Summary
It started with a jolt of electrical activity – inside a toddler’s brain. A 3-year-old boy is referred to a specialist on the suspicion he has epilepsy, a complicated and fickle condition. And this child’s seizures were just the first of several mysterious symptoms that baffled doctors.
The child was around 3 ½ years old when he was first examined by Dr. Andreas Hahn, a professor of paediatrics at the University Hospital in Gießen, Germany. Dr. Hahn is also the chief senior physician of the department of child neurology with a specialization in paediatric epilepsy. It became obvious to Dr. Hahn that the child’s epilepsy was just one symptom of a more complex condition.
“When doing physical examination I noticed the movement disorder. His motor development was delayed. He could not walk as fast as other children and his gait was peculiar, it was broad,” remembers Dr. Hahn.
The patient was unsteady on his feet, had muscle weakness and suffered from involuntary moments in his arms and legs.
“So this is what we call ataxia dysmetric movement disorders where you have problems to coordinate your eyes and your legs,” says Dr. Hahn.
The patient’s movement disorder was difficult to classify because it seemed to be a combination of two different conditions: ataxia, which is a term to describe problems with movement and coordination, and is characterized by involuntary twitching.
But he lacked a symptom of typical ataxia: tremors.
And then there was his delayed speech.
It became clear to Dr. Hahn that this case would be challenging to diagnose.
Dr. Hahn then ordered an EEG to get a closer look at what was happening in the child’s brain. While the exam did confirm paediatric epilepsy, otherwise, the insights provided weren’t particularly helpful.
“The problem is that there are so many different reasons that may cause epilepsy,” shares Dr. Hahn. “There’s a bulk of genetic disorders without a specific phenotype, and there are also many metabolic reasons that can cause epilepsy.”
When treating a patient with epilepsy, the first job of a specialist is to classify the seizures and determine if the patient suffers from seizures alone, or other symptoms that point to a specific epilepsy syndrome.
The movement disorder was a huge clue.
For Healthcare Professionals only.
Guest
Dr. Hahn has been compensated by BioMarin for his participation.
Professor Andreas Hahn, MD
Andreas Hahn is professor of Paediatrics at the Justus-Liebig-University in Giessen, Germany, and chief senior physician of the Department of Child Neurology since 2002. He started his training as a neuropaediatrician in 1991 in Göttingen, spent one year as research fellow in the Department of Rehabilitation at Poitiers, France, and worked from 1993–2001 in the Department of Neuropaediatrics in Kiel, and in the North-German Epilepsy Centre in Raisdorf, Germany. He is a member of the German Neurophysiological Society and has completed special training programs in epileptology and neurophysiology. His special fields of interest are paediatric epilepsies, neuromuscular disorders, and neurometabolic diseases. He is a member of the medical board of the German Pompe patients group, and follows infants and children with Pompe disease since many years. During the last 15 years he gained much experience in treating patients with various lysosomal storage disorders by enzyme replacement therapy and other new types of treatment. He is the main or co-author of about 200 publications in peer-reviewed journals and book chapters.
Transcript
DDx SEASON 5, EPISODE 4
Diagnosing a Complex and Mysterious Form of Paediatric Epilepsy
RAJ: This season of DDx is sponsored by BioMarin Pharmaceutical Inc.
This podcast is intended for healthcare professionals only.
Opening
RAJ: It started with a jolt of electrical activity – inside a toddler’s brain.
A three-year-old boy is referred to a specialist on the suspicion he has epilepsy.
He has mild atonic seizures, which cause his muscles to go limp.
But epilepsy is a complicated and fickle condition.
And this child’s seizures were just the first of several mysterious symptoms that would baffle doctors.
Show intro DDx Theme Music
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. Andreas Hahn, a Professor of Paediatrics at the University Hospital in Gießen, Germany. Dr. Hahn is also the chief senior physician of the Department of Child Neurology with a specialization in paediatric epilepsy.
Dr. Hahn has been compensated by Biomarin Pharmaceutical Inc. for his participation in this episode.
Chapter 1: Symptoms
RAJ: This patient was around three-and-a-half years old when he was first examined by Dr. Hahn. It became obvious that his epilepsy was just one symptom of a more complex condition.
DR. HAHN: When doing physical examination I noticed the movement disorder. His motor development was delayed. He could not walk as fast as other children and his gait was peculiar, it was broad.
RAJ: The patient was unsteady on his feet, had muscle weakness and suffered from involuntary moments in his arms and legs.
DR. HAHN: So this is what we call ataxia dysmetric movement disorders where you have problems to coordinate your eyes and your legs.
RAJ: The patient’s movement disorder was difficult to classify because it seemed to be a combination of two different conditions: ataxia, which simply means imbalance, and dystonia, which is characterized by involuntary twitching.
But he lacked a symptom of typical ataxia: tremors.
And then there was his delayed speech.
It became clear to Dr. Hahn that this case would be challenging to diagnose.
He started with an EEG to get a closer look at what was going on in the patient’s brain.
DR. HAHN: And this showed abnormalities. The background activity was a little bit slowed, and we also saw some epileptic discharges in the EEG.
RAJ: But these details weren’t particularly helpful. They confirmed the patient had epilepsy, but not much else.
DR. HAHN: The problem is that there are so many different reasons that may cause epilepsy. There’s a bulk of genetic disorders without a specific phenotype, and there are also many metabolic reasons that can cause epilepsy.
RAJ: When treating a patient with epilepsy, the first job of a specialist is to classify the seizures and determine if the patient suffers from seizures alone, or other symptoms that point to a specific epilepsy syndrome.
