Author- Dr. Md. Shamim, MD
Seizure is a transient occurrence of signs or symptoms due to abnormal excessive or synchron0us neural activity in the brain.
Epilepsy is a recurrent seizure due to chronic, underlying process.
Convulsion is a condition in which muscles contracts and relax quickly and causes uncontrollable shaking of the body.
The term Epilepsy is derived from the Greek word “Epilambanein , which means ‘to be seized’.
Epilepsy is one of the world’s oldest recognized conditions (around 4000 BC)
Around 900Â BC, Punarvasu Atreya described epilepsy as loss of consciousness.
Epidemiological Data
- Second most common neurological disease.
- 70 million people worldwide have epilepsy.
- 90% of epilepsy cases worldwide are found in developing countries.
- In India:
- >12 million people have epilepsy.
- Incidence rate – 2- 6 cases per 10000 population.
- Prevalence rate- 37-51 cases per 10000 population.
Classification of Seizure
Physiology of Neuronal Activity
Neuronal Activity in Brain in Seizure
Therapeutic Target in seizure disorders
Choice of drugs in seizure disorders
Why we need newer therapies?
Because Older Drugs have:-
- More side effects.
- Troublesome drug interactions.
- Multiple daily doses leading to reduce compliance.
- Effects wane off after some time.
- Teratogenicity.
Novel Drugs for Seizure Disorders
Novel Drugs at Older Targets
- GANAXOLONE
- CENOBAMATE
- STIRIPENTOL
- BRIVARACETAM
- ESLICABAZEPINE ACETATE
- CLOBAZAM
GANAXOLONE
- FDA Approved in March 2022 for the treatment of seizures associated with Cyclin- Dependent Kinase- like5 (CDKL5) deficiency disorder (CDD) in patients 2 years of age and older.
- It is a neuroactive steroid.
- MOA:
- Exact mechanism in CDD is unknown.
- Positive allosteric modulators of GABAA
- Dosage:
- ≤28 Kg- Initial dose- 6 mg/Kg tid (18 mg/Kg/day).
- Maxm dose- 21 mg/Kg tid (63 mg/Kg/d).
- >28 Kg- Initial dose- 150 mg tid (450 mg/d). Maxm dose- 600 mg tid (1800 mg/d).
- A/E- Somnolence, Pyrexia, Salivary hypersecretion, and Allergy.
CENOBAMATE
- FDA Approved in 2020 for the treatment of Partial onset seizures in adult patients.
- MOA-
- Exact mechanism is unknown.
- Inhibiting Voltage gated Na+
- Positive allosteric modulator of GABAA
- Dosage-
- Initial dose – 12.5 mg OD
- Maintenance dose – 200 mg OD
- Maxm dose – 400 mg OD
- A/E- Hypersensitivity, Somnolence, Dizziness, Fatigue, Diplopia and Headache.
- Other- QT Shortening, Suicidal ideation.
STIRIPENTOL
- FDA Approved in 2018 for the treatment of seizures associated with Dravet syndrome in patients 2 year of age or older.
- MOA:
- Increases GABA Release.
- Inhibits GABA reuptake.
- Extensively bound to plasma proteins.
- Potent inhibitor of CYP3A4, CYP1A2, CYP2C19.
- Adjunctive Therapy with Sod. Valproate and clobazam.
- Dosage: Initial dose 50 mg/Kg/day PO in 2 or 3 divided doses, increasing up to 100 mg/Kg/day (maximum of 4g/day).
- A/E: Loss of appetite, Drowsiness, Ataxia, Diplopia, Cognitive impairment.
BRIVARACETAM
- FDA Approved in Jan 2016 for add-on treatment to other antiepileptics to treat Partial onset seizure in patients one month of age and older.
- MOA:
- Exact mechanism of action is unknown.
- High and selective affinity for Synaptic Vesicle Protein 2A (SV2A) in the brain.
- 1o-fold greater affinity to synaptic vesicle protein 2A (SV2A) ligand than Levetiracetam.
- Dosage:
- ≥ 16 year- Initial dose- 50 mg twice daily. Maxm dose – 200 mg twice daily.
- One month to <16 year- Initial dose- 0.5 mg/Kg twice daily.
- Maxm dose- 3 mg/Kg twice daily.
- A/E: Somnolence or Sedation, Drowsiness, Dizziness, Fatigue, Nausea and Vomiting.
- Reduced suicidal ideation as compare to Levetiracetam.
