Dr Hector Thomson
Peer review: Dr Binula Wickramarachchi
While recent cases of Japanese Encephalitis have caught headlines, I recently stumbled across a disease I was embarrassed to say I had never heard of. My paediatric-trained colleagues all seemed to have heard of it, but I could scarcely find a mention in my ED textbooks, maybe because the diagnosis is never made downstairs and we call it viral meningitis pending a culture.
With a waiting room full of kids with viral URTIs, I now have a new disease to look out for along with PIMS-TS. Let me tell you about some more scary capital letters: ADEM.
So, what is ADEM?
Acute Disseminated Encephalomyelitis (ADEM)
ADEM is an autoimmune demyelinating disease of the central nervous system (CNS) which is monophasic (has a single occurrence) but multifocal in nature. So, lots of cool neurological signs but then they don’t go away; in contrast to MS, for example, where they may fluctuate.
It’s most commonly seen in children, though adults can also be affected. It was first described by Mr James Lukas, a surgeon in Leeds in the 18th Century, as “uncommon symptoms succeeding the measles”.
Criteria for Diagnosis
All of the following are needed, along with reasonable exclusion of other possible neurological conditions:
- A first multifocal clinical CNS event of presumed inflammatory demyelinating cause
- Encephalopathy: stupor and/or lethargy or behavioural changes unexplained by fever, systemic illness or postictal symptoms
- An abnormal MRI brain during the acute phase (3 months)
- No new clinical or MRI findings >3 months after clinical onset
It isn’t clear what exactly causes ADEM but as with many autoimmune conditions, the current theory is that an infectious or environment trigger in a genetically susceptible child causes an autoimmune attack on the CNS resulting in demyelination.
The disease typically starts with an abrupt onset within a day to weeks after a viral infection (75%) or immunisation. Common viruses (Epstein-Barr, measles, mumps, rubella, and Coxsackie B) are the most common pathogens associated with postinfectious ADEM. COVID has been reported as a cause but a review this year only found 31 reported cases.
Bacterial triggers are rare and less than 5% of ADEM cases follow immunisation. These have most often been associated with the MMR vaccination.
The classic presentation is a 2-5 day prodrome where fever, nausea, vomiting, headache, and weakness may be present, followed by acute-onset, rapidly progressive encephalopathy and multifocal neurological symptoms.
Encephalopathy comprises change in behaviour and/or conscious state and can range from lethargy and irritability to coma.
A wide variety of neurological deficits can be manifested, determined mainly by the localization of lesions. 80% will have a motor deficit, 50-60% ataxia, and up to 50% will have a cranial nerve deficit with optic neuritis, often bilaterally.
Yes, that means you have to go find the tendon hammer and try and get those grumpy toddlers to walk for you!
Systemic features are common, with fever (50%), headache (40-50%) and vomiting (30%) occurring frequently. 10-30% will have seizures and case series have shown between 3-25% have concurrent spinal cord involvement.
UK data suggests 25% of children with ADEM will need ICU level care. The majority of cases follow a monophasic course, but patients may have recurrence of initial symptoms (recurrent ADEM) or a second episode (multiphasic ADEM).
ADEM can occur at any age but is most common in children (mean age 5–8 years old), with a slight male predominance. Tracking the rate of ADEM is difficult as the majority of paediatric encephalitis hospitalisations never have a cause identified. Australian data identifies the incidence of ADEM at 0.68-0.79 per 100 000 person years in people aged < 14. Higher than quoted numbers in the US, UK and Asian countries.
The diagnosis of ADEM is clinical but MRI seems to be the most important investigation. T2 and FLAIR sequences will show multiple areas of demyelination in the brain and spine.
CT is not sensitive and can be reported as normal. Lumbar puncture may show pleocytosis and increased protein. EEG may show non-specific diffuse or less commonly focal slowing of background activity.
Someone may ask you to order MOG IgG and aquaporin-4 (AQP4) IgG serum autoantibody. For me, these go into the bag of the “did ya” tubes.
🤓 Definition: “Did ya” tubes.
A Hectorism. When taking blood, the process of storing excess in a serum storage tube in anticipation of a specialty registrar calling you back to ask for extra tests they have just read about on UpToDate.
In the emergency department, you will be faced with an encephalopathic child with focal neurology. The important differential to rule out in these children is acute CNS infection and these children should always be covered with antibiotics and antivirals.
The list of differentials is extremely long. The consensus guidelines for investigation of encephalitis list hits every major disease group.
Other key things to rule out are:
- Space occupying lesion
- Traumatic brain injury
- Metabolic encephalopathy
- Seizure disorder
It may be useful to frame this rare disease with something more familiar. Doesn’t this so far just sound like MS? Well yes, but there are important differences. The most relevant being that in MS there should not be any features of encephalopathy.
Image courtesy of: Dale RC, Branson JA Acute disseminated encephalomyelitis or multiple sclerosis: can the initial presentation help in establishing a correct diagnosis? Archives of Disease in Childhood 2005;90:636-639
Corticosteroids are the established first-line therapy (this is neurology, after all). There are no RCTs, but small paediatric case series dictate the standard protocol as being IV methylprednisolone followed by oral prednisolone for 4 weeks. The use of immunoglobulin and plasmapheresis have only been published in very small case series in children, and mostly in those that have not responded to steroids.
