A 5-month-old baby was brought to the emergency department with staring episodes. His parents describe them as looking to one side with his head and eyes moving to the side. Each lasts about five minutes and happen several times a day.
Unsure of the diagnosis, the treating paediatrician called Dr. Ingrid Scheffer, the director of paediatrics at the Royal Children’s Hospital and a professor of paediatric neurology at the University of Melbourne, Australia.
“It really got me thinking,” Dr. Scheffer recalls. “Even when you’ve been studying a disease for most of your career, a patient can still surprise you and deliver an answer you didn’t expect.”
After learning the child’s family medical history, a possible genetic history of seizures was discovered. The baby’s father had seizures in childhood, but they had stopped by the age of 7, and he had no long-term complications.
Even without knowing that history, when the baby went to the emergency department, “the paediatricians arranged an EEG, which was just a routine awake and sleep recording, and that was entirely normal,” says Dr. Scheffer.
The EEG and MRI were normal, but the baby’s symptoms were getting worse. There was family history of genetic epilepsy …
“The father has a history of afebrile infantile-onset seizures that resolved, and the father’s had a normal outcome,” notes Dr. Scheffer. “It’s very likely that the father has a history of benign familial infantile epilepsy, or now we’re saying self-limited familial infantile epilepsy. There is another possibility, which is benign familial neonatal infantile epilepsy, and these two syndromes have different genes.”
But these epilepsy syndromes are rare and both are associated with a specific gene variation. And the baby’s episodes are getting worse.
Dr. Scheffer and team decided to do genetic testing. And the results made her question everything she thought she knew about this case.
For Healthcare Professionals only.
Dr. Scheffer has been compensated by BioMarin for her participation.
Professor Ingrid Scheffer, AO MBBS PhD FRACP FAA FAES FRS PresAHMS
Laureate Professor Ingrid Scheffer’s work has resulted in major paradigm shifts in epilepsy syndromology and classification over many years. Her work has formed the essential basis for successful gene discovery such that her larger collaborative group has been the leaders in epilepsy gene identification for 18 years since they discovered the first gene associated with epilepsy. This body of work has resulted in insights into the biology of seizures.
Professor Scheffer is Chair of Paediatric Neurology at The University of Melbourne and Senior Principal Research Fellow at the Florey Institute of Neuroscience and Mental Health. Professor Scheffer currently leads the Australian Academy of Health and Medical Sciences as its President.
Ingrid and her colleagues have described a range of novel epilepsy syndromes beginning in infancy, childhood and adult life. Her work has meant that children and adults with sodium channel disorders, such as Dravet syndrome and related epilepsies, are diagnosed earlier and treated appropriately which improves their long term outcomes.
DDx SEASON 5, EPISODE 3
Mapping a Complicated Genetic History of Epilepsy
RAJ: This season of DDx is sponsored by BioMarin Pharmaceutical Inc.
This podcast is intended for healthcare professionals only.
DR. SCHEFFER: I’d like to tell you about a five-month-old baby boy who presented to the emergency department with staring episodes.
His parents had seen him look to one side with head and eyes moving to the side.
He lost awareness, so he wasn’t very responsive and he seemed to be a bit pale.
These episodes lasted five minutes and they happened a few times in the day.
The baby had never had a fever with any of his episodes.
The paediatricians rang me and said, what do you think’s going on?
It really got me thinking.
Even when you’ve been studying a disease for most of your career, a patient can still surprise you and deliver an answer you didn’t expect.
RAJ: This is DDx, a podcast from Figure 1 about how doctors think.
This season is all about rare paediatric disorders.
I’m Dr. Raj Bhardwaj.
Today’s case comes from Dr. Ingrid Scheffer, the Director of Paediatrics at the Royal Children’s Hospital and a professor of paediatric neurology at the University of Melbourne, Australia.
Dr. Scheffer has been compensated by BioMarin Pharmaceutical Inc. for her participation in this episode.
