Acute disseminated encephalomyelitis
Acute disseminated encephalomyelitis, or acute demyelinating encephalomyelitis, is a rare autoimmune disease marked by a sudden, widespread attack of inflammation in the brain and spinal cord. As well as causing the brain and spinal cord to become inflamed, ADEM also attacks the nerves of the central nervous system and damages their myelin insulation, which, as a result, destroys the white matter. The cause is often a trigger such as from viral infection or, in extraordinarily rare cases, vaccinations.
ADEM's symptoms resemble the symptoms of multiple sclerosis, so the disease itself is sorted into the classification of the multiple sclerosis borderline diseases. However, ADEM has several features that distinguish it from MS. Unlike MS, ADEM occurs usually in children and is marked with rapid fever, although adolescents and adults can get the disease too. ADEM consists of a single flare-up whereas MS is marked with several flare-ups, over a long period of time. Relapses following ADEM are reported in up to a quarter of patients, but the majority of these 'multiphasic' presentations following ADEM likely represent MS. ADEM is also distinguished by a loss of consciousness, coma and death, which is very rare in MS, except in severe cases.
It affects about 8 per 1,000,000 people per year. Although it occurs in all ages, most reported cases are in children and adolescents, with the average age around 5 to 8 years old. The disease affects males and females almost equally. ADEM shows seasonal variation with higher incidence in winter and spring months which may coincide with higher viral infections during these months. The mortality rate may be as high as 5%; however, full recovery is seen in 50 to 75% of cases with increase in survival rates up to 70 to 90% with figures including minor residual disability as well. The average time to recover from ADEM flare-ups is one to six months.
ADEM produces multiple inflammatory lesions in the brain and spinal cord, particularly in the white matter. Usually these are found in the subcortical and central white matter and cortical gray-white junction of both cerebral hemispheres, cerebellum, brainstem, and spinal cord, but periventricular white matter and gray matter of the cortex, thalami and basal ganglia may also be involved.
When a person has more than one demyelinating episode of ADEM, the disease is then called recurrent disseminated encephalomyelitis or multiphasic disseminated encephalomyelitis. Also, a fulminant course in adults has been described.
Signs and symptoms
ADEM has an abrupt onset and a monophasic course. Symptoms usually begin 1–3 weeks after infection. Major symptoms include fever, headache, nausea and vomiting, confusion, vision impairment, drowsiness, seizures and coma. Although initially the symptoms are usually mild, they worsen rapidly over the course of hours to days, with the average time to maximum severity being about four and a half days. Additional symptoms include hemiparesis, paraparesis, and cranial nerve palsies.ADEM in COVID-19
Neurological symptoms were the main presentation of COVID-19, which did not correlate with the severity of respiratory symptoms. The high incidence of ADEM with hemorrhage is striking. Brain inflammation is likely caused by an immune response to the disease rather than neurotropism. Cerebrospinal fluid analysis was not indicative of an infectious process, neurological impairment was not present in the acute phase of the infection, and neuroimaging findings were not typical of classical toxic and metabolic disorders. The finding of bilateral periventricular relatively asymmetrical lesions allied with deep white matter involvement, that may also be present in cortical gray-white matter junction, thalami, basal ganglia, cerebellum, and brainstem suggests an acute demyelination process. Additionally, hemorrhagic white matter lesions, clusters of macrophages related to axonal injury and ADEM-like appearance were also found in subcortical white matter.Causes
Since the discovery of the anti-MOG specificity against multiple sclerosis diagnosis it is considered that ADEM is one of the possible clinical causes of anti-MOG associated encephalomyelitis.There are several theories about how the anti-MOG antibodies appear in the patient's serum:
- A preceding antigenic challenge can be identified in approximately two-thirds of people. Some viral infections thought to induce ADEM include influenza virus, dengue, enterovirus, measles, mumps, rubella, varicella zoster, Epstein–Barr virus, cytomegalovirus, herpes simplex virus, hepatitis A, coxsackievirus and COVID-19. Bacterial infections include Mycoplasma pneumoniae, Borrelia burgdorferi, Leptospira, and beta-hemolytic Streptococci.
