Epilepsy treatment in Germany

Functional diagnostics to determine the location of the epileptic focus  is performed using the following methods:

• routine and long-term video EEG monitoring (a method of recording the electrical activity of the cerebral cortex), including video recording, in order to measure focal spike-and-wave complexes or asymmetric slow waves that indicate the presence of an epileptic focus and its location;

• monitoring of antiepileptic drugs, i.e. measurement of AED concentrations in the blood
• MRI with MAP07 analysis, a computer-based MAP07 evaluation

• so-called structural MRI:  1.5- and 3-Tesla MRI of the brain to visualise the structure of the brain and possible  epileptogenic lesions;

• functional MRI;    

• SISCOM: a purpose-developed procedure for imaging the regional increase in metabolism associated with the onset of an epileptic seizure (the SISCOM method / Subtraction Ictal SPECT Co-Registered to MRI is used as an adjunct in cases where MRI fails to reveal an obvious cause of the pathological activity. Another important task of the SISCOM protocol is precise preoperative mapping of the area of the brain that is to undergo surgery. The high accuracy with which the pathological focus is identified makes it possible to find the site where invasive seizure-suppressing electrodes will subsequently be inserted and to determine their direction);    

• FDG-PET positron emission tomography: a rarely used method of imaging reduced metabolic activity in the seizure focus (FDG-PET can show reduced metabolism in the areas surrounding epileptogenic zones and has high sensitivity and specificity for epileptogenic foci in patients with inconclusive findings);    

• SPECT – single-photon emission computed tomography;    

• electrocorticography:  a method of functionally examining the cerebral cortex by recording its biopotentials with implanted electrodes placed directly on its surface.

• language functional MRI to localise the speech area of the cerebral cortex, which can sometimes replace the Wada test; it is also known as BOLD functional magnetic resonance imaging (BOLD — blood oxygenation level dependent contrast; BOLD fMRI is one of the most widely used and best known ways of mapping brain activity; activation leads to an increase in local blood flow with a change in the relative concentrations of oxygenated (oxygen-rich) and deoxygenated (oxygen-poor) haemoglobin in that blood flow);

• the Wada test: a lateralising intracarotid Wada test with amobarbital (the intracarotid amobarbital procedure), in which the cerebral hemispheres are briefly inactivated (switched off) one after the other, making it possible to establish which hemisphere is dominant for speech and memory and to predict the patient's  functional losses and hemispheric reserves; although modern non-invasive methods of determining the lateralisation of speech and memory, such as functional MRI of the brain and  bilateral  simultaneous  carotid Doppler ultrasound, are being  introduced  into  clinical practice ever more widely, they are not  yet  the "gold standard" for predicting functional  deficits in neurosurgical  procedures;

• cortical electrical stimulation: direct electrical stimulation of the cerebral cortex to identify the functions located close to the epileptic focus.

Standardised neuropsychological tests are used to document the patient's baseline neuropsychological status so that it can be followed up and reviewed regularly after surgery. Monitoring the patient's  neuropsychological profile (a set of standard parameters) provides important information about impaired brain function. A comprehensive preoperative work-up helps to plan the surgical strategy carefully and to avoid postoperative complications.

Removing the brain tissue responsible for generating seizures and disconnecting the nerve fibres along which seizure discharges spread are safe  techniques with proven efficacy.

As part of the preoperative work-up for epilepsy, doctors have to answer the following questions:

    • has the diagnosis of "epilepsy" been established correctly?
    • has the diagnosis of "drug-resistant epilepsy" been established correctly?
    • can freedom from seizures be achieved by surgery?
    • is it possible to determine the epileptic focus precisely?
    • will the operation harm other brain functions?
    • how do the chances of a successful operation compare with its risks and with non-surgical therapy?

Once the work-up has been completed, its results are discussed in detail with the patient and their family so that a well-founded and balanced decision can be made as to whether surgery is possible or contraindicated.

