2. Precision medicine: novel treatment strategies developed from pathophysiological knowledge
Advances in the identification of the underlying causes of epilepsies led to a novel therapeutic approach which targets the underlying pathophysiology causing seizures and other comorbidities (EpiPM consortium 2015). Several conditions can now benefit from a more tailored treatment using novel compounds or drugs aiming to counteract or resolve the pathological mechanism and restore the disrupted brain function (Mei et al 2017; Perucca P, Perucca E 2020; Nabbout, Kuchenbuch 2020). We can distinguish three different categories of therapy which are used in these individual treatment strategies:
  1. Substitutive therapies
  2. Therapies that modify cell-signalling pathways
  3. Function-based therapies
Substitutive therapies
Substitutive therapies are currently used to treat disorders that are related to inherited metabolic diseases including epilepsies caused by glucose transporter type 1 deficiency (GLUT1) or by vitamin deficiencies. The GLUT1 deficiency syndrome is caused by haploinsufficiency of the SLC2A gene (solute carrier family 2, facilitated glucose transporter member 1) (De Vivo et al 1991; Klepper et al 2020). Low level of cerebral glucose, due to the impaired transport, are associated to a spectrum of symptoms from paroxysmal, often exercise induced, movement disorders to epilepsy often combined and with variable degree of intellectual disability (De Vivo et al 1991; Weber et al 2008; Suls et al 2009; Mullen et al 2010). For this hereditary neurometabolic disorder, early diagnosis and treatment with ketogenic diets (KD) is an important and individualizing treatment. The KD, a high-fat, low protein, and low-carbohydrate diet provides ketone bodies and also have a mechanism of action through GABA synthesis, resulting in a neuroprotective effect and protecting from epileptogenesis (Klepper et al 2020). Keton bodies transported through the blood-brain barrier and used as an alternative energetic substrate.
Although inborn errors of metabolism do not represent the most common cause of seizures, their early identification is of utmost importance, since for some the substitutive therapeutic measures beyond common anti-epileptic drugs, is essential either to control seizures, or to decrease the risk of neurodegeneration (van Karnebeek et al 2018)
Amongst the vitamin responsive epilepsies pyridoxine and pyridoxal phosphate (PLP) deficiencies caused by homozygous or compound heterozygous mutations of the ALDH7A1 (antiquitin) and PNPO genes are relatively frequent (Plecko B 2013, Wilson et al 2019). Administration of either pyridoxine and/or PLP determine seizures resolution and improvement of the overall general condition with a lifelong dependency on vitamin B6 supply (Coughlin et al 2021).
Cerebral folate deficiency is characterized by low levels of 5-methyltetrahydrofolate (the active metabolite of folate) in the nervous system but normal folate metabolism in the rest of the body. It may be associated mutations in the FOLR1 gene encoding the folate receptor α. The intracerebral deficiency leads to severe developmental delay, movement disorder, white matter changes, bilateral basal ganglia calcification, and drug-refractory epilepsy. Treatment includes initiation of folinic acid to correct 5- methyltetrahydrofolate CSF levels (Pope et al 2019).
Biotinidase enzyme deficiency is a rare, autosomal recessive neurometabolic disorder, classical clinical presentation includes recurrent seizures in the first few months of life. Testing for biotinidase enzyme activity in the peripheral blood is readily available and is part of neonatal screening at birth in developed countries. Genetic testing is confirmatory. Treatment is life-long biotin supplementation at 5–20 mg/d regardless of weight or age for both these disorders (Wolf 2012)
Early diagnosis is also important for the treatment of epilepsy caused by neurodegenerative diseases such as neuronal ceroid lipofuscinosis type 2 (CLN2). In 2017, enzyme replacement therapy with cerliponase alfa (recombinant human TPP1) has been approved for the treatment of CLN2 disease, a rare neurodegenerative paediatric disorder caused by autosomal recessive mutations in the TPP1  gene resulting in a deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) (Markham 2017). CLN2 is characterized by seizures between the age of 2 and 4 years, language delay, motor dysfunction and behavioural problems. Long-term outcome of patients with CLN2 has dramatically improved since the introduction of targeted therapy with recombinant human tripeptidyl peptidase (Schultz et al 2018, Specchio et al 2020). This treatment has been associated with a slowing or even stabilization of the deterioration in gait and language ability. Participants receiving this treatment have been followed-up for 3 years and this effect seems to be maintained over time (Schultz et al 2019).