EMA Publish Guideline on Clinical Investigations of Epileptic Disorders.
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Epilepsy which is defined by the recurrence of spontaneous/unprovoked seizures – i.e. seizures not provoked by transient systemic, metabolic or toxic disorders – constitutes a vast ensemble of diverse clinical situations which differ by age of onset, type of seizures (only one or several type(s) in an individual patient), aetiological background, resulting handicap, prognosis and response to treatment.
More than 50 million adults and children suffer from epilepsy world-wide. The two highest peaks of incidence are in children and in the elderly population (above 65 years). Prevalence estimates of epilepsy in the total population vary from 4 to 8 per l000 subjects.
Clinical recurrent seizures are the primary marker of the condition. They are of several types as classified in the International Classification of Epileptic Seizures, mainly: generalised onset, focal onset, which may become secondarily generalised and unclassified seizures.1
In addition to the type of the seizures, electroencephalographic monitoring allows a definition of specific epilepsy syndromes which are listed in the International Classification of Epilepsies and Epilepsy syndromes. Many are age-dependent. Brain imaging may add to the aetiological diagnosis.
Focal onset seizures, related to a focal brain dysfunction, occur in approximately 60 % of cases and include symptomatic (lesion defined), cryptogenic (no lesion detected but probably symptomatic), and idiopathic forms. Generalised seizures represent approximately 30 % of cases. They occur often in a non-lesional and genetic context; other cases are symptomatic or cryptogenic. In the remaining 10%, the classification is uncertain.
The majority of paediatric epilepsies consist of age-dependent epilepsy syndromes whose manifestations are affected by ongoing brain maturation. That is the case for the most frequent paediatric idiopathic partial epilepsies (e.g. benign epilepsy with centrotemporal spikes) and for epilepsy syndromes (e.g. West syndrome/Infantile spasms, Dravet syndrome, Lennox-Gastaut-syndrome, myoclonic-astatic epilepsy and Continuous Slow Waves during Sleep). Another major difference in paediatric and adult epilepsies is that some syndromes carry a grave prognosis for cognitive outcome due to the impact of epilepsy, the so-called epileptic encephalopathies. Focal non-idiopathic epilepsies in childhood may also have an important impact on cognitive development if not treated early and appropriately. Some age-dependent epilepsy syndromes do not persist in adulthood (e.g. West syndrome or Benign epilepsy with centrotemporal spikes).
Antiepileptic drugs (AEDs) are the main treatment option. Approximately 60% of newly diagnosed patients are seizure-free on a single AED (monotherapy). An additional 10%-20% achieve freedom of seizure with polytherapy. It follows that about 30% of patients are not satisfactorily controlled. In addition many patients suffer from significant adverse effects.
New AEDs have been developed in the last two decades with the aim of improving the benefit/ risk balance of existing AED therapy. Traditionally newer AEDs have all been evaluated in add-on studies in patients refractory to previous therapies. Typically, in these studies 20 to 40 percent of patients with focal epilepsy obtain a 50% or greater reduction in the frequency of seizures, compared to 2 to 25% of patients given placebo. However, very few patients become seizure-free, which is the ultimate goal. Differences exist in efficacy and tolerability profile depending on seizuretype and epilepsy syndrome. A given compound may for instance improve one type of epilepsy/seizure type but worsen another one.
The AEDs may have different spectra of efficacy:
- In terms of seizure types, most AEDs are effective against focal seizures with or without secondary generalisation. Certain AEDs show a broader spectrum of efficacy, including focal and many generalised seizure types. For others, efficacy is limited to one or two seizure types, for instance absence seizures only.
- In terms of epilepsy syndromes, it is important to know on the one hand which (and how) seizure types associated with a given syndrome are affected by a specific medication. On the other hand, a given seizure type may not show the same responsiveness in the various syndromes, particularly in certain age-dependent conditions. Moreover, some AEDs may exacerbate some seizure types while being efficacious in coexisting seizure types.
The knowledge of a new drug’s spectrum of effectiveness is important when considering trials in newly diagnosed patients. For many patients the precise syndrome and seizure types may not have been defined at the time of treatment initiation, and therefore, they can only be included when the test drug exhibits a broad efficacy spectrum.
Of note for most anti-epileptic agents the knowledge of their spectrum of effectiveness is limited considering that most clinical studies were performed in patients with focal seizures with or without secondary generalisation. Other seizure types have rarely been investigated in randomised controlled trials. Moreover, inclusion of patients in trials has usually been based on seizure type and not on epilepsy syndrome although the latter has a prognostic value.
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