All diagnostic procedures carried out in preparation for surgery, including implantation of a stereotactic electrode to localise the epileptic focus, are performed in close cooperation with the neurosurgery department of Beta Klinik. The gentlest operation available today is the unique MRI-guided laser ablation of the pathological focus.

Surgical treatment of drug-resistant epilepsy

1. anterior temporal lobectomy (resection) — therapeutic surgical removal of the anterior temporal lobe;

2. selective hippocampectomy / limited temporal resection — selective resection of the hippocampus and of the amygdala, which lies in the medial part of the temporal lobe.
Both procedures are used in drug-resistant temporal lobe epilepsy with the focus in the anterior part of the temporal lobe. When the epileptic focus lies in the mesial structures, which is the case in 80% of temporal lobe epilepsies, a selective amygdalohippocampectomy is performed, or a combination of it with temporal lobectomy. Complications of temporal resection may include a moderate short-term memory disorder, loss of 1/4 of the visual field and others. Up to 70% of the patients operated on become completely free of seizures, and 10% report a marked reduction in seizure frequency.

3. multilobectomy: resection of circumscribed lesions in several lobes of the brain.

4. palliative callosotomy, which consists in dividing the corpus callosum (the structure that "connects" the right and left hemispheres of the brain) and is indicated for patients with generalised seizures and bilateral independent epileptic foci in the frontal lobes, as well as for patients with frequent seizures such as "drop attacks", brief seizures in which the patient loses muscle tone and falls to the floor; callosotomy prevents seizure activity from spreading rapidly from one half of the brain to the other;

5. combined resection and disconnection procedures;

6. extratemporal neocortical resection: removal of the frontal lobe of the brain or a limited resection of an epileptogenic structure within a lobe of the brain.

7. vagus nerve stimulation with implanted electrodes.
The vagus nerve innervates the organs of the head, neck, chest and abdomen and provides:

    • motor innervation of the muscles of the soft palate, pharynx and larynx, as well as of the striated muscles of the oesophagus;
    • parasympathetic innervation of the smooth muscle of the lungs, oesophagus, stomach and intestine, and of the heart muscle; it also influences the secretion of the gastric and pancreatic glands;
    • sensory innervation of the mucosa of the lower pharynx and larynx, of an area of skin behind the ear and part of the external auditory canal, of the eardrum and of the dura mater of the posterior cranial fossa.

In essence, the nerve connects the heart, neck, lungs and abdominal cavity with the brain. This signalling pathway is what vagus nerve stimulation makes use of:  the vagus nerve can be exposed very well in the neck, where the electrodes can be attached securely. The cable runs under the skin to a pulse generator implanted in the chest wall and works much like a cardiac pacemaker. The stimulator sends signals at regular intervals (for example every 5 minutes for 30 seconds) to the vagus nerve, which has numerous connections throughout the brain.

Worldwide, vagus nerve stimulators have been implanted in around 45,000 patients with epilepsy, most of them living in the USA. In Germany about 700 vagus nerve stimulators have been implanted, 200 of them in Bonn.
In roughly 40-50% of patients there is a stable, long-lasting reduction in seizure frequency (by at least half). Vagus nerve stimulation also markedly improves quality of life and emotional wellbeing in many patients. Complete freedom from seizures, however, is achieved in at most 10% of cases. On the whole, vagus nerve stimulation is well tolerated, apart from some hoarseness during the stimulation phase.

Treatment with vagus nerve stimulation is suitable only for patients with severe forms of drug-resistant epilepsy for whom surgery is not indicated or whose chances of a successful operation are not high enough.

8. multiple subpial transections. Multiple subpial transections are vertical incisions made around the focus of epileptic activity. They are used when the focus itself cannot be removed, for example when it lies in the speech centre or in the motor cortex. Under certain conditions they can be an alternative to resection. Cutting the nerve fibres vertically makes it impossible for the pathological impulses to spread horizontally. The vertical cortical connections are preserved and no pronounced neurological disorders occur. After the procedure there is a temporary neurological deficit that resolves within a few weeks. Multiple subpial transections are effective in up to 70% of cases.

