the Management of Epilepsy in Egypt

Valproic acid (VPA): ia as a highly prevalent medication with multifaceted therapeutic applications in various neurological and psychiatric disorders. The therapeutic uses of VPA include epilepsy treatment across different seizure types, The mechanism of action for VPA involves the enhancement of inhibitory neurotransmission and the modulation of voltage-gated ion channels, If taken during pregnancy, sodium valproate can cause problems for a baby's development, including birth defects and lifelong learning difficulties. Sodium valproate is not recommended if there's a chance that you could become pregnant. [73].

Phenytoin: The FDA approved phenytoin in 1939 for the treatment of epilepsy) generalized tonic-clonic seizures, complex partial seizures, status epilepticus(

it is a hydantoin derivative, a first-generation anti-convulsant drug that is effective in the treatment of generalized tonic-clonic seizures, complex partial seizures, and status epilepticus without significantly impairing neurological function. 

Phenytoin works by blockade of voltage-dependent membrane sodium channels responsible for increasing the action potential. This action obstructs the positive feedback that sustains high-frequency repetitive firing, thus preventing the spread of the seizure focal point.

Hypersensitivity to phenytoin or other hydantoins is a contraindication for using phenytoin. Pregnancy is another absolute contraindication for phenytoin use. 

Hanson et al. reported a prevalence of fetal hydantoin syndrome (FHS) of 11% in pregnant women receiving treatment for epilepsy with phenytoin, with an additional 30% of the in utero-exposed children expressing some of the syndrome’s features such as epicanthic folds, hypertelorism, broad flat nasal bridges, an upturned nasal tip, wide prominent lips and, also, distal digital hypoplasia, intrauterine growth retardation, and diminished mental capacity. [74]

Carbamazapine: is FDA indicated for epilepsy, trigeminal neuralgia, and acute manic and mixed episodes in bipolar I disorder. Indications for epilepsy are specifically for partial seizures with complex symptomatology (psychomotor, temporal lobe), generalized tonic seizures (grand mal), and mixed seizure patterns. Carbamazepine is not indicated for absence seizures

It modulates voltage-gated sodium channels (VGSC), causing inhibition of action potentials and decreased synaptic transmission. Similar to other anti-convulsions, carbamazepine is suggested to bind to the alpha subunit of VGSC, specifically at a binding pocket formed by the external pore loop and the pore-lining part of domain IV. Researchers proposed that carbamazepine keeps sodium channels in inactivated states, leading to fewer channels to open and thus inhibits the generation of action potentials. Carbamazepine also binds to other voltage-gated ion channels, such as voltage-gated calcium channels

it is contraindicated in patients with bone marrow depression and hypersensitivity to this drug or tricyclic compounds such as amitriptyline. Before administration, monoamine oxidase inhibitors should be discontinued for a minimum of 14 days. Usage carbamazepine and nefazodone together may result in insufficient plasma concentration of nefazodone. Carbamazepine is contraindicated in use with nefazodone. [75]

Oxcarbazepine :is a 10-keto derivative of carbamazepine, which came to the market in 2000. However, the minor structural differences between oxcarbazepine and carbamazepine have led to significant differences in the induction of metabolic pathways and the metabolism of the two medications

Oxcarbazepine is a first-line choice for treating focal-onset epilepsy in several countries, including the USA. The oral suspension is a popular dosage form among clinicians, oxcarbazepine might be efficacious in decreasing seizure frequency for drug-resistant epilepsy when used as an add-on drug. Oxcarbazepine can cause ataxia, somnolence, and hyponatremia

Avoid abrupt withdrawal of oxcarbazepine. Prescribers should exercise caution in pediatric, elderly, pregnant, and renal impairment patients who have had a hypersensitivity reaction to carbamazepine. It is also contraindicated in treatment-naive patients with the HLA-B*1502 allele. [76]

Eslicarbazepine acetate: is a new anti-epileptic drug belonging to the dibenzazepine carboxamide family that is currently approved as adjunctive therapy and monotherapy for partial-onset (focal) seizures. The drug enhances slow inactivation of voltage-gated sodium channels and subsequently reduces the activity of rapidly firing neurons. Eslicarbazepine acetate has few, but some, drug–drug interactions. It is a weak enzyme inducer and it inhibits cytochrome P450 2C19, but it affects a smaller assortment of enzymes than carbamazepine. Clinical studies using eslicarbazepine acetate as adjunctive treatment or monotherapy have demonstrated its efficacy in patients with refractory or newly diagnosed focal seizures. The drug is generally well tolerated, and the most common side effects include dizziness, headache, and diplopia. One of the greatest strengths of eslicarbazepine acetate is its ability to be administered only once per day. Eslicarbazepine acetate has many advantages over older anti-epileptic drugs, and it should be strongly considered when treating patients with partial-onset epilepsy. [77]

Levetiracetam :is a novel antiepileptic drug used to treat partial, myoclonic, and tonic-clonic seizures. In 2000, the FDA approved the use of the oral formulation as adjunctive therapy for the treatment of focal seizures, myoclonic seizures, and primary generalized seizures. In addition, the FDA approved intravenous levetiracetam (LEV) in 2006 for use in patients older than 15 years as adjunctive anticonvulsant therapy when the oral formulation is not tolerated. In Europe, it is approved for treating partial seizures as a single agent and as an add-on treatment for partial seizures, tonic-clonic seizures, and myoclonic seizures.

