection or vaccination several weeks before onset. Torisu et al. Reported a prevalence of 0.64 per 100,000 in children under 15 years of age, with an average age of onset of 5.7 years and a male: female ratio of 2.3: 1 ^[4] . Tselis et al. Reported the incidence after vaccination: post-measles ADEM 1: 1000 to 1: 20,000, with the highest incidence after measles vaccination ^[5] . The occurrence of ADEM is age-related, more common in children, and the cause is unknown. It may be related to immature CNS myelin sheath development in children or different immune responses in adults. Iatrogenic factors can also lead to the occurrence of ADEM, such as kidney transplantation, application of brain tissue extracts, and the trial of A42 vaccine for AD. During the A42 vaccine trial, ADE appeared in 6% of patients, but not in the placebo group ^{[6 ]} .

Pathological changes of acute disseminated encephalomyelitis

The main pathological changes of ADEM are disseminated demyelinating changes in the brain, brainstem, cerebellum, and spinal cord. The white matter around the ventricle, the temporal lobe, and the optic nerve are more prominent. The demyelinating changes are often centered on the small veins. Inflammatory cell infiltration, the outer layer of which has a mononuclear cell-based peripheral invasion, that is, vascular cuffs, white matter myelin sheath around the veins, and scattered glial cell proliferation ^[7] . The pathological difference between ADEM and MS ^[8] : The inflammatory lesions of ADEM extend radially from small blood vessels, while the lesions of MS are mostly discontinuous; secondly, the phagocytic cells of ADEM are surrounded by small blood vessels, and the phagocytic cells of MS are Around the plaque; again, the borders of MS lesions are more clear, while those of ADEM lesions are blurred. By the end of the disease, MS patients have a stellate cell response accompanied by glial hyperplasia, but ADEM does not.

Immunopathological mechanism of acute disseminated encephalomyelitis

Current evidence suggests that ADEM is a transient autoimmune response against myelin sheath or other autoantigens induced by auto T cell activation ^[9] . It may be related to the following mechanisms: First, the molecular simulation hypothesis is often supported by viral infection and vaccination before the disease. The molecular simulation hypothesis believes that parts of the pathogen and the host structure are similar to induce T cell activation, but not enough to make it resistant. Animal tests have found that injecting myelin into healthy animals can induce acute, chronic, or relapsing-remitting encephalomyelitis (EAE). The second is the hypothesis that central infection is the triggering factor. After the central nervous system infection, an autoimmune response is secondary. The infection causes the blood-brain barrier to be destroyed, leading to the release of centrally-associated autoantigens into the blood, which are processed by lymphoid organs to break the tolerance of T cells. Causes an allergic reaction to the center. The third is the effect of cytokines. In the cerebrospinal fluid of ADEM patients, IL-4, IL-10, and TNF- were found to increase. The number of myelin-reactive T cells in peripheral blood was more than ten times higher than that of normal people, producing IFN-. The number of CD3 + T cells increased, while the number of CD4 + T cells producing IL-17 did not increase, the latter can be significantly increased in patients with MS ^[10] . The fourth is the role of antibodies. Myelin basic protein (MBP) antibody and myelin oligodendrocyte glycoprotein (MOG) antibody can be detected in the serum of ADEM patients. The latter is more common in children. MOG after treatment Antibodies often disappear, and if they persist, patients will eventually convert to MS ^[9] .

Clinical manifestations of acute disseminated encephalomyelitis

ADEM mostly occurs from 2 days to 4 weeks after virus infection, and a few occur after vaccination, and some patients have no cause before illness. Clinical manifestations of patients with multifocal neurological abnormalities suggest that the central nervous system is widely affected, and unilateral or bilateral pyramidal tract signs (60-95%), acute hemiplegia (76%), and ataxia (18- 65%), cranial nerve palsy (22-45%), optic neuritis (7-23%), epilepsy (13-35%), spinal cord involvement (24%), anaesthesia (2-3%), speech Disorders (5-21%), and many are accompanied by conscious disturbances; fever and meningeal irritation are also common, and the incidence of respiratory failure secondary to brainstem damage or disturbance of consciousness is 11-16% ^[3] . In addition, ADEM is more susceptible to peripheral neuropathy than other central nervous system demyelinating diseases and is more prominent in adult patients. A study found that about 43.6% of ADEM was associated with peripheral neuropathy ^[11] . In the definition of IPMMSG, patients are required to have the manifestation of encephalopathy, that is, mental disorders, cognitive disorders or consciousness disorders. Previous studies have concluded that the incidence of encephalopathy is 42-83%. The new definition may cause some missed diagnosis, but it is easy to rule out. Those who are prone to transition to multiple sclerosis. Acute hemorrhagic leukoencephalitis (Acute hemorrhagic leukoencephalitis), also known as Weston-Hurst disease, is a superacute variant of ADEM, which is manifested as an acute, rapidly progressing, inflammatory inflammatory hemorrhagic white matter demyelination, mostly in 1 He died of cerebral edema or severe sequelae within weeks.