9. hemispherectomy is used to treat epilepsy 20 times less often than temporal resection and is effective in 2/3 of cases;

10. focal resection consists in removing the source of the pathological impulses together with a thin layer of the adjacent cerebral cortex. As a rule, the source is a focal lesion of the cortex, an area of atrophy or dysplasia, a tumour, a cyst or a cavernous angioma. If the source of epileptic activity is the area around the pathological cortical region, an extended resection is required. Focal resection is used when the location of the focus has been clearly determined and it can be removed without significant damage to a functionally important cortical area.
After focal resection, 55-65% of patients with epilepsy experience a reduction in seizure frequency or become completely free of seizures.
Focal forms of epilepsy, which are amenable to classic block resection, occur in 1/20 of all patients with epilepsy and in 1/3 of patients with a drug-resistant form of the disease.

In major surgical procedures, what is indicated is not resection of tissue together with the blood vessels supplying it, but disconnection of nerve pathways: lobotomy, hemispherotomy or functional hemispherectomy, namely:

    • disconnection (damage to the long nerve fibres connecting different brain structures);     • callosotomy;     • multiple subpial transections (vertical incisions in the cerebral cortex without removal of tissue).

11. deep brain stimulation     

Since 2010 a new form of therapy has been available for epilepsy that is difficult to treat: deep brain stimulation (DBS).

DBS has long been used with great success in other neurological diseases (Parkinson's disease, essential tremor, dystonia).

Deep brain stimulation is particularly suitable when epilepsy is difficult to treat, that is, when various drugs have failed to reduce the number of seizures and epilepsy surgery is impossible or has not been successful.

Correctly diagnosing the epilepsy syndrome is the most important precondition for successful drug therapy. In many cases the first or second attempt, with one drug as monotherapy or two drugs in combination, is already successful. The dose must be chosen so that the drug protects effectively against seizures while side effects are kept to a minimum. It is side effects that are often the reason for stopping drug therapy.

Drug therapy is adjusted on an outpatient basis in almost all cases; only occasionally is inpatient treatment recommended. The dose must never be changed without consulting a doctor. In particular, stopping a drug abruptly, for example because of side effects, can be very dangerous.

In women of childbearing age, family planning inevitably raises a great many questions about their medication that need to be discussed with a specialist.

Below is a list of active substances and their brand names:
    Barbexaclone – Maliasin (Phenobarbital + Levopropylhexedrine) – used until the end of 2004
    Carbamazepine – carba, Carbagamma, Carbium, Carbamazepin, Finlepsin, Fokalepsin, Sirtal, Tegretal, Timonil
    Clobazam – Frisium
    Clonazepam – Antelepsin, Rivotril
    Diazepam – diazep, Diazepam, faustan, Lamra, Stesolid, Tranquase, Valiquid, Valium, Valocordin
    Ethosuximide – Petnidan, Pyknolepsinum, Suxilept, Suxinutin
    Felbamate – Taloxa
    Gabapentin – Neurontin
    Potassium bromide – dibro-Be
    Lamotrigine – Lamictal
    Levetiracetam – Keppra
    Mesuximide – Petinutin
    Oxcarbazepine – Trileptal
    Phenobarbital – Fali-Lepsin, Lepinal, Luminal, (Maliasin – used until the end of 2004)
    Phenytoin – Zentropil, Phenhydan, Epanutin, Phenytoin AWD
    Pregabalin – Lyrica
    Primidone – Liskantin, Mylepsinum, Resimatil
    Retigabine – Trobalt
    Sultiame – Ospolot
    Tiagabine – Gabitril
    Topiramate – Topamax
    Valproic acid/Valproate – Convulex, Convulsifin, Ergenyl, Leptilan, Myproin, Orfiril
    Vigabatrin – Sabril
    Zonisamide – Zonegran

There are a number of other alternative treatment strategies that some patients adopt. However, only the ketogenic diet, which is recommended above all for children with severe forms of epilepsy, has acquired a certain amount of evidence of efficacy. Other methods (acupuncture, homeopathy and so on) have no convincing evidence behind them.

