A 2-year-old boy has episodes where his face changes, his arms shoot into the air, and he collapses. His parents don’t understand what is happening, but they do know they are frightened for their child. On this episode of the podcast, we address when a rare disease diagnosis offers more questions than answers and how to support patients and families when treatment options don’t lead to a cure.
The child, we’ll call him Jamie, was medically healthy, but had experienced some developmental delays. So the family doctor recommended he see a paediatrician, who thought these episodes were most likely epileptic seizures.
But, “she found no other relevant cause for the epilepsy when she took the history,” shares Dr. Alasdair Parker, a paediatric neurologist at Addenbrooke’s Hospital, Cambridge, and an associate lecturer at the University of Cambridge, in the United Kingdom. “In particular, she checked whether he might’ve had a brain injury, preterm birth, any family history of similar disorders and none were evident. She had a careful look and examined him to see if there were any clues for a genetic disorder or any sign of any physical disability that might correlate with an epilepsy. And none were evident.”
Unable to make a clear diagnosis, the paediatrician asked if there was any video of Jamie’s episodes. Fortunately, his mom did have a video. After watching the clip, the paediatrician felt more certain that what she was seeing was epilepsy.
“As a result, the local paediatrician arranged the first-line investigations, which would include a brainwave tracing – what we call an EEG – and an MRI brain scan. She also started treatment with a first-line drug for an epilepsy at that point,” said Dr. Parker.
Jamie underwent a series of tests that eventually confirmed a rare variant of epilepsy, but receiving this rare disease diagnosis was just the beginning of his journey.
For Healthcare Professionals only.
Dr. Parker has been compensated by BioMarin for his participation.
Alasdair Parker, MD
Dr. Alasdair Parker is President of the British Paediatric Neurology Association 2021-4 and a paediatric neurologist at Addenbrooke’s Hospital, Cambridge. He developed and led the East of England Paediatric Neuroscience Service 2003-12 and 2017-20. He has launched services for video-telemetry, movement disorder, neuromuscular, acute brain injury, ketogenic diet, vagal nerve stimulation and neuro-immunology. He holds an associate lectureship at the University of Cambridge, leading in the training of undergraduates, and junior and senior doctors. His research interests include the epilepsies, genomic disorders, and quality of life. He has greatly benefitted from the support of children, families and patient organizations.
DDx SEASON 5, EPISODE 2
The Many Questions and Few Answers of a Rare Disease Diagnosis
RAJ: This season of DDx is sponsored by BioMarin Pharmaceutical Inc.
This podcast is intended for healthcare professionals only.
The details of this case study have been changed to protect patient privacy
RAJ: A two-year old boy experiences brief episodes where his face takes on an odd expression, his arms shoot straight into the air, and then he collapses.
This happens several times a day.
The parents don’t know what to make of it.
What they do know is that they’re frightened.
And a visit to the family doctor raises more questions than it answers.
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. Alasdair Parker, a paediatric neurologist at Addenbrooke’s Hospital, Cambridge, and an Associate Lecturer at the University of Cambridge, in the United Kingdom.
Dr. Parker has been compensated by BioMarin Pharmaceutical Inc. for his participation in this episode.
Chapter 1: Symptoms
RAJ: When the family doctor examined our patient, he was concerned.
Although our patient — let’s call him James or Jamie for short — was otherwise healthy, he had a developmental history that raised questions.
DR. PARKER: Although James was medically well, his development was slightly delayed. So he didn’t walk until 18 months. And by the age of two-and-a-half was only talking in a few words, whereas you’d expect children to be walking confidently by about 16 to 18 months. And we normally say 20 words or 20 months and little sentences by two.
RAJ: The family doctor referred James to a local paediatrician, who thought these episodes were most likely epileptic seizures.
DR. PARKER: So the local paediatrician assessed Jamie and she found no other relevant cause for the epilepsy when she took the history. In particular, she checked whether he might’ve had a brain injury, preterm birth, any family history of similar disorders and none were evident. She had a careful look and examined him to see if there were any clues for a genetic disorder or any sign of any physical disability that might correlate with an epilepsy. And none were evident.
RAJ: The local paediatrician reviewed the case. She asked Jamie’s mother if any of his episodes were captured on video.
DR. PARKER: Jamie’s mom explained that they were very difficult to catch on video because they’d almost finished before they’d started, but by chance, she was videoing Jamie doing something else and did have some footage. And this confirmed the description.
RAJ: Now the paediatrician felt more certain that what she was seeing was epilepsy.
DR. PARKER: As a result, the local paediatrician arranged the first-line investigations, which would include a brainwave tracing – what we call an EEG – and an MRI brain scan. She also started treatment with a first-line drug for an epilepsy at that point.
RAJ: An EEG, or Electroencephalogram, detects abnormal brain waves.
The pattern of brainwaves can say a lot about the type of seizures that a patient is having.
DR. PARKER: If the abnormality is in one small part of the brain, it would be quite likely that the epilepsy comes from that area only. And commonly those are due to acquired changes in the brain, such as a traumatic brain injury. If the pattern of the brainwaves is over the whole brain, which it was in Jamie’s case, this would imply more of a generalized tendency to epileptic seizures. And that’s commonly seen in genetic epilepsies rather than those caused after birth by a brain injury.
RAJ: The EEG confirmed that Jamie had frequent epileptic brain waves.
Unfortunately the results of EEGs are not always as specific as doctors would like, which is why the video of Jaime’s seizures was so useful.
DR. PARKER: Now you can have epileptic brain waves, even if you never have an epileptic seizure. So one has to be careful not to over-interpret that, but the type of abnormality frequency in conjunction with the video, confirmed that these were very likely to be early-onset epileptic seizures.
