Anti-epileptic drugs

The typical program for VNS involves:

1. 30 seconds of stimulation
2. 5 minutes with no stimulation.

Progesterone can be used for the treatment of catamenial epilepsy, which is related to menstrual cycles.

Phenobarbitone is widely used in undeveloped countries due to its low cost and effectiveness as a treatment option for epilepsy.

A slow withdrawal over several weeks or months is recommended to prevent withdrawal seizures and physical dependence.

Tiagabine inhibits the GABA-transporter-1 (GAT-1), leading to an increase in the concentration of GABA in the synapse. This inhibition is reversible.

Tiagabine is used as a second-line add-on therapy in patients with epilepsy.

Tiagabine is metabolized in the liver by the P450 system.

Common adverse effects include dizziness, asthenia, nervousness, tremor, depressed mood, and emotional liability.

Vigabatrin inhibits GABA transaminase (GABA-T), which leads to an increase in extracellular concentration of GABA by preventing its breakdown. This inhibition results in higher levels of GABA available in the synaptic cleft, enhancing its inhibitory effects in the central nervous system.

The adverse effects of Vigabatrin include:

• Drowsiness
• Depression
• Confusion
• Fatigue
• Dizziness
• Headache
• Double vision

Vigabatrin does not induce the activity of hepatic enzymes, which is significant for patients who may be on other medications that are metabolized by the liver.

Valproate enhances GABA activity by:

1. Inhibiting GABA-T (GABA transaminase), which prevents the breakdown of GABA, leading to an increase in GABA levels.
2. Facilitating the conversion of more glutamate into GABA by enhancing the activity of GAD (Glutamic acid decarboxylase).

During the Follicular Phase (days 1-14), estrogen levels gradually increase. In the Ovulatory Phase (days 14-16), estrogen reaches its peak. During the Luteal Phase (days 16-28), estrogen levels decline while progesterone levels increase after remaining low in the previous phases.

Epilepsy can cause various health problems, including:

• Fatigue
• Memory issues
• Sleep problems
• Mental health issues
• Potential for muscle or bone fractures

Epilepsy can significantly impact daily life, affecting:

• Work
• Driving
• Overall quality of life due to unpredictable seizures and associated health problems.

Epilepsy is the tendency to have recurrent seizures, which are functional disorders of the brain characterized by altered consciousness, movement, and actions for a brief period of time.

Seizures are caused by abnormal excessive electric discharges in the brain, leading to a sudden burst of excess electrical activity that disrupts normal message passing between brain cells.

The seizure threshold is a concept that balances inhibitory and excitatory neuronal stimuli with an individual's predisposition to seizures. A higher threshold means a lower likelihood of having a seizure.

Activities that can lower the seizure threshold include:

• Drinking alcohol
• Sleep deprivation
• Stress
• Illness
• Flickering lights and hormones (especially in women)

A high seizure threshold indicates that an individual is less likely to experience a seizure.

Seizures are broadly categorized into Partial Seizures and Generalized Seizures.

Partial Seizures are further classified into:

1. Simple Partial Seizures
2. Complex Partial Seizures

Generalized Seizures are classified into:

1. Absence Seizures
2. Myoclonic Seizures
3. Tonic Clonic Seizures
4. Tonic Seizures
5. Atonic Seizures

Partial seizures affect only one part of the brain, with a burst of electrical activity usually limited to one side. They typically originate in the temporal or frontal lobe of the brain.

The two types of partial seizures are:

1. Simple partial seizures
2. Complex partial seizures

Simple partial seizures are characterized by:

• The person remains conscious during the seizure.
• Symptoms can include sudden, involuntary jerking of a part of the body, such as an arm or leg.
• Duration typically lasts from a few seconds to minutes.

Symptoms of simple partial seizures can include:

• Unconsciousness: The person is either not aware of their actions or has a distorted memory of them.
• Behavior: They may appear dazed or confused, engaging in random activities such as walking, mumbling, lip-smacking, blinking, swallowing, or repeated movements.
• Duration: These seizures typically last a few seconds to minutes, but can extend up to 20 minutes or more.
• Commonality: This is the most common form of partial seizures found in epilepsy.

