Anticonvulsants/Antiepileptics

Anticonvulsants/Antiepileptics

• What are they?

Epilepsy is a group of CNS disorder characterized by paroxysmal cerebral dysrhythmia, showing symptoms as episodes (seizures) of loss/disturbance of consciousness, with or without characteristic body movements (convulsions), sensory or psychiatric phenomena.

The seizure episodes are unpredictable, and their frequency is highly variable. Epilepsy is seen to have a focal origin (point of origin) in the brain; hence the manifestations depend on the site of focus, and regions into which the discharges spread. The cellular mechanism involved in seizure generation is overexcitation of inward Na⁺, Ca²⁺ currents, and increased levels of glutamate and aspartate. The inhibitory mechanisms of Cl^–, outward K⁺ currents, and levels of GABA (gamma-aminobutyric acid) are diminished, causing overall hyperexcitation.

I. Generalized seizures

• Generalized tonic-clonic seizures (major epilepsy, grand mal): the most common seizure episode is lasting 1–2 min. The usual sequence seen is aura—cry—unconsciousness—tonic spasm of all body muscles—clonic jerking followed by prolonged sleep and depression of all CNS functions.
• Absence seizures (minor epilepsy, petit mal): prevalent in children, lasts about 1/2 minute. Manifestations seen include – momentary unconsciousness where patient freezes and stares in one direction, without the involvement of muscular component or little bilateral jerking.
• Atonic seizures (Akinetic epilepsy): Unconsciousness with the relaxation of all muscles due to excessive inhibitory discharges. Patients may fall due to loss of control.
• Myoclonic seizures:  Shock-like momentary contraction of limb or the whole body.
• Infantile spasms (Hypsarrhythmia): Seen in infants, manifestations include intermittent muscular spasms and mental deterioration.

II. Partial seizures

• Simple partial seizures (SPS, cortical focal epilepsy): seizures are lasting for 30 seconds–1 min. These are often secondary, and convulsions remain confined to a group of muscles or localized sensory disturbance depending on the area of the cortex without any loss of consciousness.
• Complex partial seizure (CPS, temporal lobe epilepsy, psychomotor): attacks of bizarre and confusing behavior and purposeless movements, emotional changes that last for 1–2 min along with unconsciousness. An aura often precedes. The seizure focus is in the temporal lobe of the brain.
• Simple/complex partial seizures (secondarily generalized seizures): An initial partial seizure occurs that evolves into generalized tonic-clonic seizures with subsequent loss of consciousness.

The antiepileptic drugs help in managing such conditions that may be fatal if not taken care of.

• How do they work?

Most of the cases of epilepsy are primary that remain to be idiopathic. At the same time, there have been cases of epilepsy that are secondary to trauma/surgery on the head, intracranial tumor, tuberculoma, cysticercosis, and cerebral ischemia.

The treatment is symptomatic and the same whether epilepsy is a primary or secondary type.

The drugs are used to reverse the cellular condition, i.e., they tend to increase inhibitory neurotransmitter system— GABA, decrease the excitatory neurotransmitter system—glutamate and aspartate, block voltage-gated inward positive currents of Na⁺ or Ca²⁺, or increase outward positive current of K⁺. Many antiepileptic drugs show pleiotropic action and  act via multiple mechanisms

• Different classes of these drugs

The commonly used antiseizure medications are –

• Indications in which they are preferred

Antiepileptic drugs can only be used to suppress the seizure and not cure the disorder. The drugs help to control and prevent all the seizure activity with an acceptable side-effect limit.

The currently available drugs can be therapeutic in half of the patient population. 20–30% of the patients achieve partial control, and the remaining population remains refractory.

It is essential to find the epileptic cause in the patient. Upon investigation, if found and treatable, an attempt is made to ameliorate the cause.

Management of generalized tonic-clonic, simple partial seizures – upon efficacy and toxicity evaluation, carbamazepine, and phenytoin are the first-line drugs for treatment, followed by phenobarbitone and lowest effect of primidone. Carbamazepine is most useful for partial seizures, and valproate is equally effective in secondary generalized tonic-clonic seizures. Valproate is a second-line drug that needs to be used cautiously in young children due to the associated risk of hepatic toxicity. Carbamazepine is preferred over phenytoin in young girls because of cosmetic side effects o the latter.

Complex partial seizures – The complete control of this epilepsy is difficult, and relapses are very common upon medication withdrawal. Carbamazepine is the preferred drug, along with adjunctive therapy of phenytoin or valproate. In the case of refractory episodes, newer drugs, including levetiracetam, lamotrigine, gabapentin, topiramate, or zonisamide, are added as per the severity.

Absence seizures – Ethosuximide and valproate are the most commonly used medications. Both are equally efficient, but valproate is used commonly; since it also prevents the kindling and emergence of generalized tonic-clonic seizures. Valproate is more effective in the mixed absence and generalized tonic-clonic seizures that are more common than pure absence seizures. Recently, Lamotrigine is being used as an effective alternative medication. Clonazepam is used as a second-line drug, but the use is limited due to its sedative effects and incidence of tolerance. A better-sustained response is seen in clobazam.

Myoclonic and atonic seizures – Valproate is the first line preferred drug, and lamotrigine is used as an effective alternative. Topiramate and levetiracetam are generally used as adjuncts if the patient does not respond to first-line therapy.

Febrile convulsions – some children under 5 years of age develop convulsions during fever. Seizures reoccur every time with fever, and few children become chronic epileptics if ignored. It should be seen that temperature rise is controlled paracetamol and external cooling.

Infantile spasms (hypsarrhythmia) – Therapy is unsatisfactory as antiepileptic drugs do not provide relief. Corticosteroids use provides symptomatic relief. Valproate and clonazepam have adjuvant value.

Status epilepticus – When seizure activity occurs for more than 30 minutes, or two or more seizures occur without recovery of consciousness; the condition is called status epilepticus. Recurrent tonic-clonic convulsions with no consciousness in between is an emergency, and the fits are controlled as soon as possible to prevent morbidity and permanent brain damage. I.V. antiepileptics are given for the management.

General monitoring of airway (intubation if required), oxygenation, fluid and electrolyte balance, BP, cardiac rhythm, glycaemic levels, and care of the unconscious is essential.

• Side effects

Common side effects –

• Dizziness and headache
• Drowsiness and fatigue
• Dry mouth
• Itching
• Muscle aches and pain
• Fits
• Exfoliation of skin
• Vitamin D deficiency

Severe side effects requiring medical attention –

• Abdominal pain
• Blurred/double vision
• Blood dyscrasia
• Loss of appetite
• Dementia/ cognitive impairment
• Palpitations
• Coordination problems
• Ringing sound in the ear
• Swelling of limbs
• Hives and skin rashes

Drug-specific side effects

• Phenytoin – Hirsutism, gingival hyperplasia, hypersensitivity
• Carbamazepine – granulocyte suppression, respiratory depression, aplastic anemia, agranulocytosis, hyponatremia in elder patients
• Valproate – hepatotoxicity, spina bifida (teratogen), negative interactions with other anti-epileptics
• Ethosuximide – lethargy and fatigue, lupus erythematosus, gastric distress
• Gabapentin – ataxia, and tremors
• Benzodiazepines – sedation, paradoxical hyperactivity in children, tolerance

• Contraindications
• recent myocardial infarction, heart failure, and stroke
• brain lesions
• increased intracranial pressure
• intracranial hemorrhage
• active bleeding
• pregnant women
• aneurysms/ vascular malformations
• pheochromocytoma
• retinal detachment
• severe liver disease
• glaucoma
• COPD
• porphyria