RAJ: The MRI, or magnetic resonance imaging, scans the brain and provides clear detailed images of its structure, revealing any abnormalities.
Jaime’s MRI showed a brain structure that was normal for his age.
The paediatrician asked a colleague who specializes in epilepsy to review the case.
He confirmed the EEG abnormality and agreed that the prescribed medication was a good treatment for the type of seizures Jaime was experiencing.
But Jamie’s condition didn’t really improve.
DR. PARKER: Jamie remained well for the next few weeks, but slowly these drop attacks recurred. And around three to four months after the first assessment, he had an episode when he dropped to the ground and shook all his limbs all over. His mother got very clear footage of that. And the local paediatrician was able to confirm that’s what we call a generalized tonic clonic, epileptic seizure.
RAJ: A generalized tonic clonic epileptic seizure is a full-body convulsive seizure.
It’s challenging to interpret a patient’s brain waves during one of these seizures, which is another reason why a video can be so helpful.
DR. PARKER: When we record those on a brain wave tracing, often the patient is moving so vigorously it’s difficult to interpret the brainwaves, but it once more points towards a process that is affecting the whole of Jamie’s brain and again, suggests a genetic process.
RAJ: Jaime continued to experience convulsive seizures.
The local paediatrician prescribed a second medication and gradually escalated the dose.
Although Jaimie’s seizures decreased in number, they didn’t go away.
DR. PARKER: So the local paediatrician phoned a friend, the local specialist in children’s epilepsy, working in a regional center, and the neurologist working at the regional center was very happy to assess Jamie.
RAJ: While waiting for the paediatric neurologist’s assessment, a third medication was prescribed and the second medication withdrawn without much clear benefit.
DR. PARKER: By this point, Jamie was approximately three years old. He had stagnation of development, had developed two different troublesome seizure types that were resistant to three different medications.
RAJ: The paediatric neurologist thought all signs pointed to early-onset genetic generalized epilepsy. As the name suggests, it’s epilepsy that begins early in life and is believed to have a genetic cause. It’s also characterized by seizures with specific EEG patterns.
So… what next?
DR. PARKER: The first thing a specialist in the area does is actually go through the history again and double check that this is likely to be a genetic disorder, looking for the examples of brain injury, such as preterm birth or meningitis in early life. And then redo the examination, this time looking predominantly for clues for a genetic disorder.
The next stage used to be a number of metabolic investigations. And these had a relatively low yield, and this field has changed quite significantly in the last years because we now have access to something called whole genome sequencing.
RAJ: Whole genome sequencing is the very complex process of deciphering our DNA, revealing variations that might be linked to genetic diseases.
DR. PARKER: When the expert saw Jamie, he undertook the examination carefully and did not find any red flag signs on examination. However, he noted that there was a very significant stagnation of development, and that in conjunction with the onset of a drug resistant epilepsy under three warrants very extensive and expert investigation because this can be how some degenerative disorders present.
So when a child has either stagnation or slow development of milestones, that clearly is very significant. And with childhood-onset epilepsies, if the seizures continue and are resistant to drug treatment, particularly on the ones who onset under the age of five years, a very significant impact on development is almost invariable.
Chapter 2: Diagnosis
RAJ: The specialist spoke to the family about whole genome sequencing, and they agreed it was the best course of action.
DR. PARKER: They were able to get the whole genome sequencing result back within a matter of weeks and that showed a variant, which had been reported to cause a very similar early-onset epilepsy with the drop seizures and the generalized tonic clonic seizures in other children. And after discussion with the geneticist, they conclude that was the likely cause of Jamie’s epilepsy.
Only one case in the whole world had exactly the same variant as Jamie, but there were a small number of children across the world who had a variant in the same gene, which had caused a very similar epilepsy to Jamie.
RAJ: But even though doctors knew the diagnosis…
DR. PARKER: Unfortunately it didn’t suggest a treatment which would stop the seizures and normalize the development. But it did confirm that Jamie had a genetic and generalized epilepsy. And from that point of view it opened a rational treatment journey.
And, in particular, they felt that there was one other drug that would be appropriate to try, bearing in mind the genomic cause of the epilepsy; and, if that failed, the specialist, high-fat diet had been reported to be more effective than drug therapy in other children.
RAJ: Over the next six months, the new medication wasn’t helpful, but the diet Dr. Parker mentioned, known as the ketogenic diet, was.
It’s a high-fat low carbohydrate diet that forces the body to produce ketones to fuel the brain’s need for energy, instead of glucose.
DR. PARKER: And you might argue, well, why don’t we just start treatment for those very early in the journey? And that’s because those treatments are very complex and definitely have certain risks.
RAJ: But the diet was the right choice for Jamie.
DR. PARKER: And Jamie was initiated on that with a really dramatic improvement in his seizure control. And over the next few months, his seizure burden dropped by over 90% to such a point that the drop attacks were very infrequent and he no longer had any of the large convulsive seizures.
RAJ: Jamie’s prognosis was good. He was given a lower dose of his medications.
Dr. Parker estimates that he has a long and healthy life ahead.
Chapter 3: Lessons
DR. PARKER: One of the things we should emphasize is that we may not be able to cure the child of the epilepsy or even produce a dramatic reduction, but there are lots of different ways we can support the family. And I think it’s really important to get that support in. So it’s not all about genetics and metabolics and drugs, it comes back to good old fashioned tender, loving care, and it’s very important.
RAJ: Thanks to Dr. Parker 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 for healthcare professionals only.
For more information on diagnostic testing go to paediatricseizures.com
Thanks for listening.