Vagus nerve stimulation (VNS) is a therapy for drug-resistant epilepsy that involves implanting a stimulator under the skin on the left side of the chest. This device regularly stimulates the vagus nerve in the neck, sending impulses to the brain to help prevent excess electrical activity that causes seizures. While it does not cure epilepsy, it can reduce the frequency and severity of seizures.

1. Congenital defects: Born with brain defects.
2. Brain damage: Caused by birth trauma, lack of oxygen, or infection.
3. Vascular issues: Strokes due to blockage of blood vessels leading to insufficient oxygen.
4. Scarred brain tissue: Resulting from severe head injuries or trauma.
5. Tumors: Both benign and malignant tumors can cause epilepsy.
6. Substance abuse: Alcohol and drug abuse can lower seizure thresholds.
7. Infectious diseases: Such as meningitis, encephalitis, malaria, and tuberculosis that can affect the brain.
8. Neurocysticercosis: Caused by consuming food infected with tapeworm eggs.
9. Unknown causes: Idiopathic epilepsy where the cause is not identified.

Mutations in several genes have been linked to some types of epilepsy, particularly those that code for protein subunits of ion channels, such as sodium channels. These mutations can lead to hyper-excitable neurons by causing defective sodium channels to remain open for too long, which brings the neuron closer to the action potential threshold. Additionally, mutations can affect the production of inhibitory neurotransmitters like GABA, leading to ineffective inhibitory action in the brain.

The generation of an action potential relies on the influx and outflux of various ions, as well as the processes of membrane polarization and depolarization. Specifically, voltage-gated calcium channels open to allow Ca++ ions to enter the presynaptic cell, triggering neurotransmitter release, which can then lead to action potentials in the postsynaptic cell.

Reflex epilepsy is a type of epilepsy that requires a specific trigger to provoke seizures. For example, flashing lights can trigger seizures in individuals who already have epilepsy, but not everyone exposed to flashing lights will experience seizures.

Common triggers for seizures include:

1. Fatigue & chronic loss of sleep
2. Over-excitement
3. High stress
4. Heavy usage of alcohol
5. Drugs and other toxic substances
6. Loud noises
7. Flashing lights
8. Illnesses with a high fever
9. Diarrhea & vomiting
10. Playing Mahjong
11. Reading
12. Menstrual cycle in women (Catamenial epilepsy)

About 1 in 20 individuals with epilepsy are sensitive to flickering light, which is referred to as photosensitive epilepsy.

The contrast or change in light can act as a trigger for seizures in individuals with epilepsy, particularly those who are sensitive to visual stimuli.

Approximately 70% of individuals with epilepsy can manage to live normal lives with proper treatment.

The main treatment options for epilepsy include:

1. Surgery - Not curative, but can help manage symptoms.
2. Stimulation therapy - Such as vagus nerve stimulation, which sends signals to suppress electrical activity in the brain.
3. Psychological counseling - To support mental health.
4. Medications - To control seizures.

Vagus nerve stimulation is a form of stimulation therapy that sends signals to the vagus nerve to suppress electrical activity in the brain. It is not curative but can help manage seizures.

The primary goal of neurosurgery in epilepsy treatment is to alleviate the severity or frequency of seizures by removing the seizure focus or decreasing the ability of seizures to spread.

Surgical treatment for epilepsy is only performed on individuals who are resistant to medications.

Surgical treatment for epilepsy is very risky and can potentially cause brain damage.

A functional hemispherectomy involves extensive cortical resection in the temporal and central cortex with disconnection of the residual frontal and occipital cortex by transecting white matter fibers.

Types of surgical procedures for epilepsy treatment include:

A neurologist can adjust the following parameters of the VNS device:

• Stimulation amplitude: 1.0 to 3.0 mA
• Stimulation frequency: 30 Hz
• Pulse width: approximately 500 microseconds

Patients can activate their VNS implant using a special magnet when they experience seizure triggers.

The potential benefits of vagus nerve stimulation include:

• Improved seizure control
• Elimination of pain
• Reduction of tiredness due to muscle twitching

The goals of psychological counseling for epileptic patients include:

1. Improving quality of life by controlling the frequency of convulsions.
2. Recognizing triggers that may lead to seizures, such as specific objects or situations.
3. Managing mental health issues like stress, anxiety, and low self-esteem through therapy.

