Interview with Prof. Martin Holtkamp
Epilepsy remains one of the most complex neurological disorders, affecting millions worldwide and demanding lifelong management for many patients. Despite the availability of over thirty antiseizure medications (ASMs), treatment outcomes have plateaued over the past decades; roughly one-third of patients continue to experience uncontrolled seizures. This persistent therapeutic gap underscores the importance of precision medicine, clinical experience, and patient-centered decision-making in epilepsy care.
Prof. Martin Holtkamp, a leading epileptologist at Charité – Universitätsmedizin Berlin, has devoted his career to improving epilepsy management through both clinical practice and research. As Head of the Epilepsy-Center Berlin-Brandenburg, his work bridges cutting-edge science with compassionate, individualized patient care.
During his recent visit to the American Hospital Tbilisi, Prof. Holtkamp delivered an insightful lecture titled “Starting and Stopping Antiseizure Medication,” organized with the support of Prof. Dr. Nino Gzirishvili, Head of the Epilepsy and Sleep Disorders Unit. On the following day, during a multidisciplinary meeting focused on evaluating patient cases for potential surgical intervention, he shared further insights with us in an in-depth interview, discussing individualized drug selection, treatment withdrawal, challenges in managing status epilepticus, and the future of antiseizure drug development.
Given the heterogeneity of epilepsy syndromes and patient responses, how do you approach individualized antiseizure medication selection when starting treatment or adjusting for breakthrough seizures?
So, when we decide what medication the patient should take, the first thing we need to consider is the type of epilepsy. There’s focal epilepsy, where seizures start at one point in the brain – this accounts for 60 to 70% of cases. Then there’s generalized epilepsy, where seizures begin simultaneously in both hemispheres, making up about 20 to 25% of cases. This is the primary distinction. Different drugs are more effective for generalized epilepsy and generalized onset seizures compared to focal seizures. So, that’s the first distinction we make.
Next, we consider the patient’s sex. For example, some drugs can’t be prescribed to females due to their teratogenic effects. A key example is valproic acid, which we avoid in younger females. We also take the patient’s age into account – different medications may be prescribed to younger patients versus older ones, and in elderly patients, we adjust the dosage accordingly. These are the main factors. Additionally, we sometimes consider comorbidities and other medications the patient may be taking, as we need to be cautious of potential drug interactions.
We don’t focus on the etiology, as there are no specific etiologies tied to response to particular drugs. So, the five main factors we consider are the type of epilepsy, the patient’s sex, age, comorbidities, and any concomitant medications. Based on these, we then choose the most suitable drug for the patient’s initial therapy.
Could you share your thoughts on yesterday’s meeting about stopping antiseizure medication? What were the key takeaways, and are there any new developments or consensus in this area?
Stopping the medication is often overlooked. The issue is that, in most cases, neither the doctors nor the patients really consider it. Doctors are content when patients are seizure-free, and patients are, of course, happy with that outcome as well. So, doctors tend to be hesitant about stopping the medication, mainly due to fear of a seizure relapse, and patients are even more reluctant to discontinue their medication.
We conducted a study at Charité that showed younger, less experienced doctors are more likely to continue medications. On the other hand, more experienced doctors, like myself with 30 years of practice, tend to have a broader perspective and are more inclined to discuss stopping the medication with patients. However, both sides remain very hesitant. As I mentioned yesterday, about 40% of patients experience a seizure recurrence within five years if they stop their medication, while those who continue still face a 20% risk. So, the risk essentially doubles. Ultimately, it’s a very individual decision.
For example, if a patient has a young child they care for all day, I would not recommend stopping the medication. Similarly, if a young student is about to travel abroad alone to a country where they are unfamiliar with the healthcare system, I do not recommend stopping the medication. Driving is another important factor to consider. These are all individual circumstances that need to be discussed thoroughly between the doctor and the patient. The decision is never made solely by the doctor.
