Dr Hannah Wood, Dr Melody Bacon, Dr Louise Hartley
What is ADEM?
ADEM is a rare, inflammatory, neurological disorder seen in children and young adults. It also has associations with chronic conditions like multiple sclerosis. These patients usually present a few weeks after an upper respiratory tract infection with confusion, headache and sudden onset neurological symptoms. ADEM can be tricky to diagnose – hopefully this article will help you to identify and treat it.
Who gets ADEM?
ADEM usually seen in children between 5 and 8 years old. Boys are affected slightly more often than girls with a ratio of 1.3:1. It’s rare – only 0.6 cases per 100,000 people are described per year. Children can become quite sick with around a quarter of cases needing a PICU admission – usually due to respiratory compromise. Little ones under the age of 2 tend to do worse with more severe disease and a higher mortality.
What causes ADEM?
It’s not completely understood, but one theory is that an infectious or environmental trigger causes inflammation and demyelination in the central nervous system of a child who is genetically susceptible.
There are loads of different viruses and bacteria that have been linked to ADEM: coronaviruses, coxsackie, Epstein-Barr, herpes simplex and varicella zoster to name a few (to name a few more: Borrelia burgdorferi, chlamydia, Mycoplasma pneumoniae, and beta hemolytic Strep). It’s also been reported following vaccination. What might be going on (at a cellular level) is that the antigens of whichever pathogen is to blame cause an autoimmune response against myelin basic protein. For example: the viral nuclear antigen of EBV has very similar protein
structures to myelin basic protein – so when the immune system reacts to an EBV infection by producing antibodies, these antibodies ALSO react with myelin auto-antigens which means that there can be damage to the myelin sheath.
There is some evidence to support these ideas – children with ADEM are 10 times more likely to have T-cells which react to myelin basic protein. Some other important antibodies that can be found in ADEM patients are myelin oligodendrocyte glycoprotein immunoglobulin G antibodies (this is a bit of a mouthful so they’re usually called MOG IgG antibodies).
The inflammation and damage which causes the symptoms of ADEM happens when an activated T-cell crosses the blood brain barrier and triggers an inflammatory response causing a whole host of cytokines, chemokines, free radicals and phagocytes to damage the myelin sheath. This process can carry on for weeks!
When the inflammation dies down the myelin sheath repairs itself – however the repaired sheath isn’t quite as good as undamaged myelin and so is more vulnerable to being injured in the future.
How does ADEM present?
Most children (about 75%) will have recently felt run down with a fever in the 2 weeks before they start showing signs of ADEM.
For the diagnosis of ADEM children present with encephalopathy (such as headache, vomiting, drowsiness, and meningism) and neurological signs. These symptoms come on quickly – over hours to days and usually are at their worst between days 4 and 7 of illness.
The neurological signs can be really varied – any part of the CNS can be affected and the symptoms depend on where the inflammation and swelling is. Children can have hemiparesis, cerebellar ataxia or cranial nerve neuropathies. Sometimes the damage can occur right across the spinal cord causing a transverse myelitis. If this happens in the neck region they can have problems with their bladder and bowel and even develop respiratory failure – these are the patients who need those PICU beds as well as those who present with reduced consciousness (GCS <8).
What else could it be… and how can I tell?
If a child presents with encephalitis and focal neurology ADEM should be a differential diagnosis but other causes should always be considered. The most important alternative diagnosis is infection, so these children should be covered with antibiotics and antivirals until test results rule this out.
There are other CNS demyelinating and inflammatory disorders, such as multiple sclerosis, which you should be thinking about as well as other causes like vasculitis, CNS malignancy or haemophagocytic lymphohystiocytosis; which can start with CNS symptoms before other organs become involved.
Imaging: MRI brain and spine with contrast is the best imaging choice as CT is not sensitive and can be reported as normal. White matter lesions can be seen within 72 hours of the onset of symptoms – so consider the timing of the MRI.
The number, size and location of lesions in ADEM vary from patient to patient and large lesions can cause mass effect. Usually lesions are bilateral and asymmetric. Most patients have lots of diffuse, poorly defined lesions in the deep and subcortical white matter. The periventricular white matter is not usually affected. MRI findings can help differentiate ADEM from related conditions such as MS. MRI changes usually improve over time.
If a follow up MRI after 3 months shows new changes you should consider whether this is a relapsing disease especially in younger children look for MOG antibodies, and in the teenager think of MS.
CSF: Lumbar puncture is for ruling out infection and can show evidence of inflammation with raised white cell count and/or protein. There may also be oligoclonal bands found on LP, although this is also associated with MS.
Bloods: Usually at presentation patients have bloods sent to screen for viral and bacterial infection. Specialist tests for ADEM include the MOG IgG autoantibody mentioned before as well as aquaporin-4 (AQP4) IgG serum autoantibody. If a patient tests positive for these antibodies it means they are more likely to have a relapsing course.
Often these patients also have a whole host of tests sent including throat swabs, NPAs and stool samples to see if there is an infective cause.
What about treatment?
Most patients will be treated with broad spectrum antibiotics and Aciclovir due to their initial encephalopathy and these are continued until infection is ruled out.
As you might have guessed with an inflammatory condition, ADEM is initially treated with high dose corticosteroids. Methylprednisolone is used for 3-5 days with an oral taper over 4-6 weeks. Watch out, some patients may relapse during tapering. Response to treatment is measured clinically: if their mental status or neurological signs have improved this shows a good response to treatment. Continuing neurological deterioration is a sign of poor response.
The second line treatment for patients who are steroid resistant is intravenous immunoglobulin, this is also useful where steroids are contraindicated. Plasma exchange has also been used in severe cases. In cases which do not respond to less toxic therapies (steroids, IVIG and/or plasma exchange), cyclophosphamide may be used for treatment.
What is the outlook?
In general patients with ADEM get better; especially if the need for cardiorespiratory support is quickly recognised and medical therapy is started early, there is low mortality with 65-85% of patients having good functional recovery in 4-6 weeks. However, this cohort of patients can go on to have ADHD (44%), behavioural problems and learning disabilities (21%), which means that paediatric follow up is a good idea. Patients below the ages of 2 years are more at risk of poor recovery with residual neurological problems.
Up to 25% of paediatric patients with ADEM will go on to have MS. The risk is highest in those children who weren’t sick beforehand and didn’t have a significant encephalopathy, as well as those who had an abnormal CSF immunoprofile.
Can you get it again?
Up to 10% of patients have a second episode of ADEM in the 2-8 years after the initial onset of symptoms. This is known as multiphase ADEM. However, if symptoms are frequently relapsing you should be thinking about an alternative diagnosis, such as Multiple Sclerosis or neuromyelitis optics spectrum disorder (NMOSD). If specific antibodies such as anti-MOG antibodies are found during investigation there is some debate as to whether this fits under the diagnostic criteria of ADEM or if it is a separate diagnosis.
Take Home Messages
Dr Hannah Wood, paediatric SHO, and Dr Melody Bacon, paediatric registrar with special interest in Neurology, Royal London Hospital
Consultant review by Dr Louise Hartley, consultant in Paediatric Neurology