DR. HAHN: First of all, we try to categorize the seizures of the patient and we do additional neurological examinations like an MRI and EEG, and we try to find a specific epilepsy syndrome, and if I come to a specific epilepsy syndrome, then I can estimate the prognosis of the patient: the course of disease and which drugs will work best for the patient.
Sometimes this is easy. In this case, this was not easy. And I was not sure what epilepsy syndrome this patient had because the EEG findings were unspecific, the seizures were also unspecific and in addition he had this peculiar movement disorder.
RAJ: The movement disorder was a huge clue.
DR. HAHN: This peculiar movement disorder brought me to the idea there has to be a specific genetic syndrome perhaps causing epilepsy. I also kept in mind that this could be a metabolic epilepsy, although this is a very rare cause of epilepsy in children.
Chapter 2: Diagnosis Tests
RAJ: Dr. Hahn went to work performing diagnostic tests. The EEG came first, but many others followed.
DR. HAHN: What we did was an MRI. And what we also did during this time was some kind of metabolic examination. This means that we exclude by a battery of screening tests, a lot of metabolic disorders. And what we also did is a lumbar puncture. So this means we examined cerebral spinal fluid.
RAJ: It took two long months for all the test results to arrive.
And once they did, the findings were… underwhelming.
DR. HAHN: We found nothing abnormal. We had done a lot of diagnostic tests, but we found nothing, and so the cause of epilepsy remained unclear.
RAJ: But this result isn’t as rare as you might think. In the majority of toddlers with epilepsy, no metabolic abnormalities or brain malformations are typically found.
When it comes to rare disorders, narrowing the DDx is sometimes a slow process of elimination.
DR. HAHN: So this is not unusual. We know many diseases a patient does not have, and this is also not so bad.
RAJ: At this point the patient had been in Dr. Hahn’s care for approximately two months.
DR. HAHN: And so I talked with the parents and told them that we do not know the cause of his disease, but we had to start treating the patient with some anti-epileptics.
RAJ: A month passed. The medication was ineffective. The patient continued to have minor seizures three to four times a week.
Dr. Hahn decided it was time to talk to the parents about genetic testing.
Chapter 2: Genetic Testing
DR. HAHN: I told the parents, this is somewhat time consuming, it can last up to three months until we get the results of this kind of genetic testing. And probably the results of this testing will not affect the treatment of the patient.
RAJ: Again, this isn’t unusual.
But there is value in genetic testing, even for a disease without an obvious treatment.
DR. HAHN: First of all, there is a small chance that you find something you can treat, and it could also be that we will have a treatment in the future. So there are many disorders we can treat now that we couldn’t treat three or four years ago, for example. So this is one point.
And I personally think that every child that has a chronic disorder merits a diagnosis.
Chapter 3: Diagnosis
RAJ: Dr. Hahn conducted the genetic testing.
Three months after the genetic tests were ordered, results arrived.
DR. HAHN: We unraveled the exact cause of his epilepsy. And what we had detected was a genetic defect in the GLUT 1 gene. This is a glucose transporter that shuffles glucose into the brain. So this was the exact cause of epilepsy in this patient.
RAJ: Dr. Hahn is describing Glucose transporter type 1 deficiency syndrome, or De Vivo disease. It’s a rare genetic disorder resulting from a variation in the GLUT1 gene, which prevents it from producing a protein responsible for transporting glucose from the blood to the brain.
Seizures, movement disorders, speech and learning delays can all be a result of the brain lacking glucose… And to make diagnosis even harder, sometimes symptoms come and go…
Remember that lumbar puncture that was done along with the MRI and metabolic tests? That’s generally an accurate way to test for De Vivo disease, as the concentration of glucose in the spinal fluid will reveal the diagnosis.
If positive, it’ll be low when compared to the levels of glucose in the patient’s blood.
But if that’s the case, why did the spinal tap Dr. Hahn conducted turn out to be normal?
There are a couple of reasons for this.
Number one: the patient had a mild form of the disease — type 1 — so the levels of glucose in the spinal fluid weren’t unusually low.
And number two: The concentration of glucose in the spinal fluid can vary depending on the time of day and whether the patient has eaten.
So performing the test first thing in the morning – before the patient has had breakfast – is vital to getting an accurate result.
DR. HAHN: After this case, I will never forget that we did the lumbar puncture at noon and he had his last meal early in the morning. So probably this was the reason that we missed this diagnosis by our metabolic testing. And of course this shows how important it can be to do additional genetic testing.
RAJ: The genetic testing was conclusive. Dr. Hahn knew what was causing this patient’s epilepsy and he had a specific treatment in mind.
DR. HAHN: I also told the parents there is a special kind of treatment that we can apply to the patient. And this is something we call the ketogenic diet.
RAJ: The ketogenic diet is a high-fat low carbohydrate diet that can be effective at managing drug-resistant epilepsy. Under strict medical supervision, the diet causes the body to produce ketones, which are used by the brain as an alternative to glucose as a source of energy.
DR. HAHN: Indeed the treatment was effective with regard to epilepsy and the seizures in this patient.
RAJ: Today the patient is 12 years old.
His coordination has improved. He can walk, run, and jump.
His last seizure was six years ago.
Chapter 4: Lessons
Music transition
DR. HAHN: What we learned is that genetic testing is really something that is complementary to metabolic testing and now times have changed a lot and genetic testing has become much better and cheaper.
Genetic testing is an easy and powerful diagnostic method. And I think we should apply this technique relatively early in the course of disease.
So, this is my opinion, all patients with epilepsies where we do not know the exact cause should undergo next generation sequencing and what I also learned from this case is that there was a small chance that we find something we can treat and something that changes the game. And this was true in this case.
Show Closing
RAJ: Thanks to Dr Andreas Hahn 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 brought to you 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.