You mentioned patient factors. Could you elaborate on the key clinical factors that guide this decision (stopping antiseizure medications)?
The most important biomarker is the duration of seizure freedom. The longer a patient has been seizure-free, the more likely he/she is to remain seizure-free after stopping medication. Typically, we recommend at least two years of being seizure-free. However, the longer the duration of seizure freedom, the better the outcome. For example, a patient who has been seizure-free for 20 years has a much higher chance of remaining seizure-free compared to someone with just three years of freedom. That’s the most crucial factor. The second important consideration is structural lesions. For example, if a patient has a structural lesion on their MRI, I would be more hesitant to stop medication, as the risk of a recurrence is higher. On the other hand, if the MRI is completely normal, it’s more likely they will remain seizure-free. These are perhaps the two most important biological markers to consider.
Drug-drug interactions remain a major concern in antiseizure polytherapy. What strategies do you recommend to optimize combination regimens while minimizing adverse interactions?
There can be drug-drug interactions between two or more antiseizure medications. Still, we also need to consider interactions between antiseizure medications and other medications, such as those for high blood pressure. Many newer medications approved for monotherapy tend to be quite neutral in this regard. For example, levetiracetam has very few drug interactions, while lamotrigine is a good drug but has slightly more interactions. It’s important to keep this in mind, as the situation is quite individual and requires careful consideration. In some cases, these drug interactions can be advantageous. For instance, valproic acid can increase lamotrigine serum concentrations, which can be beneficial. However, we must also be cautious about some interactions, such as those with oral contraceptives. Lamotrigine, for example, reduces the efficacy of oral contraceptives, which increases the risk of pregnancy. So, all of these factors must be taken into consideration.
Based on your recently published SOP guideline for managing status epilepticus in adults, what are the main clinical challenges in applying these protocols, and how have your recommendations impacted treatment outcomes in real-world practice?
In status epilepticus, it’s important to differentiate whether it occurs in individuals with a history of epilepsy, which is typically easier to treat, often due to missed medication or a fever triggering a prolonged seizure. This situation is generally straightforward to manage. However, it becomes more complex when status epilepticus occurs in someone without a prior history of epilepsy, often due to a new onset brain lesion, such as autoimmune encephalitis or sinus venous thrombosis. These cases can be much more challenging to treat, especially when they progress to refractory stages of epilepticus. The problem is that, in many cases, patients are initially undertreated because doctors are hesitant to act. If a seizure lasts for five minutes and doesn’t stop spontaneously, treatment should begin immediately. In the case of status epilepticus, if the seizure persists beyond five minutes without spontaneous resolution, antiseizure medication should be started following strict protocols outlined in guidelines—typically with high-dose benzodiazepines. When centers review studies and look back at how they treated patients, they often find that in 70 to 80% of cases, patients were undertreated. Doctors were too cautious, which worsens patient outcomes. Failing to adhere to hospital SOPs can significantly lower the chances of treatment success. Even with full adherence to the protocols, one-third become refractory, continuing to have seizures despite benzodiazepines and a second drug, such as intravenous levetiracetam, lacosamide, or valproic acid.
Could you comment on the paradox that, despite many newer antiseizure medications, seizure control rates have not markedly improved? What does this imply for future ASM development and treatment strategies?
That’s a very important and challenging point. When you look at phenytoin, which was developed and marketed in the late 1930s and early 40s, it had a success rate of about 65% for patients becoming seizure-free. Now, even with newer drugs that are much more expensive and have been developed in the past few years – over 30 different drugs – the efficacy is still around 65%, and one-third of patients remain drug-resistant. This highlights the need to return to basic science and gain a better understanding of epilepsy’s pathophysiology to design drugs with different mechanisms of action. Most of the currently available drugs, such as lamotrigine, carbamazepine, and lacosamide, primarily function as sodium channel blockers. So, we can’t expect significant improvement if we continue relying on the same mechanism.