- Exposure to vaccines: The only vaccine proven related to ADEM is the Semple form of the rabies vaccine, but hepatitis B, pertussis, diphtheria, measles, mumps, rubella, pneumococcus, varicella, influenza, Japanese encephalitis, and polio vaccines have all been associated with the condition. The majority of the studies that correlate vaccination with ADEM onset use only small samples or are case studies. Large-scale epidemiological studies do not show increased risk of ADEM following vaccination. An upper bound for the risk of ADEM from measles vaccination, if it exists, can be estimated to be 10 per million, which is far lower than the risk of developing ADEM from an actual measles infection, which is about 1 per 1,000 cases. For a rubella infection, the risk is 1 per 5,000 cases. Some early vaccines, later shown to have been contaminated with host animal central nervous system tissue, had ADEM incidence rates as high as 1 in 600.
- In rare cases, ADEM seems to follow from organ transplantation.
Diagnosis
Given that the definition is clinical, it is currently unknown if all the cases of ADEM are positive for anti-MOG autoantibody; in any case, it appears to be strongly related to ADEM diagnosis.
Differential diagnosis
Multiple sclerosis
While ADEM and MS both involve autoimmune demyelination, they differ in many clinical, genetic, imaging, and histopathological aspects. Some authors consider MS and its borderline forms to constitute a spectrum, differing only in chronicity, severity, and clinical course, while others consider them discretely different diseases.Typically, ADEM appears in children following an antigenic challenge and remains monophasic. Nevertheless, ADEM does occur in adults, and can also be clinically multiphasic.
Problems for differential diagnosis increase due to the lack of agreement for a definition of multiple sclerosis. If MS were defined only by the separation in time and space of the demyelinating lesions as McDonald did, it would not be enough to make a difference, as some cases of ADEM satisfy these conditions. Therefore, some authors propose to establish the dividing line as the shape of the lesions around the veins, being therefore "perivenous vs. confluent demyelination".
The pathology of ADEM is very similar to that of MS with some differences. The pathological hallmark of ADEM is perivenous inflammation with limited "sleeves of demyelination". Nevertheless, MS-like plaques can appear
Plaques in the white matter in MS are sharply delineated, while the glial scar in ADEM is smooth. Axons are better preserved in ADEM lesions. Inflammation in ADEM is widely disseminated and ill-defined, and finally, lesions are strictly perivenous, while in MS they are disposed around veins, but not so sharply.
Nevertheless, the co-occurrence of perivenous and confluent demyelination in some individuals suggests pathogenic overlap between acute disseminated encephalomyelitis and multiple sclerosis and misclassification even with biopsy or even postmortem ADEM in adults can progress to MS
Multiphasic disseminated encephalomyelitis
When the person has more than one demyelinating episode of ADEM, the disease is then called recurrent disseminated encephalomyelitis or multiphasic disseminated encephalomyelitis.It has been found that anti-MOG auto-antibodies are related to this kind of ADEM
Another variant of ADEM in adults has been described, also related to anti-MOG auto-antibodies, has been named fulminant disseminated encephalomyelitis, and it has been reported to be clinically ADEM, but showing MS-like lesions on autopsy. It has been classified inside the anti-MOG associated inflammatory demyelinating diseases.
Acute hemorrhagic leukoencephalitis
Acute hemorrhagic leukoencephalitis, acute hemorrhagic encephalomyelitis, acute necrotizing hemorrhagic leukoencephalitis, Weston-Hurst syndrome, or Hurst's disease, is a hyperacute and frequently fatal form of ADEM. AHL is relatively rare, it is seen in about 2% of ADEM cases, and is characterized by necrotizing vasculitis of venules and hemorrhage, and edema. Death is common in the first week and overall mortality is about 70%, but increasing evidence points to favorable outcomes after aggressive treatment with corticosteroids, immunoglobulins, cyclophosphamide, and plasma exchange. About 70% of survivors show residual neurological deficits, but some survivors have shown surprisingly little deficit considering the extent of the white matter affected.This disease has been occasionally associated with ulcerative colitis and Crohn's disease, malaria, sepsis associated with immune complex deposition, methanol poisoning, and other underlying conditions. Also anecdotal association with MS has been reported
Laboratory studies that support diagnosis of AHL are: peripheral leukocytosis, cerebrospinal fluid pleocytosis associated with normal glucose and increased protein. On magnetic resonance imaging, lesions of AHL typically show extensive T2-weighted and fluid-attenuated inversion recovery white matter hyperintensities with areas of hemorrhages, significant edema, and mass effect.