Psychotherapy plays a significant part in treating epilepsy when it is accompanied by mental health conditions such as depression or anxiety disorders. Psychotherapy helps to improve the patient's quality of life.
In addition, seizure self-control and teaching patients how to behave when a seizure occurs can help to reduce seizure frequency, but they do not remove the need for  drug therapy.

The first epilepsy operation using MRI-guided laser ablation was successfully performed at Beta Klinik in Bonn.

Three years ago, approval was granted in Europe for the first time for interventional minimally invasive laser ablation surgery under MRI guidance using the Visualase™ system for the treatment of epilepsy. Since then, the minimally invasive MRI-guided VISUALASE™ laser ablation technology has been used successfully in the treatment of epilepsy. With VISUALASE™ technology, patients with drug-resistant epilepsy can undergo gentle surgical treatment. Beta Klinik, a private multidisciplinary hospital in Bonn, was one of the first clinics in Germany to treat patients with epilepsy successfully using minimally invasive VISUALASE™ laser ablation technology.

The operation was performed by the neurosurgeon Prof. Dr. med. Thomas Gasser together with the renowned Prof. Dr. med. Christian Elger, head of the specialist neurological Epilepsy Centre at Beta Klinik, and a team of neurosurgeons. This modern technology enabled the surgeons to reach the most inaccessible areas of the brain and to destroy the epileptic focus with maximum precision and minimal invasiveness.

The preoperative epilepsy work-up and the localisation of the epileptic focus by means of video-Doppler imaging and EEG were carried out by Christian Elger, head of the specialist neurological Epilepsy Centre at Beta Klinik.

The patient suffered from drug-resistant left temporal lobe epilepsy with complex partial seizures. Minimally invasive laser ablation surgery gave him a unique opportunity to be cured of his epilepsy.

Conventional surgery in the temporal lobes, and in the left temporal lobe in particular, carries a risk of impairing the patient's cognitive abilities and memory, because classic surgical techniques damage the structures that form memories. The high precision and minimal invasiveness of the VISUALASE™ laser procedure considerably reduce the risks for the patient.

How does the Visualase™ system work?

MRI-guided laser ablation consists of several consecutive stages. The first is the stereotactic procedure, or neuronavigation, which involves acquiring 3D images and determining the location of the pathological area of the brain. Unlike ordinary 2D images, a stereotactic study produces a three-dimensional image and therefore provides more complete information.

Once the stereotactic coordinates of the pathologically altered area of the brain have been determined, the neurosurgeons move on to the intervention itself. To gain access to the brain, the surgeon carefully makes a tiny opening in the skull (the opening is only 3.2 mm in diameter). During the operation a laser catheter (probe) 1.65 mm in diameter is introduced through the hole drilled in the skull under MRI guidance and advanced to the required area of the brain. The ultra-thin, flexible catheter preserves as much healthy brain tissue as possible.

When the catheter reaches the target area of the brain, the laser inside it starts to emit energy. The energy delivered through the laser diffusing fibre raises the temperature in the area of epileptic activity and thereby destroys the pathologically active soft tissue of the brain. The effect of the laser on the brain is tracked and controlled in real time by magnetic resonance imaging. The doctors adjust the intensity and duration of the laser exposure. Special thermographic images allow the temperature of the surrounding tissue to be assessed — this is essential for protecting vital areas of the brain.

Finally, when the active part of the procedure (thermal ablation) is complete, the surgeon carefully removes the catheter, closes the defect in the skull and sutures the skin. The patient then returns to their room and remains under medical observation for one to two days.

