08:11am Friday 28 July 2017

Epilepsy: innovative substances and interventions fly in the face of therapy resistance

Epilepsy: innovative substances and interventions fly in the face of therapy resistance

Numerous new medicines now deliver effective help for epilepsy patients. However, up to a third of patients do not respond to the available therapies sufficiently, if at all. A group of new substances including cannabinoids and neurosteroids were discussed at the Congress of the European Academy of Neurology in Amsterdam as a possible answer in the search for suitable treatments for severe, therapy-resistant forms of epilepsy. Less invasive neurosurgery techniques and the use of radiotherapies also provide new therapeutic options.

Amsterdam – Epilepsy is incorrectly labelled a rare disorder: around ten per cent of all people will experience an isolated, single epileptic fit in their lifetime. Another three to five per cent experience periods during which there are recurring seizures. And 0.6 to 0.8 per cent of the population suffer from acute epilepsy. But the real number may be much higher. The good news is that thanks to advances in modern medicine, a broad range of highly effective treatment options are now available. Over the past two decades, around 20 medicines have been introduced which have delivered significant improvements in quality of life for many sufferers. Today, more than two thirds of patients are seizure-free thanks to anticonvulsants, and in some cases individuals can come off medication altogether after a certain period of time.

Neurosurgery becoming less invasive

“Despite enormous advances, none of the new antiepileptic medicines have delivered a breakthrough,” Prof Christian E. Elger, Head of the Department of Epileptology at the University Hospital of Bonn told the Congress of the European Academy of Neurology in Amsterdam. “Although they are safer and have fewer side effects for those patients who do respond to them, none of these drugs have been able to impact the rate of pharmaceutical resistance.”

Epilepsy can only be cured using surgical interventions. Advances in diagnostic imaging and neurosurgical techniques mean that more and more patients are being operated on, with improved long-term outcomes. “Today we are able to remove the brain lesions that cause seizures and deliver freedom from this neurological condition for the 10 to 20 per cent of sufferers who do not respond to medication,” Prof Elger explained. “Unfortunately this option is still used far too rarely. The benefits of a procedure like this should be taken into consideration for patients who have not responded to therapy for five years. Or fewer, in the case of children.” For surgery to be an option, two conditions must be satisfied: firstly, the area that the seizure originates from cannot be in a sensitive part of the brain, and, secondly, there is still the matter of pinpointing these tiny lesions using magnet resonance imaging. “It is imperative that the diagnostic process is performed in a specialist centre,” Prof Elger advised. “In two-thirds of cases, we end up discovering a lesion in follow-up checks, even when the original MRI results are supposedly clear.”

The range of applications has also been expanded thanks to the use of stereotactic laser thermocoagulation, a process which involves using a high-frequency electrical current to deliver highly focused heat therapy. “This enables surgeons to destroy pathological tissue without damaging adjacent structures,” said Prof Elger. “Unlike standard procedures, this method does not require a large opening in the skull and avoids damage to the cortex, even with deep-lying lesions. This makes it possible to use the technique close to eloquent areas of the brain.”

One other way to avoid serious damage to sensitive parts of the brain is neuromodulation with low-dose, high-precision radiation, which is also used in a similar way to treat tumours. In a very small study involving just six patients and two different types of radiation therapy (hypofractionated stereotactic radiotherapy [hfSRT] and low-dose radiosurgery [SRS]), this completely side-effect-free therapeutic approach left two patients seizure-free and brought about a significant reduction in another. No lasting effects were observed in the remaining three. “There are currently very few studies on the use of stereotactic radiotherapy as an epilepsy treatment,” Prof Elger confirmed. “However, initial outcomes show its potential as a less invasive alternative in cases where conventional procedures could result in neurological damage. The only drawback is that the full effect may be observed after one year or later.”

Freedom from seizures is top-priority

“Many of the medications now available work in a new way and have delivered promising results even for patients with severe or rare forms of epilepsy,” Meir Bialer, David H. Eisenberg Professor for Pharmacy at the School of Pharmacy, Faculty of Medicine at the Hebrew University in Jerusalem, Israel, comments at the occasion of the EAN Congress. “However, the medicines that have been approved over the course of the past one or two years still have to prove themselves in everyday clinical practice, where conditions often vary hugely from those in closely controlled clinical trials,” the expert says.

“It goes without saying that reducing the frequency of seizures represents a huge step forward,” Prof Bialer says. “But even if someone has just one seizure a year, they are still not allowed to drive and have to live with various other personal and social limitations.” What is more, sufferers of drug-resistant forms of epilepsy also experience other significant medical issues. Injuries, accidents and co-morbidities such as depression, anxiety and suicidal tendencies all contribute to a death rate among epileptics that is three times higher than that of the general population.

On top of this come significant side effects – particularly in serious cases where doses of long-term medication are high – ranging from changes to the blood count to liver damage and psychiatric disorders. In children, the condition has a negative impact on their general development. “In light of this situation, our stated aim and overarching priority must be to develop medication that guarantees complete freedom from seizures for all patients,” Prof Bialer adds. “It is also important for the medications to have minimal side effects and interactions. After all, the majority of epilepsy patients have to take medication for their entire lives.”

Cannabinoids a source of hope

Preclinical trials and phase I-III clinical trials of almost 20 substances designed to treat patients with therapy-refractory forms of epilepsy are currently in progress. Research into neurosteroids, e.g. allopregnanolone, and cannabidiol, a non-psychotropic component of cannabis, is particularly well advanced. The latter, a non-psychotropic cannabis constituent, has delivered promising results in some trials, particularly those involving children with drug-resistant and rare forms of epilepsy such as Dravet syndrome or Lennox-Gastaut syndrome. In one case study, the number of seizures dropped by around a half, with nine per cent of patients completely seizure-free. “These substances are not intended for broader use with all forms of epilepsy,” Prof Bialer explains, “However, they do appear to be a possible therapeutic option for serious cases involving children and young people up to the age of about 20.” Experts expect cannabidiol to be approved by the US Food and Drug Administration (FDA) as a treatment for these indications before the end of 2017. Approval from the European Medicines Agency (EMA) could follow soon.

Source: Bialer et al. Progress report on new antiepileptic drugs: A summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII). Epilepsia 2017, 58(2); Bialer et al. Seizure defection and neuromodulation: A summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII). Epilepsy Res 2017, 130:27-36; Hoppe et al, Stereotactic laser thermocoagulation in epilepsy surgery. Nervenarzt 2017, 88(4); Boström et al. Low-dose radiosurgery or hypofractionated stereotactic radiotherapy as treatment option in refractory epilepsy due to epileptogenic lesions in eloquent areas. Preliminary report of feasibility and safety. Seizure 2016, 36

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