Big companies and researchers need to go back to animal models and delve deeper into the pathophysiology of epilepsy to develop new treatment approaches. It’s true that, over the last 80 years, there hasn’t been much progress in terms of efficacy. However, one key change has been in tolerability – newer drugs are much better tolerated than the older ones. This is crucial because quality of life is far more affected by the tolerability of medication than by the number of seizures a patient experiences, whether it’s two, four, or six per month. So, while the improvement in tolerability is significant, you’re right, efficacy has remained unchanged.
Regarding today’s review of patient cases for epilepsy surgery, could you clarify which types of epilepsy typically qualify patients for surgical intervention?
Today, we had the entire team involved: neurosurgeons, basic scientists, neurophysiologists, neuropsychologists, and neurologists. The key requirement for surgical eligibility is that the patient has focal epilepsy, which accounts for 60-70% of cases. They must also be drug-resistant, meaning they haven’t responded to at least two drugs—typically, we try three or four different drugs sequentially, not simultaneously. Once this is established, all patients are eligible for presurgical evaluation.
The first step is taking a detailed acute history: understanding the nature of the seizures, the aura, and identifying the first clinical signs. After that, we look at the MRI. If we find any abnormalities, we proceed accordingly, but even if the MRI is normal, surgery may still be an option. Next, we need a video-EEG recording, which typically lasts between three and seven days, during which we try to capture seizures. By watching the video and analyzing the EEG at seizure onset, we assess whether the data align, meaning that the MRI findings, seizure history, clinical symptoms, and both ictal and interictal EEG are congruent. If everything fits together, the chances of becoming seizure-free after surgery are quite high.
However, we always have to consider potential deficits. For example, if surgery is near the speech center, there’s a risk the patient could have significant issues with speaking or word-finding, so we avoid operating in that area. Similarly, surgeries near the motor center could lead to paralysis, which we also try to avoid. It’s quite rare for us to operate in the occipital lobe due to the risk of visual defects, but there are many areas of the brain where surgery can be performed without impacting function.
For right-handed individuals, we can remove large parts of the frontal or temporal lobe on the right side without significant functional neuropsychological impairment. While specific tests may reveal some differences. However, in daily life activities, there are typically no noticeable changes. The goal is to ensure that patients remain functional after surgery.
The process of presurgical evaluation in patients with epilepsy is quite complex, involving multiple disciplines. We rely heavily on the neurosurgeons, who assess whether surgery is feasible and what the associated risks are. Of course, the neuropsychologists and our team, who have long-term experience with these patients in our clinic, are integral to the decision-making process.
Finally, what are the most common pitfalls or challenges you see neurologists encounter in managing antiseizure medication, and how can they be addressed?
I think the challenge arises when patients do not respond to medication. If you try one of the five first-line drugs and the patient becomes seizure-free without side effects, everything is fine – 60 to 70% of patients respond this way. The goal is no seizures, no side effects. However, for one-third of patients who are not seizure-free, the situation becomes more complicated. In these cases, we typically recommend referring patients to an epilepsy outpatient clinic, where specialists are better equipped to explore other drug options and combinations.
There are newer drugs available now, such as cenobamate (Xcopri), though I’m not sure if it’s available in Georgia. If it isn’t, patients with the financial means can sometimes import it through international pharmacies. Cenobamate is a potent drug introduced in the last few years. In the countries where it is available, doctors are often hesitant to prescribe it, as they’re still adjusting their practices to include these newer treatments. Some doctors feel it’s too soon to prescribe such medications, continuing to rely on the same treatments over and over.
But studies from places like Philadelphia and London have shown that even with the medications we already have, including here, simply increasing the dose or changing the compound can lead to improvements in about 20% of patients. As we discussed today, sometimes raising the dose to the highest level can yield additional benefits. So, the key message is not to give up on the patient. Instead, continue thinking about dose increases, exploring new combinations, and making the most of what’s available. It’s easy to feel like nothing can be done, but there’s always more to try before resorting to that conclusion.
