When my 2yr old daughter started daycare in Australia 5 years ago, the educators were pretty impressed with her imagination as she kept telling them about the zebras in her granny’s garden. Except that this wasn’t a vivid creation of her young mind and in fact my mother in law is fortunate to live in a stunning game reserve in South Africa and does indeed have zebras in her garden.
Faced with a somewhat precocious little girl with an English accent straight out of Peppa Pig and not long off the plane from London it made no sense that she was telling the truth so a quick assumption was made and the educators soon established an alternative plausible explanation for the tale.
How does this relate to zebras in the Emergency Department?
As a paediatric emergency physician I’ve reflected on this incident many times in the years since. I use it as a self-check and a reminder that when everything is not as it seems in a clinical scenario then perhaps the sound of hooves really could be zebras rather than horses and it’s time to start considering the more unusual diseases that we really do not want to miss in the paediatric resus room.
A study by Pelaccia et al in 2014 found that emergency physicians generate 25% of diagnostic hypotheses before meeting the patient and 75% of hypotheses in the first 5 minutes of an encounter.
This is a somewhat frightening statistic and when you also subscribe to the mantras (as I do) that common things are common, less is more in terms of investigations and that most patients will get better in spite of what we do rather than because of what we do then rare diagnoses are at risk of being missed.
Rare is common
Paradoxically, in fact, rare diseases are collectively common affecting 6-10% of the population equating to 1.2 million Australians, similar to the number of patients with diabetes.
Rare diseases do not observe the catchment areas of tertiary hospitals with specialist services and so patients with these conditions could present to anyone’s place of work (yes, including yours) whether that be an adult ED where a parent walks through the door with a collapsed child or a baby with seizures brought by ambulance to a small rural department.
This means that everyone is likely to see these conditions at some stage in their clinical practice. Many of these conditions have their origin in childhood and are associated with significant disability, impaired quality of life and premature death.
Patients with rare diseases often face lengthy diagnostic delays, some families seeing up to 10 different doctors and waiting >5 years for a definitive diagnosis but for those with rare diseases who present in extremis in our resus rooms there simply isn’t the time to miss the diagnosis and catastrophic consequences can ensue.
Estimates from Europe report that of deaths in children aged < 1 year, 35% are due to rare diseases and approximately 10% in those aged between 1 and 15yrs.
No fault errors
Most medical professionals, I would argue, are used to thinking outside the box but when we delve into the taxonomy of diagnostic errors, missed rare diseases are often categorised under “no fault errors” due to atypical presentations. I think that this frame is a potential disservice to our patients, their families and also to ourselves as intelligent well-trained individuals striving to do our best for ALL our patients.
The published literature of diagnostic reasoning identifies “no fault errors” as by definition difficult to change in clinical practice and whilst there may not be any “quick wins” in this arena; education about uncommon conditions can increase awareness and hence reduce these errors particularly if coupled with repetition over time to remain salient. We can all play our part in this.
Rare diseases are under-researched resulting in a lack of evidence for translation into clinical practice and health and social policy – and we as physicians have an important role in advocating for this neglected group of children.
In a recent survey conducted by Australian Paediatric Surveillance Unit published last year less than half of paediatricians said rare diseases were adequately covered in their medical degree, and only 50% said they were adequately covered during FRACP training.
There are approximately 8000 rare diseases so it is unrealistic to include every disease in medical school and postgraduate curriculums and even harder to fit them into a single blog post!
So instead, let’s think about inherited metabolic conditions as an example of how, by careful history, thorough examination and judicious use of investigations, we can play our part in early diagnosis leading to more favourable outcomes in line with the ongoing development of increasingly effective treatments and even cures for some of these conditions.
The take home messages from this post are not intended to be in the minutiae of metabolic pathways (not least because you’d need someone much cleverer than me to tell you about those) but the prompts to ask more frequently – “could this be a rare disease?” and to be vigilant about deviations from common pattern of diseases which should prompt more in depth investigation and wise collaboration with specialist services for more precise diagnostic clarity.
So which patients may have an inherited metabolic disorder?