Auxiliary examination of acute disseminated encephalomyelitis

Cerebrospinal fluid was normal or showed increased cells and proteins, viral PCR tests were negative, OB were mostly negative, or transiently positive, and intrathecal IgG synthesis rate increased. Imaging features: MRI is the most important diagnostic tool. The T2 and FLAIR phases show a high signal with flaky borders, multiple occurrences, and bilateral asymmetry. The lesions are extensive and include the subcortex, the center of the semiovel, the gray-white junction of the bilateral hemispheres, the cerebellum, the brainstem, and the spinal cord. The thalamus and basal ganglia are often involved, and the lesions are mostly asymmetric. The corpus callosum and paraventricular white matter are less affected, and changes in these areas are more likely to occur in MS. Enhanced lesions can occur in 11-30% of patients. There are four forms of cranial MRI lesions of ADEM ^[12] : multiple small lesions (<5mm), diffuse large lesions can be tumor-like with peripheral edema and occupying effects, bilateral thalamic lesions, hemorrhagic lesions, four forms Can appear alone or combined. In 80% of patients with spinal cord symptoms, spinal MRI can detect lesions, which can be focal or segmental, but most of them are longer spinal segments (> 3) or even the whole spinal cord. Follow-up MRI showed that lesions disappeared in 37-75% of patients, and lesions improved in 25-53% of patients. IPMSSG recommends that ADEM patients should be followed up at least twice within 5 years of onset to exclude MS and other diseases.

Diagnosis of Acute Disseminated Encephalomyelitis

Due to the lack of specific biomarkers, the diagnosis of ADEM is based on clinical and imaging features. Clinically, the diagnosis of ADEM is supported by bilateral optic nerve involvement, cortical symptoms and signs, peripheral nerve involvement, altered consciousness, cognitive dysfunction, increased cerebrospinal fluid cells, negative OB or positive soon afterwards. The International Children's Multiple Sclerosis Study Group developed new diagnostic criteria in 2007 as follows. The clinical criteria are as follows: the first occurrence of a multifocal demyelinating disease with acute or subacute onset, which is manifested as multiple symptoms with encephalopathy ( Behavioral abnormalities or changes in consciousness), most of the symptoms or MRI have improved after hormonal treatment, and there may be residual symptoms. Clinical events without previous demyelination characteristics, exclude other causes, new symptoms or fluctuations in existing symptoms within 3 months Should be listed as part of this disease; neuroimaging: focal or multifocal involvement of white matter in the brain, and no indication of old white matter damage, brain MRI manifestations of large (1-2 cm), multifocal on the curtain Or under the curtain white matter, gray matter, especially the basal ganglia and thalamus, a small number of patients present as a single large isolated lesion, and the spinal cord may appear as a diffuse intramedullary abnormal signal with varying degrees of enhancement. In addition, IPMSSG has standardized the concept of relapsed and polyphasic ADEM: relapsed ADEM: after 3 months of the first ADEM event or after 1 month of complete hormone therapy, a new ADEM event appears, but the new event is only time There were no recurrences, and the symptoms and signs were the same as the first. The imaging findings showed that only the old lesions were enlarged and no new lesions appeared. Polyphasic DEM (MDEM): New ADEM events occur 3 months after the first ADEM event or 1 month after complete hormonal therapy, and the new events are related to both time and space. The first time was different, so new lesions appeared in symptoms, signs, and imaging.

Differential diagnosis of acute disseminated encephalomyelitis

Differential diagnosis of ADEM is classified according to different MRI features. If it is multifocal brain parenchymal damage, it needs to be associated with MS, NMO spectrum disease, primary central nervous system vasculitis, lupus erythematosus, Behcet's disease, sarcoidosis, Hashimoto's encephalopathy, mitochondrial encephalopathy, and viral encephalitis; if it is bilateral thalamus or striatum, it must be related to venous sinus thrombosis, acute necrotizing encephalopathy, bilateral thalamic glioma, Leigh disease, West Nile virus Encephalitis, Epstein-Barr virus encephalitis, Japanese encephalitis, etc .; If it is bilateral diffuse white matter lesions, it needs to be distinguished from white matter malnutrition, toxic white matter encephalopathy, and glioma disease; if accompanied by tumor-like demyelination Lesions need to be distinguished from astrocytomas. The following highlights the identification with viral encephalitis, MS, NMO, and primary central nervous system vasculitis.

ADEM Acute disseminated encephalomyelitis ADEM and viral encephalitis

Both can develop fever, headache, disturbance of consciousness, and mental and behavioral abnormalities, but viral encephalitis is a virus that invades the brain parenchyma, and the symptoms of brain parenchymal injury are more severe and prominent. Cerebrospinal fluid examination has increased virus antibody titer or virus PCR positive. MRI manifestations are mainly cortical lesions. In addition to ADAM, optic nerve, spinal cord, and peripheral nerve lesions can appear. Brain MRI manifests as diffuse long T1, long T2 abnormal signals, mainly white matter damage. The two respond differently to drug treatment. Viral encephalitis has a long treatment cycle and is prone to residual cognitive impairment, while ADEM responds well to hormones and has a good prognosis.