The good news is that thankfully, most of these kids do very well. 65-85% of paediatric ADEM patients have a good functional outcome and improvement is usually seen within a few days of starting treatment. Whether this is just the natural course of the illness or due to the steroids is a point of debate. Mild neurocognitive deficits and behaviour problems are not uncommon, with children younger than 5 being at higher risk.
In a small proportion, the course is more fulminant, frequently resulting in death. In such cases, the lesions may demonstrate haemorrhage and the condition is then known as acute haemorrhagic leukoencephalitis (Hurst disease). This disease appears to have overlap with cerebral vasculitis.
I don’t think we should, or are likely to be making this diagnosis. It definitely helps to know it exists, though. In the 4-year-old with irritability and focal neurological findings our job is to not send them home, empirically treat dangerous infections and facilitate appropriate investigations. Accessing sedation and imaging lists can be challenging for inpatient teams, so do your best to help with facilitating these, and advocate for these patients.
I’m going to try and remember this as the drunk toddler who just got over a cold. Irritable, staggering around and can’t see straight.
Take home messages
- ADEM often presents 1-4 weeks after a febrile illness
- Do your best to do a complete a neuro exam on the irritated toddler – focal findings should make you stop and think hard about not just “another URTI”
- ADEM remains a clinical diagnosis, however, early MRI is key for early diagnosis and prompt initiation of treatment. We should do our best to help facilitate these tests
- Empirically give antibiotics and antivirals
- ADEM is treated with high dose steroids +/- IVIG or plasmapheresis
References / Want to read more?
- Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC, et al. International pediatric multiple sclerosis study group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013;19(10):1261–7.
- Britton PN, Eastwood K, Brew B, Nagree Y, and Jones CA. Consensus guidelines for the investigation and management of encephalitis. Med J Aust 2015; 202 (11): 576-577. || doi: 10.5694/mja14.01042
- Filippi, M., Rocca, M.A. (2020). Acute Disseminated Encephalomyelitis. In: White Matter Diseases . Springer, Cham. doi: 10.1007/978-3-030-38621-4_5
- McLendon LA, Rao CK, Da Hora CC, Islamovic F, Galan FN. Post-COVID-19 Acute Disseminated Encephalomyelitis in a 17-Month-Old. Pediatrics. 2021 Jun;147(6):e2020049678. doi: 10.1542/peds.2020-049678. Epub 2021 Mar 24. PMID: 33762311.
- Huynh W, Cordato DJ, Kehdi E, Masters LT, Dedousis C. Post-vaccination encephalomyelitis: literature review and illustrative case. J Clin Neurosci. 2008 Dec;15(12):1315-22. doi: 10.1016/j.jocn.2008.05.002. Epub 2008 Oct 30. PMID: 18976924; PMCID: PMC7125578.
- Bisker Kassif, O., Orbach, R., Rimon, A., Scolnik, D., & Glatstein, M. (2019). Acute disseminated encephalomyelitis in children – clinical and MRI decision making in the emergency department. The American Journal of Emergency Medicine, 37(11), 2004–2007. doi: 10.1016/j.ajem.2019.02.022
- Absoud M, Parslow RC, Wassmer E, Hemingway C, Duncan HP, Cummins C, Lim MJ; UK & Ireland Childhood CNS Inflammatory Demyelination Working Group and the the Paediatric Intensive Care Audit Network. Severe acute disseminated encephalomyelitis: a paediatric intensive care population-based study. Mult Scler. 2011 Oct;17(10):1258-61. doi: 10.1177/1352458510382554. Epub 2010 Sep 27. PMID: 20876155.
- George T, Basin A, Avva U, Taylor M, Muhammed J, Ogedegbe C. Early Recognition and Treatment of Acute Disseminated Encephalomyelitis in Pediatrics: A Case Series. Pediatr Emerg Care. 2019 Apr 9. doi: 10.1097/PEC.0000000000001771. Epub ahead of print. PMID: 30973501.
- Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. Neurology. 2002;59(8):1224–31
- Ravaglia S, Piccolo G, Ceroni M, Franciotta D, Pichiecchio A, Bastianello S, et al. Severe steroid-resistant post-infectious encephalomyelitis: general features and effects of IVIg. J Neurol. 2007;254(11):1518–23.
- Keegan M, Pineda AA, McClelland RL, Darby CH, Rodriguez M, Weinshenker BG. Plasma
- Leake JA, Albani S, Kao AS, Senac MO, Billman GF, Nespeca MP, Paulino AD, Quintela ER, Sawyer MH, Bradley JS. Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J. 2004 Aug;23(8):756-64. doi: 10.1097/01.inf.0000133048.75452.dd. PMID: 15295226.
- Berzero G, Cortese A, Ravaglia S, Marchioni E. Diagnosis and therapy of acute disseminated encephalomyelitis and its variants. Expert Rev Neurother. 2016;16(1):83–101.
- Koelman DL, Mateen FJ. Acute disseminated encephalomyelitis: current controversies in diagnosis and outcome. J Neurol. 2015;262(9):2013–24.
- Britton PN, Khoury L, Booy R, et al. Encephalitis in Australian children: contemporary trends in hospitalisation. Archives of Disease in Childhood 2016;101:51-56.
Hector (the one on the left) is an Emergency Medicine Advanced Trainee at The Alfred. He’s still clinging to the basic science knowledge he gained during primary exam prep and enjoys shoulder dislocations, trauma, rugby union, fresh pasta and good gin. He doesn’t like vague allergies or cats.