The presentations of children with metabolic conditions, particularly in the emergency department, are often non-specific making it even more likely of a missing the diagnosis but the key is to think metabolic or indeed rare disease when things don’t quite fit together…
It’s any sick neonate where things don’t quite fit the expected pattern, they need covering for infection of course, but a sick neonate is more likely to have multiple repeated septic screens looking for an elusive infection before someone thinks to do a metabolic workup.
It’s the child with repeated episodes of seemingly innocuous viral gastroenteritis but whose parents report they get very drowsy when unwell unlike their siblings who seem to bounce back.
It’s the baby with refractory seizures or the child in extremis without a clear cause and it could be any child with unexpected laboratory abnormalities.
So we’ve made that all important first step of actually thinking about metabolic disorders, what next?
History, as ever is key, and whilst metabolic conditions can present at any age, they tend to occur at times of stress. The neonatal period goes without saying, but without specific questioning it may not be obvious that the symptoms have occurred after weaning with an increased protein load or first exposure to a new diet component such as in hereditary fructose intolerance. Infection can be a trigger with the combination of metabolic stress associated with decreased intake so the presence of sepsis does not preclude a metabolic condition.
Family history may also provide major flags for metabolic disorders and it is important to ask specifically not just about siblings but about how many pregnancies there have been as recurrent miscarriage or previous neonatal or infant death may not uncommonly be a clue to a previously undiagnosed cases within the family.. Recessive inheritance is the commonest mode of inheritance so consanguinity would also point in that direction – certainly in London where I trained it was pretty standard to ask parents if they were related but if it is not part of your routine history taking you need to remember it when it could count.
So we just need to do a metabolic screen then?
If only it were so easy…the advances in tandem mass spectrometry mean that in the future the elusive one stop shop metabolic test might exist but in the meantime we need to be targeted in our stepwise approach.
It’s a balance and one parent of a child with a rare undiagnosed disease is quoted in the literature to have said of her experience “ I had to find the right doctors, to be insistent but not obstinate. On the one hand I had to save her from unnecessary diagnostic tests, often saying “no” and “why”. On the other hand I had to ensure that she received everything she needed.”
In the ED it is vital that we commence first line metabolic investigations but also entirely appropriate that we seek expert specialist guidance if anything further is required and liaising with your local metabolic team is also likely to speed up the results.
So after initial ABC management, DEFG, as you know, stands for DON’T EVER FORGET GLUCOSE. Hypoglycaemia (defined as a glucose less than or equal to 2.6 on a formal sample – which should be checked if you get a reading of less than 3 on a glucometer) is a common problem in sick children and yet it is an area where the opportunity to take crucial samples at the time to secure the diagnosis and avoid further investigation is often missed.
The challenge is of course to remember which bottles are needed for which tests in addition to getting a line in a wriggling sick child flanked by worried parents, so if your department doesn’t already have pre-designated packs of tubes to be taken in the case of a child with hypoglycaemia then I’d strongly encourage you to go away and implement this change which will take the thinking out of an already difficult situation.
Whether the child with hypoglycaemia is ketotic or not at the time of the event will be crucial when working out through the differential later down the track and the first urine is also needed in addition to the blood tests.
If you’re still worried about the child it’s likely that you will have taken a blood gas and a metabolic acidosis certainly needs further consideration. Our local metabolic team gets calls several times a month about patients with metabolic acidosis with a normal anion gap which is usually due to bicarbonate loss but it is a raised anion gap metabolic acidosis signifying the presence of organic anions which may be acquired or reflect an underlying metabolic disorder depending on the clinical context.
The other clue from a blood gas might be an unexpected respiratory alkalosis, particularly in an encephalopathic patient, due to the respiratory stimulant effect of ammonia on the brainstem. A free flowing sample must be taken for ammonia and the lab notified in advance. Locally we have had several urea cycle disorders diagnosed because ED physicians thought about hyperammonamemia in an unconscious baby or child with respiratory alkalosis and in fact patients with mild versions have presented similarly in adult life.
So we need to remember metabolic disorders that present acutely can be grouped into those with hyperammonaemia and those with metabolic acidosis and hypoglycaemia may be present either without or without metabolic acidosis.
First line investigations also recommended are lactate which you should already have on your gas, FBC, electrolytes, LFTS, plasma amino acids and acylcarnitines as well as urine organic and amino acids.
