Résumé de section

  • Comprehensive Lecture on Antiepileptic Drugs 

    1. Introduction to Epilepsy

    Epilepsy is a chronic neurological disorder characterized by recurrent, unprovoked seizures resulting from abnormal electrical activity in the brain. It affects approximately 50 million people worldwide (WHO).


    Etiologyز

    - Genetic factors: Ion channel mutations (e.g., SCN1A, KCNQ2)

    - Acquired causes:

      - Traumatic brain injury (TBI)

      - Stroke

      - Brain tumors

      - CNS infections (e.g., neurocysticercosis)

      - Developmental disorders (e.g., cortical dysplasia)


    Pathophysiology

    - Neuronal hyperexcitability: Imbalance between glutamate (excitatory) and GABA (inhibitory)

    - Ion channel dysfunction: Sodium, potassium, calcium channels

    - Synaptic reorganization: Mossy fiber sprouting in temporal lobe epilepsy

    2. Classification of Seizures (ILAE 2017)

    A. Focal Onset Seizures

    1. Focal aware (previously "simple partial")

    2. Focal impaired awareness (previously "complex partial")

    3. Focal to bilateral tonic-clonic

    B. Generalized Onset Seizures

    1. Absence (typical/atypical)

    2. Myoclonic

    3. Tonic-clonic

    4. Atonic ("drop attacks")

    C. Unknown Onset


    3. Mechanisms of Action of AEDs

    | Mechanism                    | Drug Examples            | Target Seizures       |

    |-----------------------------|---------------------------|--------------------------|

    | Sodium channel blockade     | Carbamazepine, Phenytoin  | Focal, tonic-clonic      |

    | GABA enhancement            | Benzodiazepines, Vigabatrin | Myoclonic, absence      |

    | Calcium channel (T-type) inhibition | Ethosuximide           | Absence                 |

    | Glutamate inhibition        | Topiramate, Perampanel    | Refractory seizures     |

    | SV2A modulation             | Levetiracetam             | Broad-spectrum          |


    4. First-Generation AEDs

    A. Phenytoin (Dilantin®)

    - MOA: Use-dependent Na+ channel blockade

    - Kinetics: Nonlinear metabolism (zero-order at high doses)

    - Adverse effects:

      - Gingival hyperplasia

      - Hirsutism

      - Cerebellar atrophy (chronic use)

    B. Valproate (Depakote®)

    - MOA: Multiple (GABA↑, Na+↓, Ca2+↓)

    - Therapeutic range: 50-100 mcg/mL

    - Black box warnings:

      - Hepatotoxicity

      - Teratogenicity (neural tube defects)

    C. Carbamazepine (Tegretol®)

    - MOA: Na+ channel blockade

    - Unique risks:

      - HLA-B*1502 → SJS (Asian populations)

      - Hyponatremia (SIADH)

    5. Second-Generation AEDs

    A. Levetiracetam (Keppra®)

    - Advantages:

      - No hepatic metabolism

      - Few drug interactions

    - Side effects: Irritability ("Kepprage")

    B. Lamotrigine (Lamictal®)

    - Dosing: Slow titration (↓rash risk)

    - Pregnancy: Category B (preferred in women)

    C. Topiramate (Topamax®)

    - Additional uses: Migraine prophylaxis

    - Adverse effects:

      - Cognitive slowing ("Dopamax")

      - Metabolic acidosis

    6. Drug Selection Criteria

    Treatment Algorithm (2022 AAN Guidelines)

    | Seizure Type           | First-line               | Alternatives             |

    |------------------------|--------------------------|--------------------------|

    | Focal                  | Lamotrigine, Levetiracetam | Zonisamide, Carbamazepine |

    | Generalized tonic-clonic | Valproate               | Topiramate, Lamotrigine  |

    | Absence                | Ethosuximide            | Valproate, Lamotrigine   |


    Considerations:

    -Comorbidities: Depression (avoid phenobarbital)

    - Cost: Generic carbamazepine vs. brand-name lacosamide

    - Dosing frequency: QD (extended-release) vs. TID

    7. Adverse Effects

    Neurotoxic Effects

    - Acute: Nystagmus, ataxia (phenytoin toxicity)

    - Chronic: Peripheral neuropathy (phenytoin)


    Idiosyncratic Reactions

    - DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)

    - Aplastic anemia (felbamate - 1:5000 risk)


    Long-term Complications

    - Bone health: Vitamin D deficiency (enzyme-inducers)

    - Reproductive: PCOS (valproate)

    8. Drug Interactions

    Major Interactions

    | AED                 | Interacting Drug       | Effect                     |

    |---------------------|-----------------------|---------------------------|

    | Carbamazepine       | Warfarin              | ↓ INR (induces CYP2C9)    |

    | Valproate           | Meropenem             | ↓ Valproate levels        |

    | Phenytoin           | Oral contraceptives   | Contraceptive failure     |


    Therapeutic Monitoring

    - Free vs. total levels (important in hypoalbuminemia)

    - Salivary drug monitoring (emerging technology)


    -9. Special Populations

    A. Pregnancy

    - Highest risk: Valproate (11% malformation rate)

    - Safest options: Lamotrigine, Levetiracetam

    - Folate supplementation: 4 mg/day (all women on AEDs)


    B. Elderly

    - Avoid: Phenobarbital (falls risk)

    - Preferred: Gabapentin (also treats neuropathic pain)


    C. Renal Impairment

    - Dose adjust: Levetiracetam, Gabapentin

    - Avoid: Topiramate (nephrolithiasis risk)

    10. Non-Pharmacological Treatments

    A. Dietary Therapies

    - Ketogenic diet: >50% seizure reduction in 50% of patients

    - Modified Atkins diet: Less restrictive alternative


    B. Surgical Options

    1. Resective surgery (e.g., temporal lobectomy)

    2. Neuromodulation:

       - Vagus nerve stimulation (VNS)

       - Responsive neurostimulation (RNS)


    C. Emerging Therapies

    - Focal cooling devices

    - Optogenetics (experimental)

    11. Future Directions

    - Cannabinoids: Epidiolex® (CBD) for Dravet/Lennox-Gastaut

    - Gene therapy: Targeting SCN1A mutations

    - Precision medicine: Pharmacogenomic testing (e.g., HLA screening)

    Conclusion:

    Antiepileptic drug selection requires careful consideration of seizure type, comorbidities, and patient-specific factors. Emerging therapies offer hope for the 30% of patients with drug-resistant epilepsy. Ongoing research into biomarkers and targeted therapies promises to revolutionize epilepsy management.