The ketogenic diet is a high fat, low carbohydrate diet used since the 1920s, particularly where medication has been ineffective. It can lead to a 50% reduction in the number of seizures in children. The diet works by reducing the amount of glutamate (an excitatory neurotransmitter) in the brain and enhancing the synthesis of GABA (an inhibitory neurotransmitter).

Complementary treatments such as relaxation, yoga, aromatherapy, and acupuncture have not been conclusively shown to work alone. They are not alternatives to conventional treatments but may be employed as adjunct therapies to help control seizures.

Anti-epileptic drugs (AEDs) stabilize the electrical activity in the brain to prevent the development of 'electrical storms' and help maintain seizure control.

It is important to maintain a relatively stable constant amount of drugs in the bloodstream throughout the day and night to effectively control epilepsy.

Approximately 30% of people with epilepsy do not achieve seizure control even with the best available medications, and some cannot be treated by medications at all.

Medication for epilepsy is often lifelong, meaning individuals may need to continue taking AEDs for an extended period to manage their condition.

If medications are ineffective, alternatives such as surgery or Vagus Nerve Stimulation (VNS) may be considered for treatment.

There are 155 registered pharmaceutical products in Hong Kong that are classified as anti-epileptic drugs (AEDs) and approved by the Department of Health.

Neurotransmitters are chemicals released from synaptic vesicles into the synaptic cleft, facilitating communication between neurons by binding to receptors on the postsynaptic neuron, leading to excitatory or inhibitory effects.

Excitatory synapses increase the likelihood of the postsynaptic neuron firing an action potential, while inhibitory synapses decrease this likelihood, thus regulating neuronal activity and maintaining balance in the nervous system.

The myelin sheath insulates axons, allowing for faster transmission of electrical signals (action potentials) along the neuron, which enhances the efficiency of synaptic transmission and overall neuronal communication.

The key structures involved in the development of seizures include:

• Neurons
• Ion channels
• Receptors
• Glia
• Inhibitory synapses (GABA)
• Excitatory synapses (glutamate)

EPSPs are associated with:

• Na+ influx
• Ca++ currents
• Paroxysmal depolarization

IPSPs are linked to:

• K+ efflux
• Cl- influx

The balance between EPSPs and IPSPs determines the likelihood of seizure activity versus control.

The primary goal of antiepileptic drugs (AEDs) is to favor inhibition over excitation in neuronal activity, thereby preventing seizure activity.

The main phases of an action potential are:

1. Resting State: The neuron is at -70 mV, with potassium (K+) moving out and sodium (Na+) and calcium (Ca++) moving in.

2. Threshold: The membrane potential reaches -55 mV, triggering the action potential.

3. Depolarization: The voltage rapidly increases to +40 mV as sodium (Na+) and calcium (Ca++) move in, while potassium (K+) moves out.

4. Repolarization: The voltage decreases past -70 mV as potassium (K+) moves back in and sodium (Na+) moves out.

5. Refractory Period: The neuron temporarily cannot fire another action potential before returning to the resting state.

The threshold is significant because it is the critical level of depolarization (-55 mV) that must be reached for an action potential to be initiated. If the membrane potential does not reach this threshold, the neuron will not fire, preventing the transmission of signals.

The action potential graph illustrates the following changes in voltage over time:

• Starts at -70 mV (Resting State).
• Rises sharply to -55 mV (Threshold).
• Peaks at +40 mV (Depolarization).
• Falls below -70 mV during Repolarization and enters the Refractory Period before returning to the resting state.

1. Sodium channel blockers: Phenytoin, Carbamazepine, Lamotrigine
2. Calcium current inhibitors: Ethosuximide
3. GABA enhancers: Includes GABA_A Agonists (Clobazam, Clonazepam, Phenobarbitone), Uptake Inhibitor (Tiagabine), GABA-transaminase inhibitor (Vigabatrin), and GAD modulation (Gabapentin, Valproate)
4. Glutamate blockers: Topiramate
5. Hormones: Progesterone
6. Synaptic vesicle protein 2A binding agents: Levetiracetam
7. Potassium channel openers: Retigabine

Sodium channel blockers work by blocking sodium channels and preventing the influx of sodium ions, which helps achieve the resting state of the neuron and prevents the generation of action potentials.