ESLICABAZEPINE ACETATE
- FDA Approved in Nov 2013 as an adjunctive treatment for Focal seizure.
- MOA: Inhibits voltage dependent Na+
- Rapidly converted to S (+)-licarbazepine (active form).
- Less neurotoxic than carbamazepine and oxcarbazepine.
- Does not undergo autoinduction.
- Dosage- 400-1200 mg/day OD
- A/E: Headache, Dizziness and Nausea, Less incidence of HYPONATREMIA.
- Minimal interaction with Cytochrome P450 liver enzymes.
CLOBAZAM
- FDA Approved in 2011 for adjunctive treatment of seizure associated with Lennox- Gastaut syndrome (LGS) in patients 2 year of age or older.
- MOA- Binds to Benzodiazepine site of the GABAA receptor to potentiate the GABAergic neurotransmission.
- Dosage-
- ≤30 Kg- Initial dose- 5 mg OD PO
- Maxm dose-20 mg OD PO
- >30 Kg- Initial dose- 10 mg OD PO
- Maxm dose- 40 mg OD PO
- Doses >5 mg should be divided into 2 doses.
- A/E- Somnolence, Sedation, Drooling, Constipation, Urinary Tract Infection, Dysarthria and Fatigue.
- Monitor for suicidal thoughts or behaviours.
- Alcohol increases the blood levels of Clobazam by approximately 50%.
Novel Drugs at Novel Targets
- FENFLURAMINE
- CANNABIDIOL
- PERAMPANEL
- RETIGABINE
FENFLURAMINE
- FDA Approved in Mar 2022 for the treatment of seizures associated with Dravet syndrome and Lenoux- Gastaut syndrome in patients 2 years of age and older.
- MOA:
- Exact mechanism as antiseizure drug is not known.
- May exhibit agonist activity at serotonin 5- HT2 receptors.
- Dosage:
- Initial dose- 0.1 mg/Kg twice daily.
- Maxm– 0.35/Kg twice daily.
- A/E: Decreased appetite, Sedation, Lethargy, Asthenia, Ataxia and salivary hypersecretion.
CANNABIDIOL
- FDA Approved in April 2018 for treatment of Lennox- Gastaut syndromre and Dravet syndrome in patients 2 years of age and older.
- It is a cannabinoid that naturally occurs in the Cannabis sativa
- MOA- Exact mechanism is unknown. Cannabidiol does not appear to exert its anticonvulsant effects through interaction with cannabinoid receptors.
- Dosage-
- Initial dose- 2.5 mg/ Kg twice daily
- Maintenance dose- 5 mg/ Kg twice daily
- Maxm dose- 10 mg/ Kg twice daily
- A/E- Somnolence, decreased appetite, Diarrhoea, Fatigue, Insomnia and Asthenia.
- May cause Foetal Toxicity.
PERAMPANEL
- FDA Approved in Nov 2012 for treatment of refractory partial onset seizures with or without secondarily generalised seizure in patients 4 years of age and older.
- MOA:
- Exact mechanism is not known.
- Highly selective noncompetitive α- Amino-3-hdroxy- 5-Methyl-4-isoxazole Propionic Acid (AMPA) type glutamate receptor antagonist.
- Dosage:
- Initial dose- 2 mg once daily.
- Maxm dose- 12 mg once daily.
- A/E: Dizziness, Somnolence, Fatigue, Vertigo, Ataxia and Weight gain.
- Boxed warning about the risk for serious neuropsychiatric events like irritability, aggression, anger, anxiety, and rarely homicidal ideation.
Non-Pharmacological Advances
Vagus Nerve Stimulator (VNS)
- FDA Approved Device.
- Provides chronic intermittent electrical stimulation of the Vagus nerve.
- Exact mechanism is not known.
- Indicated in patients with Refractory seizure
- Partial or Generalised
- Lennox- Gastaut Syndrome.
A/E- Cough, Hoarseness of voice, Difficulty in swallowing, Throat discomfort.
Deep Brain Stimulation
- Based on stimulating widespread inhibitory pathways.
Summary & Conclusion
- Seizure disorder can be treated but complete cure??
- Classical Antiseizure drugs having pros and cons.
- Needs long term therapy.
- Need for new treatment with novel mechanism of action.
- Non pharmacological therapy showing promise.
References
- Harrison’s Principle of Internal Medicine.
- Current Medical Diagnosis and Treatment.
- Basic and Clinical Pharmacology- Katzung.
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