So now we’ve thought that it might be metabolic, we’ve explored for clues in the history and even done the right investigations, but how do we treat it?
Thankfully this is pretty standard recipe regardless of the underlying diagnosis. The treatment is to 1) Stop feeds to reduce the toxin load 2) Stop catabolism– by giving 10% dextrose as a basic fluid with appropriate electrolyte additives 3) Remove metabolites – with agents specific to the presumed/ known diagnosis
It’s at stage three of the treatment where you should definitely phone a friend to provide guidance with respect to the specific agents and there’s also a great online resource at the British Inherited Metabolic Disease Group website which has quick reference guidelines for emergency presentations.
So that’s a whistle stop tour of metabolic presentations to your department
Maybe this post has sparked your interest in metabolic and other rare diseases, or more importantly maybe a patient on your next shift, or next year will spark your interest and make you wonder if there is something more unusual going on.
There are lots of other resources out there to help with these patients. There are online portals such as www.Orpha.net where diseases are searchable by symptom so you don’t even need to have heard of the diagnosis and www.rarediseases.org with physician guides to many conditions and the Australian Paediatric Surveillance Unit has more local information and a strong role in advocacy for these patients.
So where to from here?
If your area of practice is an adult ED with an occasional child that slips through the door or a rural mixed ED then individually these are cases you might see once in your career but if we don’t think about them and we miss or delay the diagnosis there can be serious unintended consequences. So we need to talk about these cases. We need to chat about them with our colleagues whilst we get coffee, we need to read case studies in journals and we need to talk about them at conferences so that we can recognise when things don’t quite fit and need further assessment.
The message I’d like to leave you with and the message I repeat to myself on regular occasions is that we need to see the signs even if we do not see the diagnosis. We have to recognize when things aren’t quite as we expect and to use the resources that are out there to help us find the zebras among the horses when we hear the sound of hooves.
Podcasts & Blogposts
Anderson M, Elliott EJ, Zurynski YA. Australian families living with rare disease: experiences of diagnosis, health services use and needs for psychosocial support. Orphanet journal of rare diseases. 2013 Feb 11;8(1):1.
Champion MP. An approach to the diagnosis of inherited metabolic disease. Archives of Disease in Childhood-Education and Practice. 2010 Apr 1;95(2):40-6.
Ghosh A, Banerjee I, Morris AA. Recognition, assessment and management of hypoglycaemia in childhood. Archives of disease in childhood. 2015 Dec 30:archdischild-2015.
Graber ML, Franklin N, Gordon R. Diagnostic error in internal medicine. Archives of internal medicine. 2005 Jul 11;165(13):1493-9.
Jaffe A, Zurynski Y, Beville L, Elliott E. Call for a national plan for rare diseases. Journal of paediatrics and child health. 2010 Jan;46(1‐2):2-4.
Kirby T. Australia makes up for lost time on rare diseases. The Lancet. 2012 May 5;379(9827):1689-90.
Pelaccia, T., Tardif, J., Triby, E., Ammirati, C., Bertrand, C., Dory, V. and Charlin, B., 2014. How and when do expert emergency physicians generate and evaluate diagnostic hypotheses? A qualitative study using head-mounted video cued-recall interviews. Annals of emergency medicine, 64(6), pp.575-585.
Warrick C, Patel P, Hyer W, Neale G, Sevdalis N, Inwald D. Diagnostic error in children presenting with acute medical illness to a community hospital. International Journal for Quality in Health Care. 2014 Jul 6;26(5):538-46.
Zurynski Y, Deverell M, Dalkeith T, Johnson S, Christodoulou J, Leonard H, Elliott EJ. Australian children living with rare diseases: experiences of diagnosis and perceived consequences of diagnostic delays. Orphanet journal of rare diseases. 2017 Dec;12(1):68.
Zurynski YA, Frith K, Leonard H, Elliott EJ. Rare childhood diseases: how should we respond?. Archives of disease in childhood. 2008 Aug 6.
Zurynski Y, Gonzalez A, Deverell M, Phu A, Leonard H, Christodoulou J, Elliott E. Rare disease: a national survey of paediatricians’ experiences and needs. BMJ paediatrics open. 2017;1(1).
Rasmussen, K. Spotting the Zebras, Don't Forget the Bubbles, 2018. Available at: