Is it OK for children with a CHD2 diagnosis to take multiple anti-seizure drugs?

Should parents worry when their child has been prescribed multiple anti-seizure drugs? The answer probably depends on which ones. This post explores how each of a number of popular drugs prescribed to control seizures act on the brain and how some are very similar in their action and others quite unique. It questions: “Are parents receiving sufficient information from medical professionals to help them to make choices about drugs?” Or at least: “Do parents feel they understand the rationale for trying a new drug?”

Neurological conditions like epilepsy are not fully understood. Conditions like CHD2 are understood even less. However, perhaps parents could be better prepared to discuss changes in medication with experts if they were simply provided with more information. After all, we live in a world where the average parent finds a ‘level-playing field’ discussion with a neurologist as hugely challenging as it is vitally important.

I mean, it’s a child’s brain isn’t it?

Pills — Image by Michal Jarmoluk from Pixabay

Background: my experience as the mother of a child with CHD2

As a parent of a child with CHD2 I have always been worried about the effects of giving her a combination of strong anti-seizure medications. However, over time, we have gradually introduced many new drugs. By trying to achieve control over the epilepsy, we have found ourselves with a cupboard full of various packets of pills and bottles of liquid, some of which seem to work and others I’m still not convinced about.

Now that our daughter is 13, she is on four drugs—and at the beginning of puberty—and her seizures are still not under control. It seemed like the right time to me to look at the drugs she is on and consider whether it’s a good thing or a bad thing to have a broad spectrum approach to seizure control, especially since CHD2 is so often associated with intractable (hard to control) epilepsy.

Research on Combining Drugs

There is some research available about how anti-seizure drugs affect the brain and the efficacy of combination. Michael Rogawski and Graeme J. Sills discusses the various mechanisms of action of anti-seizure drugs and highlights the importance of targeting multiple pathways to achieve better seizure control. Their article from 2020 emphasises that anti-seizure drugs affect the generation and spread of epileptic hyperexcitability by acting on voltage-gated sodium, calcium, and potassium ion channels, as well as modulating excitatory and inhibitory neurotransmission.

Another study (Sarhan et al., 2020) discusses the efficacy of combining two or more anti-epileptic drugs (AEDs) to improve seizure control and tolerability. It highlights that while 70% of epileptic seizures can be controlled with monotherapy, a combination of AEDs may be required for better outcomes.

A study published by JAMA Neurology (Cavazos et al., 2014) suggests that combining antiepileptic drugs with different mechanisms of action is the most effective treatment for partial onset seizures if you want to achieve optimal seizure control.

What do these drugs actually do? How do they work?

As a parent with a non-medical education, I find it hard to understand much of the technical detail around anti-epileptic drug mechanisms: enzymes, receptors, gates, channels and more. However, I can see there are some drugs which sit in the same family, and some which don’t, and it does make me think that if you tried one from one family and it didn’t work, perhaps trying one from another family would be a better idea than another one from the same?

I have used AI to produce a summary of the different families of anti-epileptic drug mechanisms and list some of the specific drugs in those families. Don’t worry if you don’t understand all the detail about these! It’s probably enough just to see which drugs fit into which families, which may help you understand what a neurologist is trying to achieve by prescribing one or more of these. The sources used for the AI summary are listed at the bottom of this post.

a. GABA Modulation

Drug	Action
Epilim (sodium valproate)	Increases GABA levels, which has a calming effect on the brain.
Clobazam	Enhances the effect of GABA at the GABA-A receptor.
Briviact (brivaracetam)	Modulates neurotransmitter release via SV2A and affects GABAergic transmission.
Cenobamate	Enhances GABA-A receptor-mediated inhibitory currents.
Clonazepam	Enhances the effect of GABA at the GABA-A receptor.

b. Sodium Channel Blockers

Drug	Action
Lamotrigine	Blocks voltage-gated sodium channels.
Phenytoin	Stabilizes the inactive state of voltage-gated sodium channels.
Rufinamide	Prolongs the inactive state of voltage-gated sodium channels.
Carbamazepine	Inhibits voltage-gated sodium channels.
Topiramate	Blocks voltage-gated sodium channels.
Lacosamide	Enhances the slow inactivation of voltage-gated sodium channels.
Zonisamide	Blocks voltage-gated sodium channels.

c. Calcium Channel Blockers

Drug	Action
Ethosuximide	Inhibits T-type calcium channels.
Zonisamide	Blocks T-type calcium channels.

d. AMPA Receptor Antagonists

Drug	Action
Perampanel	Non-competitively antagonizes AMPA receptors.

e. Carbonic Anhydrase Inhibitors

Drug	Action
Sulthiame	Inhibits carbonic anhydrase, leading to increased levels of carbon dioxide in the brain.
Acetazolamide	Inhibits carbonic anhydrase, leads to increased levels of carbon dioxide and bicarbonate in the brain.

f. Drugs and therapies with more unique characteristics

Some anti-epileptic drugs and other treatments do not fit into the above categories and have more unique actions. These are listed below.