It is chemically unrelated to other antiepileptic drugs. However, its favorable safety profile, distinct mechanism of action, and fewer drug interactions make it an attractive therapeutic choice for treating seizures.

Most common adverse effects are neurobehavioral, like sedation, fatigue, mood swings, headache, agitation, irritability, aggression, depression, memory loss, confusion, paresthesia, a decline in cognition, and increased suicide risk. Most of the time, the side effects are mild. [78].

Brivaracetam: is a third-generation antiepileptic racetam derivative and a 4-n-propyl analogue of levetiracetam. While the exact mechanism of action of brivaracetam is unknown, its anticonvulsant effects are believed to be due to its highly selective affinity for synaptic vesicle protein 2A (SV2A) in the brain. The SV2A glycoprotein is a protein-coding gene implicated in synaptic signal transduction. It is believed to play a role in the regulation of neurotransmission by stimulating vesicle fusion and maintaining a reserve of secretory vesicles. Studies in SV2A-deficient animals have demonstrated an increased propensity for seizures. Brivaracetam’s actions as an SV2A ligand lend it broad-spectrum activity against partial onset seizure.

Brivaracetam approved as adjunctive therapy for the treatment of POS in adults and adolescents 16 years of age and older. This medication has shown promise in patients with epilepsy whose seizures persist despite adequate treatment. Brivaracetam was well tolerated throughout all three phase 3 trials, which led to its FDA approval. The drug offers improved seizure control with minimal safety risks for patients with epilepsy. [79]

Topiramate: is approved as monotherapy for epilepsy for individuals aged 2 years and older with primary generalized onset tonic-clonic or partial-onset seizures. Additionally, it is sanctioned for adjunctive therapy in adults and pediatric populations from ages 2 to 16 years with primary generalized onset tonic-clonic seizures, partial-onset seizures, and for those aged 2 years or older with seizures associated with Lennox-Gastaut syndrome.

Topiramate blocks voltage-gated sodium channels, likely leading to sustained depolarization control during seizures. Topiramate reduces membrane depolarization via AMPA/Kainate receptors and enhances GABA-A receptor activity, strengthening inhibitory effects. Additionally, topiramate acts as a weak carbonic anhydrase inhibitor; acidosis in the brain partially protects against seizures by downregulating NMDA receptor activity.

The most common adverse effects in epilepsy trials included central nervous system involvement (paresthesia, fatigue, cognitive problems, dizziness, somnolence, psychomotor slowing, memory/concentration difficulties, nervousness, confusion), endocrine/metabolism issues (weight loss, anorexia), respiratory problems (infection), and miscellaneous effects (fever, flushing). In trials involving patients with migraine, the most common adverse effects are paresthesia and dysgeusia.

Severe adverse drug reactions include:

Acute myopia and secondary angle-closure glaucoma 

Oligohidrosis and hyperthermia (uncommon, reversible with cessation of the drug). [80]

Lamotrigine: is an anti-seizure/anti-epilepsy drug first approved for use in the USA in 1994. It is considered a first-line treatment for primary generalized tonic-clonic seizures (including simple and complex partial seizures and focal-onset tonic-clonic seizures) and Lennox-Gestault syndrome

The mechanism of action for lamotrigine is not entirely understood. It is a triazine, and research has shown that lamotrigine selectively binds and inhibits voltage-gated sodium channels, stabilizing p resynaptic neuronal membranes and inhibiting presynaptic glutamate and aspartate releas

Lamotrigine follows first-order kinetics with a half-life of 29 hours

Lamotrigine can cause serious rashes requiring hospitalization and discontinuation of this medication. Rash severity varies but includes a risk for Stevens-Johnson syndromeLamotrigine is present in breast milk and is detectable in the blood of breastfed infants. Symptoms of lamotrigine in infants include poor feeding, drowsiness, rash, and apnea. These symptoms can improve with the discontinuation of lamotrigine. If the benefits outweigh the risks in treating epilepsy during lactation/breastfeeding, clinicians should consider monitoring infant lamotrigine levels. [81]

Lacosamide: is an antiepileptic drug used to treat seizures. As a chiral functionalized amino acid, it works by blocking slowly inactivating components of voltage-gated sodium currents. Lacosamide exhibits a stereoselective mode of interaction with sodium channels
In the US and Europe, lacosamide is indicated for the treatment of partial-onset seizures in children and adults. In Canada, it is reserved for use in adults.