Chapter 1: Symptoms
RAJ: Our 5-month old patient had been healthy and developing normally before his staring episodes began.
But his family history gave Dr. Scheffer pause.
DR. SCHEFFER: The family history was very interesting. The father had a history of seizures, which began at the age of nine months and they stopped by seven years. He was now a very normal guy who held down a regular job, and a devoted father.
RAJ: Now, keep this in mind as we return to that moment when Dr. Scheffer first encountered our patient…
DR. SCHEFFER: When the baby first presented with possible seizures to the emergency department, the paediatricians arranged an EEG, which was just a routine awake and sleep recording, and that was entirely normal.
RAJ: An EEG, or Electroencephalogram, detects abnormal brain waves.
DR. SCHEFFER: They also booked an MRI and that was done a few weeks later and was also normal.
RAJ: The MRI or magnetic resonance imaging, scans the brain and provides clear detailed images of its structure, revealing abnormalities in the process.
DR. SCHEFFER: The paediatricians asked me, what should we do next? It didn’t trouble me at all that the EEG was normal. That’s very commonly the case. If it’s abnormal, it gives you supporting evidence for your diagnosis, but if it’s normal, it doesn’t help you either way. The MRI I expected to be normal. So it was reassuring to know that there was no structural abnormality of the brain.
RAJ: But then there was the family history…
DR. SCHEFFER: The father has a history of afebrile infantile-onset seizures that resolved, and the father’s had a normal outcome. It’s very likely that the father has a history of benign familial infantile epilepsy, or now we’re saying self-limited familial infantile epilepsy. There is another possibility, which is benign familial neonatal infantile epilepsy, and these two syndromes have different genes.
RAJ: These epilepsy syndromes are rare – both are associated with a specific gene variation – but each has an excellent prognosis.
The paediatricians had prescribed an anti-epileptic drug.
Meanwhile, our patient’s condition was worsening.
Dr. Scheffer decided the best course of action was to order genetic testing.
DR. SCHEFFER: Now the baby’s about six months old and he’s having more of these focal impaired awareness seizures without fever, but they’re long, they’re like 12 minutes. So the beginning ones were all a couple of minutes, these are much longer. He looks more unwell with them.
Chapter 2: Diagnosis
RAJ: The genetic testing would frame the course of treatment that Dr. Scheffer would choose.
DR. SCHEFFER: It may be important in terms of genetic counseling. This family have only got one other child and they may want more. So will it affect their genetic counseling? And critically, if we know what the syndrome is with the gene, we can give them a much better idea of the prognosis of their beautiful baby.
RAJ: Three weeks later, the results of the genetic testing had arrived… and made Dr. Scheffer question everything she thought she knew about this case.
DR. SCHEFFER: Then we got the result back, and I was really surprised because the baby had an SCN1A truncation variant. This SCN1A mutation changes the baby’s prognosis considerably. Suddenly we’re dealing with a very severe developmental and epileptic encephalopathy, which are the worst or the most severe group of epilepsies. And it carries a much more concerning prognosis. When I got the result about the SCN1A truncation mutation, it was a game changer.
RAJ: As it turns out, our patient had a very rare and severe form of epilepsy: Dravet syndrome.
DR. SCHEFFER: Most people with Dravet syndrome have intellectual disability, and very few in the world have normal intelligence. The baby’s going to be at risk of having very prolonged seizures, requiring intensive care unit, and the baby is likely to develop additional seizure types. So this gene finding is a complete game changer in terms of his diagnosis, prognosis.
RAJ: Although Dravet has been classically defined as a syndrome that presents before the age of one with a fever and prolonged seizures (which radically slow the child’s development) many cases of Dravet syndrome have atypical symptoms, making diagnosis and treatment even more complex.
But we’ll return to that later.
At this point, the diagnosis of Dravet syndrome presented Dr. Scheffer with another critical question.