Sodium channel blockers enhance the inactivation of sodium channels, making it difficult for the axon to propagate action potentials. By stabilizing sodium channels in the inactive state, these drugs prevent repetitive firing of the axons.

Sodium channel blockers are important in epilepsy treatment as they prevent excessive neuronal firing by stabilizing sodium channels in the inactive state, thus reducing the likelihood of seizures.

Carbamazepine works by blocking sodium channels during rapid, repetitive, sustained neuronal firing, stabilizing them in their inactive state.

Common adverse effects include dizziness, diplopia (double vision), nausea, ataxia, and blurred vision.

Carbamazepine is a first-line antiepileptic drug and is the most widely used AED in the world, having been used for epilepsy since 1968.

Carbamazepine induces hepatic cytochrome P450 activity, which increases its own clearance as well as that of other AEDs, potentially weakening their effects.

Phenytoin works by:

1. Preventing sodium influx through sodium channels.
2. Inhibiting calcium influx through channels, which inhibits voltage-dependent neurotransmission at the synapse.

Using Phenytoin during pregnancy can result in:

• Cleft palate
• Cleft lip
• Congenital heart disease
• Slowed growth rate
• Mental deficiency.

Phenytoin has a highly protein-bound nature (>90%) and utilizes P450 enzymes for metabolism, which can lead to significant drug interactions.

Phenytoin is available in capsules, chewable tablets, suspension, and injection forms.

Ethosuximide reduces the amount of neurotransmitter release, which can lead to mood swings and depression-like symptoms.

Phenytoin is a strong inducer of hepatic enzymes and alters the levels of other drugs. It lowers the blood levels of various antiepileptic drugs (AEDs) and other medications, necessitating dosage adjustments for the initial AED when combined with phenytoin.

1. Block voltage-dependent sodium-channel conductance.
2. Inhibit depolarization of the glutaminergic presynaptic membrane, thus inhibiting glutamate release.

Lamotrigine is considered a preferred choice for pregnant women due to its low incidence of congenital malformations.

Lamotrigine is metabolized by the liver and excreted through the kidneys.

At low doses, Lamotrigine does not induce or inhibit hepatic enzymes.

Calcium channels act as pacemakers of normal rhythmic brain activity.

Both Ethosuximide and Valproate block T-type calcium channels, preventing calcium ions from passing through and reducing calcium influx.

The influx of calcium currents produces a partial depolarization of the membrane, facilitating the development of an action potential.

Calcium ions are essential for the release of neurotransmitters from vesicles, as they facilitate the process necessary for neurotransmitter release into the synaptic cleft.

Ethosuximide blocks T-type calcium channels, inhibiting the depolarization necessary to generate an action potential, which prevents neurotransmitter release and excitatory postsynaptic potentials (EPSPs).

Ethosuximide acts as a calcium channel blocker, which blocks depolarization and action potentials, leading to reduced neurotransmitter release.

GABA is a major inhibitory neurotransmitter in the brain. It helps to balance excitatory and inhibitory activity. A seizure reflects an imbalance where excitatory activity exceeds inhibitory activity. Enhancing GABA can strengthen inhibitory signals, potentially preventing seizures.

When GABA binds to a GABAA receptor, it causes an influx of chloride ions (Cl-) into the cell. This influx increases the negativity of the cell, making it more difficult for the cell to reach the action potential, thereby inhibiting neuronal firing.

Enhanced GABA activity leads to an influx of chloride ions, which increases the negativity of the neuron. This results in greater difficulty for the neuron to reach the action potential, thus reducing excitability and the likelihood of seizures.

GABAᴀ agonists, such as Clobazam and Clonazepam, act on GABA receptors to increase the availability of GABA in the synaptic cleft, leading to enhanced inhibitory neurotransmission.

GABA reuptake inhibitors, like Tiagabine, inhibit the GABA transporter-1 (GAT-1), preventing the reuptake of GABA into the presynaptic neuron, thus increasing GABA levels in the synaptic cleft.