It is also used as an adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients four years of age and older.

The extended-release capsules of lacosamide are indicated for the treatment of partial-onset seizures in adults and in pediatric patients weighing at least 50 kg.

lacosamide selectively enhances the slow inactivation of voltage-gated sodium channels, shifting the slow inactivation curve to more hyperpolarized potentials and augmenting the maximal fraction of channels in the slow inactivated state. This results in the stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. Lacosamide does not affect the fast component of voltage-gated sodium currents, unlike traditional sodium channel blockers.The most common side effects are Double vision,Dizziness, Headache,Nausea ,Sleepiness and the most serious are Suicidal Thoughts and Actions,Heart Rhythm Changes and severe allergic reactions . [82]

Perampanil: was FDA approved in October 2012 as an adjunctive agent for the treatment of POS with or without secondary generalization in patients with epilepsy at least 12 years of age. In June 2015, the agency approved a second indication for primary generalized tonic-clonic (PGTC) seizures in patients with epilepsy who are at least 12 years of age.

is a novel non-competitive selective antagonist at the postsynaptic ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor.

the most common adverse effects seen in patients taking perampanel were dizziness, fatigue, headache, somnolence, irritability, vertigo, vomiting, weight gain, contusion, nausea,abdom inal pain, and anxiety

This medication is classified as pregnancy category C, indicating it may cause fetal harm. [83]

Rufinamide: is a tri-azole derivative drug structurally unrelated to any other anti-seizure drug (ASD).[1] It was developed first in 2004 and later was granted an orphan drug status in October 2004, and was first marketed in Europe in January 2007. It was approved by the US FDA on November 14, 2008, for the adjunctive treatment of seizures associated with Lennox Gastaut syndrome (LGS).

it stabilizes the inactive state of the sodium channel, limiting the sustained bursts of high-frequency action potentials and preventing sodium channels from returning to an activated state, therefore decreasing the neuronal hyperexcitability and action potential propagation. In this way, it modulates the activity of the sodium channel, prolonging its inactivity.

The major contraindication to the use of rufinamide is familial short QT syndrome. As discussed above, rufinamide was associated with significant ventricular arrhythmia, including cardiac death in patients with a history of short QT syndrome. [84]

Vigabatrin :was first formulated in 1974 for the treatment of seizures. Five years later, clinical trials on the drug started in Europe, followed by the US in 1980. This testing led to the approval of vigabatrin in the UK's market in 1989, which was then prescribed widely for infantile spasms and refractory complex partial seizures. However, despite the increased incidence of peripheral vision loss in patients on vigabatrin, officials raised concerns about its safety in 1997 despite its efficacy. Finally, in 2009, after a series of studies, the FDA approved vigabatrin for the treatment of infantile spasms as a single drug and refractory complex partial seizures as an additional drug to other anti-epileptic drugs. Given the potential risks of visual loss, the approval comes with a supplemental "Risk Evaluation and Mitigation Strategy”.

Vigabatrin: is an irreversible inhibitor of gamma-amino-butyric acid transaminase (GABA-T), an enzyme that degrades GABA. It is structurally the same as GABA with an extra vinyl group. Given this fact, it acts as a substrate for GABA-T, freeing GABA in the synaptic cleft. The concentration of GABA, a neuro-inhibitory transmitter, increases in the brain, terminating seizure activity. Besides inhibiting GABA-T, vigabatrin prevents neuronal uptake of GABA and stimulates its release into the synapse. Some studies show that vigabatrin enhances the action of the inhibitory neurotransmitter glutamine, which researchers believe adds to its anticonvulsant effect.

Significant side effects include visual disturbances ,Peripheral visual field defect (VFD) concentrically occurs in both eyes as early as 9 months and 11 months in adults and children, respectively, after treatment onset. On average, visual field defects are mostly detected 5 to 6 years after treatment with vigabatrin. Patients tend to turn their heads and move their eyes in a particular direction to compensate for the visual loss. In contrast to peripheral vision, central vision remains mostly unaffected. Because of potential toxicity, the FDA made it compulsory to conduct a baseline ophthalmologic examination before starting vigabatrin treatment in any patient. For patients older than 9 years of age, perimetry testing serves to detect any VFD. On the other hand, electroretinography should be done twice for younger patients to confirm VFD diagnosis,and  MRI changes including hyperintensities in the basal ganglia, thalami, and brainstem on diffusion-weighted and T2/FLAIR sequences. Such findings are insignificant and disappear on vigabatrin cessation. [85]