Advantages of the innovative technology of laser ablation with the Visualase™ system

1. The use of the world's smallest and most flexible neurosurgical catheter, only 1.65 mm in diameter, allows the surgeon to work in the most inaccessible areas of the brain.
2. An almost invisible 3.2 mm skin incision and a tiny opening in the skull. A single suture is usually enough to close the skin incision completely.
3. Using the Visualase™ system makes it possible to reduce or completely avoid shaving the head.
4. Treatment with the Visualase™ system involves no blood loss, and patients report neither dizziness nor headaches. The hospital stay lasts 1-2 days.
5. Excellent visualisation of the surgical field during the procedure allows doctors and patients to avoid the removal of large areas of the skull. MRI replaces direct visual contact and provides even more accurate, three-dimensional images.
6. Only the pathological areas of the brain are completely destroyed, while the neighbouring tissue remains viable, because thermal ablation is superbly controlled under MRI guidance.

What other diseases can be treated with MRI-guided laser ablation using the Visualase™ system?

The Visualase™ thermal ablation system is able to destroy soft tissue with extremely high precision. Because the ablation can be controlled, the method is ideal for removing or destroying even small pathological changes in the brain, for example:

1. brain tumours, including gliomas, glioblastoma multiforme and anaplastic astrocytomas, as well as radiation-resistant and inoperable tumours in hard-to-reach locations (a small tumour is not an obstacle, since prior stereotactic marking makes it clearly visible during the operation);
2. metastases of various tumours in the brain;
3. besides neurosurgery, MRI-guided laser ablation technology is used in other fields of medicine such as cardiovascular surgery, ENT surgery, head and neck surgery, gynaecology, urology and radiology. New areas of application are being developed and studied in clinical trials. The Visualase™ system may, for instance, be useful for removing areas of radiation necrosis that have formed after previous radiotherapy.

How safe is stereotactic laser ablation?

MRI-guided laser ablation with the Visualase™ system was first approved in July 2007 by the US Food and Drug Administration (FDA), an agency of the US Department of Health and Human Services and one of the most reliable and competent organisations in the world responsible for quality management in healthcare.

A clinical trial of Stereotactic Laser Ablation for Temporal lobe Epilepsy (SLATE) was then launched. The trial enrolled adult patients with temporal lobe epilepsy and was designed to assess the risks and benefits of using the Visualase™ system to improve their clinical condition. The results were impressive, and the method is now the preferred treatment option for patients with drug-resistant temporal lobe epilepsy.

In mid-2018 the Visualase™ laser system made by Medtronic underwent conformity assessment against the requirements of the EU directives and the harmonised standards of the European Union and received the CE mark from the European Union. This confirms that the treatment technology meets the highest European standards of treatment efficacy and safety.

Does the Visualase™ system have any contraindications?

MRI-guided laser ablation with the Visualase™ system is very well tolerated. Nevertheless, there are several limitations and even absolute contraindications to this intervention. The most important of them are listed below.

General contraindications to MRI: an absolute contraindication is the presence of metal implants in the body (for example coronary and peripheral artery stents, artificial heart valves, cochlear implants and devices for treating gastro-oesophageal reflux disease), pacemakers or defibrillators, tattoos and cosmetics containing metal particles, claustrophobia and so on.

Long-term use of certain drugs, such as Avastin (bevacizumab), which is used to treat glioblastoma, including recurrent forms of the disease, metastatic cervical cancer and colorectal cancer. The patient will have to stop taking the drug as soon as treatment with the Visualase™ system is scheduled.

Where can treatment with the Visualase™ system be obtained?

Until April 2018, procedures using the Visualase™ system were performed only in large hospitals in the USA. The total number of such procedures was limited to a few hundred a year, and only US citizens could receive this innovative treatment.

The situation changed dramatically when the Visualase™ system was certified in the European Union and leading European clinics were able to offer it to patients with epilepsy and brain tumours — and, importantly, are ready to treat international patients.

Beta Klinik hospital in Bonn is one of the few clinics in Europe to offer clinical use of the VISUALASE™ system for the treatment of epilepsy and malignant brain tumours.

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