WHAT CAUSES EPILEPSY?

Epilepsy is generally referred to in the plural because there is such a wide variety not only of seizure types, but also of causes. There are many causes of epileptic seizures. The main ones are structural epilepsies and idiopathic epilepsies.
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STRUCTURAL EPILEPSIES

These epilepsies result from a diffuse or local cerebral lesion leading to generalised or focal seizures. The lesion is most often visible on a cerebral MRI scan (this can be called a symptomatic lesion). Sometimes it is not visible (known as a cryptogenic lesion). There are a wide variety of lesions:

  • Hippocampal sclerosis is a scar found in the hippocampus, a structure involved in memory, which often results from repeated epileptic seizures, in a context of fever in children.
  • A brain tumour affecting the cerebral cortex
  • The after-effects of a cerebrovascular accident affecting the cerebral cortex
  • A malformation of the cerebral cortex due to a defect in the migration of neurons during development, the most common being focal cortical dysplasia.
  • The after-effects of a cranial trauma, often serious
  • After-effects of infection, such as herpes encephalitis or parasitic infection

AUTOIMMUNE EPILEPSY

Many autoimmune encephalitides are accompanied by epileptic seizures. These can be diseases which lead to :

  • the aberrant production of antibodies, which target brain proteins and thus disrupt the functioning of neurons.
  • infiltration of the brain by inflammatory cells, such as lymphocytes, which attack the neurons.

Early identification of these diseases enables immunosuppressive drugs to be administered, which is the only way of reducing epileptic seizures.

The Epilepsy Unit headed by Professor Vincent Navarro at the Salpêtrière Hospital, a reference centre for rare epilepsies, has extensive expertise in the management of these epilepsies, which require rapid assessment and sophisticated tests.

Research work has recently been carried out by Professor Vincent Navarro’s ‘Dynamics of epileptic networks and neuronal excitability’ research team at the ICM: the mechanisms of seizures observed during autoimmune encephalitis linked to an LGI1 antibody have been elucidated: the brief muscular jerks of the arm and face characteristic of this disease have been shown to be linked to hyperexcitability of the neurons, due to a lack of potassium (Baudin et al, Prog Neurobiol 2022).

 

GENETIC EPILEPSIES

There are several forms of genetic epilepsy:

  • idiopathic epilepsies, presumed to have a genetic cause, as often another member of the family has epilepsy, but for which a mutation in a gene has not been identified. Idiopathic epilepsies are defined by the absence of a cerebral lesion detectable on MRI, as well as by a characteristic age of onset, a good response to anti-epileptic treatments and, more often than not, remission after several years. The electroencephalogram shows typical abnormalities. These may be focal or generalised.
  • Familial epilepsy due to mutations identified in genes.

Depending on the mutated gene, brain abnormalities may be identified, such as Bourneville Tuberous Sclerosis. When the mutated genes code for ion channels (proteins forming tunnels that allow ions such as sodium and potassium to pass into the neuron), no abnormality is detectable on MRI. Mutations in neurotransmitter receptors have also been identified.

 

SITUATIONAL” EPILEPTIC SEIZURES

Sometimes a seizure occurs in a particular context, when there is no underlying brain lesion and no long-term predisposition to recurrent seizures. In such cases, long-term correction of the disorder is sufficient, and it is not necessary to introduce long-term anti-epileptic treatment.

  • Excessive and unusual alcohol consumption, withdrawal or chronic alcoholism.
  • Taking cocaine or amphetamines
  • Taking pro-convulsant drugs
  • Hypoglycaemia (lack of sugar)
  • Hypocalcaemia (lack of calcium)
  • Hyponatremia (lack of sodium)

 

At the Paris Brain Institute

The “Genetics and Pathophysiology of Epilepsy” team, led by Stéphanie BAULAC and Eric LEGUERN, is interested in the genetic causes of focal epilepsy and cortical developmental malformations.

In 2013, the team identified the DEPDC5 gene at the origin of hereditary focal epilepsy and cortical brain malformations (Ishida et al 2013, Baulac et al 2015). The team is one of the pioneers in identifying so-called somatic mutations, present only in a few brain cells in cortical focal dysplasias. These somatic mutations appeared de novo during brain development (Baldassari et al Acta Neuro 2019, Ribierre JCI 2018).

More recently, Stéphanie Baulac’s team has provided proof of concept that it is possible to detect somatic mutations causing focal epilepsy in association with cortical malformation, present in a few brain cells, using DNA circulating in cerebrospinal fluid (Kim et al. DOI: 10.1002/ana.26080) or from tissue adhering to SEEG electrodes used in the pre-surgical exploration of patients (manuscript in preparation). These discoveries open up new avenues for the genetic diagnosis of these pathologies.