ADEMMS Acute disseminated encephalomyelitis ADEM and MS

The first onset of MS and ADEM need to be differentiated. The International Pediatric Multiple Sclerosis Research Group published a consensus on the differential diagnosis of ADEM and MS. ^[3] : ADEM has a younger age, and there is no difference between men and women. In men; ADEM often has a precursor infection or vaccination, and MS may not be present; ADEM often has symptoms of encephalopathy, may have seizures, and MS is rare; ADEM mostly has a unipolar course, and MS has multiple attacks; ADEM MRI manifestations can be seen In large gray matter lesions, the lesions can disappear or decrease significantly after improvement. MS relapses and new lesions appear over time; ADEM cerebrospinal fluid white blood cells often increase in varying degrees, and OB is negative; MS cerebrospinal fluid white blood cells rarely exceed 50, OB There are many positive; ADEM is better than MS in response to glucocorticoids.

Relapsed and heterogeneous ADEM is fundamentally different from MS. ADEM has no chronic demyelination during relapse, and MS patients have chronic inflammatory demyelination pathology even without clinically visible attacks. The magnetic resonance characteristics of relapsed and polyphase ADEM are different from those of MS. The MRI lesions of ADEM patients will eventually disappear completely or be significantly improved, while those of MS will continue to have asymptomatic lesions, which will accumulate to a certain degree and then have symptoms; the pathology of MS Both the image and the image appear as plaques with clear edges ^[13] . Mikaeloff et al. Found that recurrence (same or different locations) was followed for more than 5 years in 132 pediatric patients and was related to the following factors ^[14] : optic nerve involvement, family history of demyelinating disease, and nuclear magnetic resonance in compliance with Barkhof's multiple sclerosis criteria, and No sequelae were left after the first episode.

ADEM NMO Acute disseminated encephalomyelitis ADEM and NMO spectrum disease

NMO brain damage includes the thalamus, the mesencephalon, the third or fourth ventricle, and the lateral ventricles. When the mesencephalon and thalamus are involved, disturbances of consciousness and cognition can occur. Therefore, the first NMOSD is accompanied by mesencephalic or thalamic damage, or diffuse brain White matter damage is difficult to identify with ADEM. ADEM is more likely to involve cortical gray matter and gray-white junctions. The lesions are scattered and multiple. NMO affects the ventricle-aqueduct-central duct surrounding tissues of aquaporins. In addition, AQP-4Ab is more common in NMOSD patients. Positive, but ADEM is mostly negative. Recently, there have been reports of NMOSD, which was first published with clinical and imaging features of ADEM ^[15] , which illustrates the importance of close follow-up.

ADEM Acute disseminated encephalomyelitis ADEM and primary central nervous system vasculitis

The characteristics of primary central nervous system vasculitis include: intermittent or persistent headaches, focal or multifocal neurological deficits, a chronic recurrent disease that can affect gray matter, and angiography due to microangiitis. Brain biopsy can help diagnose.

Treatment of Acute Disseminated Encephalomyelitis

There are currently no large-scale, multicenter, randomized, placebo-controlled trials of ADEM drug therapy. Glucocorticoids are widely considered as first-line treatment (class IV). Drug selection, dosage, and reduction methods for hormonal use have not been unified, and a retrospective study found that quixoterol was superior to dexamethasone. The use of methylprednisolone: 20-30mg / kg (maximum dose does not exceed 1g) / d, rest point for 3-5 days, followed by prednisone 1-2mg / kg / d orally for 1-2 weeks, then Gradually reduce the dose and discontinue it for 4-6 weeks. If the hormone reduction time is less than 3 weeks, the risk of relapse will increase. Dale et al. Found that the average time of hormone use in relapsed patients was 3.2 weeks, while that of non-relapsed patients was 6.3 weeks ^[16] . If the hormone is intolerant or contraindicated, or the effect is not good, IVIG is a second-line treatment drug. The use of IVIG: 2g / kg (total), take a static point for 2-5 days. Plasma exchange: It mainly regulates humoral immunity and can remove pathological antibodies, complements and cytokines. It is used for acute fulminant CNS demyelinating diseases that do not respond to hormones. It is exchanged 5-7 times every other day, with anemia as a side effect. , Hypotension, immunosuppression and infection. Other immunosuppressants, such as cyclophosphamide, are only used in patients with ADEM who do not respond to hormones in adults. Specific dosage: 500-1000mg / m2, given once a day, or dividedly on days 1, 2, 4, 6, and 8. Serious side effects include secondary malignant tumors, infertility, hemorrhagic cystitis, congestive heart failure, immunosuppression, infection, Stevens-Johnson syndrome, pulmonary interstitial fibrosis, and so on.

Prognosis of acute disseminated encephalomyelitis disease

The prognosis is good in pediatric patients and less in adults. Several studies on pediatric ADEM have shown that 57-94% of patients have fully recovered, and deaths are rare. Most of the deaths are lesions with bleeding or high intracranial pressure. The recovery time is 0.25 to 6 months. Those with residual neurological deficits can manifest as: movement disorders, paresthesia, visual impairment, cognitive decline, epilepsy, etc. ^[17] .