GABA-transaminase inhibitors, such as Vigabatrin, inhibit the breakdown of GABA, leading to increased GABA concentrations in the synaptic cleft and enhanced inhibitory signaling.

Modulation of Glutamic acid decarboxylase (GAD), as seen with Valproate, enhances GABA synthesis, thereby increasing GABA concentration and promoting inhibitory neurotransmission.

1. GABAA receptor agonist to enhance chloride influx.

2. Blocks voltage-sensitive calcium channels and sodium channels, making it difficult for neurons to fire action potentials.

• Sedation
• Dizziness
• Ataxia
• Blurred vision
• Diplopia
• Depression
• Weakness

The development of tolerance is a major clinical problem with Clobazam.

Clobazam is metabolized by the liver and has a long half-life of approximately 50 hours.

Clonazepam acts as a GABA_A receptor agonist, enhancing chloride influx and blocking sodium-channel conductance.

The potential adverse effects of Clonazepam include:

• Sedation
• Ataxia
• Hyperactivity
• Restlessness
• Depression
• Cardiovascular or respiratory depression
• Hypersalivation

Drug withdrawal from Clonazepam may induce seizures, so it is important to implement a slow withdrawal process.

• Hair loss
• Curling of hair
• Hepatotoxicity
• Increased appetite
  Valproate should be used with caution in women of reproductive age.

Pregabalin binds to the α₂-δ protein of voltage-gated Ca²⁺ channels in the CNS, which reduces the release of several excitatory neurotransmitters such as glutamate and norepinephrine.

Common adverse effects of Pregabalin include:

• Drowsiness
• Dry mouth
• Edema
• Blurred vision
• Weight gain

Pregabalin has been approved for use since 2004 as an add-on therapy for partial seizures in patients older than 18 years.

• Oral administration
• Does not induce hepatic enzymes
• Little drug interactions
• Useful in renal or hepatic disease and in patients with complex drug regimens, especially those with renal issues and epilepsy.

Glutamate is the main excitatory amino acid neurotransmitter that binds to various receptors, leading to neuronal excitation.

When glutamate binds to its receptor, it causes:

1. Influx of sodium
2. Influx of calcium
3. Outflux of potassium

Net result = excitation.

The main glutamate receptor subtypes are:

1. Metabotropic site (GluR 1-7) receptor
2. Kainate site
3. AMPA (Alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid) receptor
4. NMDA (N-methyl-D-aspartate) receptor

1. Inhibits the AMPA and kainate subtype glutamate receptors.

2. Inhibits sodium conductance, decreasing the duration, bursts, and frequency of action potentials.

3. Enhances GABA by unknown mechanisms.

Common adverse effects include:

• Ataxia
• Impairment of concentration
• Confusion
• Dizziness
• Fatigue
• Anorexia
• Depression
• Slowness of speech

Additionally, it may cause weight loss in many patients due to appetite suppression, which can be beneficial for obese patients with epilepsy.

Topiramate was initially developed as an anti-diabetic drug before being used for epilepsy and diabetes mellitus (DM).

Hormones have a direct effect on the cells of the brain, which may contribute to the development of seizures as individuals enter puberty. This is observed in both men and women, as the increase in sex hormones correlates with the onset of seizures.

Progesterone is an inhibitory hormone that increases chloride conductance at GABAA receptors, decreases the glutamate excitatory response, and increases glutamic acid decarboxylase (GAD) mRNA.

Estrogen is an excitatory hormone that reduces chloride conductance and acts as an agonist at glutamate receptors (NMDA).

Levetiracetam binds to synaptic vesicle protein 2A (SV2A), inhibits presynaptic calcium channels, and reduces the release of excitatory neurotransmitters.

Common adverse effects of Levetiracetam include asthenia, dizziness, and upper respiratory tract infection.

Retigabine is a potassium channel opener that allows K+ efflux (potassium ions leaving the cell). By prolonging the opening of potassium channels, it stabilizes the membrane potential and acts as 'brakes' to limit neuronal excitability.

Retigabine is used as an add-on therapy for partial epilepsy that is uncontrolled by current medications.

By opening potassium channels and allowing K+ to flow out, Retigabine stabilizes the membrane potential, which serves to limit neuronal excitability.