Drug	Action
Keppra (levetiracetam)	Binds to SV2A, modulating synaptic transmission and reducing seizure propagation.
Epidiolex (cannabidiol)	Modulates multiple targets, including GPR55, TRPV1, and adenosine transport.
Melatonin	May have neuroprotective effects and reduce inflammation.
Vitamin D	May play a role in neuroprotective processes and seizure control by modulating calcium homeostasis.
Pyridoxine (Vitamin B6)	Reduces seizure activity by addressing deficiencies in the brain’s metabolism of certain enzymes.

What do I do now?

Talk to your medical professionals. If it’s not already clear to you, find out the rationale behind each drug being prescribed and assure yourself that there are no concerning contraindications. Ask for more information if explanations are not clear. Trust your instincts. Keep records of the side-effects. The more sharing we do about successes (and failures), the more our children will benefit from others. We hope that one day the treatment plans for our children will be much clearer.

Further detail on drug action

Medication	Mechanism of Action
Epilim (sodium valproate)	Increases the amount of gamma-aminobutyric acid (GABA) in the brain, which has a calming effect by blocking transmission across nerves. It also inhibits voltage-gated sodium channels and T-type calcium channels, reducing neuronal excitability[1][2].
Keppra (levetiracetam)	Binds to synaptic vesicle protein 2A (SV2A), which is involved in neurotransmitter release, thereby modulating synaptic transmission and reducing seizure propagation. It also inhibits N-type calcium channels and affects GABAergic and glycinergic transmission[3][4].
Lamotrigine	Blocks voltage-gated sodium channels, stabilizing neuronal membranes and inhibiting the release of excitatory neurotransmitters like glutamate and aspartate[5][6].
Clobazam	Enhances the effect of GABA at the GABA-A receptor, increasing chloride ion influx and causing hyperpolarization of the neuron, which reduces neuronal excitability[7][8].
Cenobamate	Blocks persistent sodium currents and enhances GABA-A receptor-mediated inhibitory currents, reducing neuronal excitability and preventing seizures[9][10].
Phenytoin	Stabilizes the inactive state of voltage-gated sodium channels, reducing the ability of neurons to fire at high frequencies and preventing the spread of seizure activity[11][12].
Briviact (brivaracetam)	Binds with high affinity to synaptic vesicle protein 2A (SV2A), modulating neurotransmitter release and reducing neuronal excitability. It also inhibits voltage-gated sodium channels[13][14].
Rufinamide	Prolongs the inactive state of voltage-gated sodium channels, stabilizing neuronal membranes and preventing the spread of seizure activity[15][16].
Epidiolex (cannabidiol)	Modulates multiple targets, including GPR55, TRPV1, and adenosine transport, reducing neuronal excitability and seizure activity[17][18].
Carbamazepine	Inhibits voltage-gated sodium channels, stabilizing hyperexcited neuronal membranes and reducing synaptic transmission of excitatory signals[19][20].
Topiramate	Blocks voltage-gated sodium channels, enhances GABA-A receptor activity, antagonizes AMPA/kainate glutamate receptors, and inhibits carbonic anhydrase, reducing neuronal excitability[21][22].
Lacosamide	Enhances the slow inactivation of voltage-gated sodium channels, stabilizing hyperexcited neuronal membranes and reducing repetitive neuronal firing[23][24].
Clonazepam	Enhances the effect of GABA at the GABA-A receptor, increasing chloride ion influx and causing hyperpolarization of the neuron, which reduces neuronal excitability[25][26].
Zonisamide	Blocks voltage-gated sodium and T-type calcium channels, inhibits carbonic anhydrase, and modulates GABAergic and glutamatergic neurotransmission.
Ethosuximide	Inhibits T-type calcium channels in thalamic neurons, reducing the rhythmic cortical discharge associated with absence seizures.
Sulthiame	Inhibits carbonic anhydrase, leading to increased levels of carbon dioxide in the brain, which has an anticonvulsant effect.
Perampanel	Non-competitively antagonizes AMPA receptors, reducing excitatory neurotransmission and preventing seizure activity.
Acetazolamide	Inhibits carbonic anhydrase in the central nervous system, leading to increased levels of carbon dioxide and bicarbonate in the brain. This results in a decrease in neuronal excitability and an increase in inhibitory neurotransmission, which helps to control seizures.
Melatonin	May have neuroprotective effects and reduce inflammation, which could help in reducing seizures.
Vitamin D	May play a role in neuroprotective processes and seizure control by modulating calcium homeostasis and neuronal excitability.
Pyridoxine (Vitamin B6)	Reduces seizure activity by addressing deficiencies in the brain’s metabolism of certain enzymes involved in neurotransmitter synthesis.