DR. SCHEFFER: Most children with Dravet syndrome have a mutation of the gene SCN1A and it’s now found in more than 90% of patients with Dravet syndrome. Now, most of that 90%. have a new mutation in the child, which means it’s not present in mum or in dad, just in the child.
So my dilemma with this child was that there was a clear family history suggesting that the father was likely to have whatever the baby had. Except it didn’t make sense. Here you have a normal intelligence father in a syndrome where the father’s outcome should not be that good. He shouldn’t have grown out of his epilepsy. He shouldn’t have had normal development.
RAJ: One explanation would be that the baby had a different biological father. But that wasn’t the case.
DR. SCHEFFER: So the only way that could make sense is if the father didn’t have that mutation in every cell in his body and that he was mosaic, which means that he would have the mutation in some of the cells, but not all of the cells. So the normal cells were compensating and he could grow out of his epilepsy and learn and develop normally.
So I asked the question then, could this father be mosaic?
RAJ: Dr. Scheffer tested the father for the same genetic variation present in our patient.
DR.SCHEFFER: And he was indeed mosaic. And that’s interesting too, because all the tissues in his body may have different degrees of mosaicism. So he was 32% in blood, but it may be different in brain. He might be 5%, which might be why he’s so good. And when you’re mosaic, you can have a less severe disease.
Chapter 3: Lessons
RAJ: But having a father with mosaicism wasn’t the only unique feature of this case.
DR. SCHEFFER: This baby had an atypical presentation of Dravet syndrome.
RAJ: Our patient was a little younger than what’s defined as typical for Dravet syndrome. Initially, his seizures were less severe. And he had no fever, which could also be interpreted as misleading.
DR. SCHEFFER: Most babies with Dravet syndrome present with a seizure triggered by fever. And this baby did not have a fever. But once I saw the SCN1A mutation I could see features that made me realize this was right, which was the longer seizures.
RAJ: So what were the major lessons from this case?
DR. SCHEFFER: The major lessons I learned from this case is you’ve always got to keep thinking about the patient in front of you and listen to what the families tell you, and think about it: Does it fit with my diagnosis? If it doesn’t fit, what other differential diagnoses should I come up with? How do I go about investigating that? And always keep your mind open to the twists and turns that the patient presents, so that you don’t miss anything.
RAJ: Dravet syndrome is really tough to treat, and prolonged seizures can damage the developing brain, so the faster we can get to a diagnosis, the better…
DR. SCHEFFER: The more you can control seizures the better the baby can get on with learning and developing, and the less likely they are to regress or lose skills. And regression is quite common when they have prolonged seizures.
RAJ: The journey for families of a child with Dravet syndrome is often very difficult.
DR. SCHEFFER: They have to deal with uncontrolled seizures, developmental concerns. Some of the Dravet children have behavioral issues. So there are a whole raft of issues that go hand-in-hand with the seizures. And, as a doctor, we need to support families in dealing with this long and often a hard journey.
You don’t want to be too pessimistic. You want to be upbeat and optimistic, but you also want to be realistic because otherwise it’s hard for families to know what to do next.
It’s very important that the families engage with Dravet syndrome foundations in their country and get really good information to support their journey, so that it can be as good for everyone in the family moving forward.
RAJ: Thanks to Dr. Scheffer for speaking with us.
This is DDx, a podcast by Figure 1.
Figure 1 is an app that lets doctors share clinical images and knowledge about difficult to diagnose cases.
I’m Dr. Raj Bhardwaj, host and story editor of DDx.
You can follow me on Twitter at Raj BhardwajMD.
Head over to figure one dot com slash ddx, where you can find full show notes, photos and speaker bios.
This season of DDx is sponsored by BioMarin Pharmaceutical Inc.
This podcast is intended for healthcare professionals only.
For more information on diagnostic testing go to paediatricseizures.com
Thanks for listening.