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Epilepsy 1% of world population has epilepsy It is the second most common neurologic disorder after stroke Epilepsy is a heterogeneous symptom complex – a chronic disorder characterized by recurrent seizures Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons


Epilepsy The site of the origin of discharge is called “epileptic focus” à from here the discharge spreads to the surrounding areas of the brain


Etiology Infection - cerebral meningitis & brain abscess Neoplasm Head injury - brain lesions, mainly due to birth trauma Metabolic disorders like lack of oxygen, alkalosis, hypoglycaemia , hypocalcaemia, hyperpyrexia & Vit B 6 deficiency Sudden withdrawal of many drugs of abuse (Barbiturates, Alcohol) Viewing television, disco flashes, & listening full blast Pop music ( Musicogenic temporal lobe seizures) Heredity

Pathophysiology of Epilepsy:

Pathophysiology of Epilepsy Mutations in several genes have been linked to some types of epilepsy. Several genes that code for protein subunits of voltage-gated and ligand -gated ion channels have been associated with forms of generalized epilepsy and infantile seizure syndromes. Several ligand -gated ion channels have been linked to some types of frontal and generalized epilepsies. Speculated mechanism for some forms of inherited epilepsy are mutations of the genes which code for sodium channel proteins , these defective sodium channels stay open for too long &making the neuron hyperexcitable Glutamate, an excitatory neurotransmitter released from these neurons in large amounts, by binding with glumtamanergic neurons & triggers excessive calcium (Ca +2 ) release in these postsynaptic cells, which is neurotoxic to the affected cell


Classification Partial seizures Simple partial seizures Complex partial seizures Partial seizures secondarily generalized Generalized seizures Generalized tonic – clonic (grand mal) seizures Absence (petit mal) seizures Tonic seizures Atonic seizures Clonic & myoclonic seizures

Generalized tonic – clonic (grand mal) seizures :

Generalized tonic – clonic (grand mal) seizures These are usually associated with an aura prior to seizures. The patient falls to the ground in stiff tonic phase (legs extended) with an epileptic cry, caused by tonic contraction of laryngeal muscles, followed by clonic convulsions (repetitive bilateral muscle jerking) & coma which may last for about 15-30 min Recovery is associated with stupor, amnesia, mental confusion, postictal (post seizure) depression, incontinence & exhaustion EEG shows a bilateral diffused pattern of high voltage polyspikes of 10-3- Hz/sec in tonic-clonic phase

Petit Mal or Absence Seizures :

Petit Mal or Absence Seizures There is no aura associated with this disorder & attack appear without warning & no loss of consciousness This seizure lasts for few seconds, lapse of consciousness for 5 seconds with no loss of postural control & no postictal confusion or amnesia Absence seizures are characterized by subtle bilateral motor symptoms such as rapid blinking of eyelids, chewing movements or small amplitude clonic jerks of the hands for few seconds EEG 3Hz spike that begins & ends suddenly In 15-20% children this type of seizures & children may experience absence seizures hundred times per day


Management Drugs used in Partial & Generalized tonic – clonic (grand mal) seizures Phenytoin Carbamazepine Valproate Barbiturates

Mechanism of action of drugs used in Grand Mal & Partial Seizure 1) Inhibition of Use-Dependent Na+ channel:

Mechanism of action of drugs used in Grand Mal & Partial Seizure 1) Inhibition of Use-Dependent Na+ channel Many drugs ( e.g., phenytoin , carbamazepine , valproate , lamotrigine ) block the Na+ channels that remain open due to repetitive neuronal firing, they block the use-dependent or voltage dependent Na+ channel These drugs prolongs the duration of ‘inactivated phase’ delay its reversion to the resting phase à it reduces the chances of becoming available for activation again

2) Enhancement of GABAergic action:

2) Enhancement of GABAergic action Some of the antiepileptic drugs ( e.g., Phenobarbital & benzodiazepines ) activates GABA A receptors , to facilitate GABA-mediated opening of Cl - channels Benzodiazepines increases the frequency of opening of Cl - channel Phenobarbital increases the duration of opening of Cl - channel Vigabatrin inhibit the enzyme GABA- transminase which is responsible to metabolise GABA thus increases the neuronal concentration of GABA Tigabine inhibits GABA uptake by inhibiting GABA uptake transporter in neurons & glia it enhances the availability & inhibitory actions of GABA at postsynaptic GABA A receptors Neursteroid like Ganaxolone acts on selective & separate modulatory site on the GABA A receptor complex increases Cl - conductance Drugs that facilitate GABA or onhibit glutamate pathways more likely to induce amnesia& impairment of learning as side effect

3) Blockade of NMDA receptors:

3) Blockade of NMDA receptors Activation of NMDA receptors produces depolarizing responses & initiates seizure activity Felbamate blocks NMDA receptors but they are not available for clinical us

Mechanisms of Drugs Used in Petit Mal (Absence Seizures):

Mechanisms of Drugs Used in Petit Mal (Absence Seizures) Inhibition of T-type Ca +2 channels Ethosuximide is a major drug used for the treatment of absence seizures It inhibits the low threshold Ca +2 currents which are responsible for generating the thalamic cortical rhythm in the form of 3Hz spikes & waves seen in petit mal attack

Mechanism of action:

Mechanism of action Phenytoin It alters Na + K + , Ca +2 conductance, membrane potentials, and the concentrations of amino acids and the neurotransmitters norepinephrine (NE), Ach, & GABA It blocks the high frequency repetitive firing of action potentials It prevents Na + conductance by prolonging the inactivated state of Na + channels

Mechanism of action:

Mechanism of action Phenobarbital It blocks the high frequency repetitive firing of neurons by preventing Na+ conductance It blocks Ca+ currents (L-type & N type) It binds to an allosteric regulatory site on the GABA BZD receptor, and it enhances the GABA receptor mediated current by prolonging the opening of Cl - channels Both the enhancement of GABA mediated inhibition and the reduction of glutamate mediated excitation

Mechanism of action:

Mechanism of action Vigabatrin It is an irreversible inhibitor of GABA-T, the enzyme responsible for the degradation of GABA It acts by increasing the amount of GABA at synaptic sites, there by enhancing inhibitory effects Used in the treatment of partial seizures

PowerPoint Presentation:

Mechanisms of drugs used in Grand Mal & Partial Seizures

PowerPoint Presentation:

Mechanisms of drugs used in Grand Mal & Partial Seizures

Toxicity of antiseizure drugs:

Toxicity of antiseizure drugs Teratogenicity There is fetal malformations seen in pregnant ladies receiving these drugs Phenytoin causes fetal hydantoin syndrome, similar syndromes have been attributed to both phenobarbital & and carbamazepine Pregnant woman taking valproic acid has 1-2% risk of having a child with spina bifida

Toxicity of antiseizure drugs:

Toxicity of antiseizure drugs Teratogenicity Folic acid supplements may be added as many antiepileptic drugs cause folic acid deficiency which is responsible for neural tube defects ( spina bifida & anencephaly) Antiepileptic drugs which are enzyme inducers, lower the maternal plasma levels of Vitamin K leading to postpartum haemorrhage , oral Vit K should be supplemented during the last two weeks of the pregnancy

Toxicity of antiseizure drugs:

Toxicity of antiseizure drugs Withdrawal Withdrawal of antiseizure drugs whether by accident or by design, can cause increased seizure frequency and severity Barbiturates and benzodiazepines are most difficult to discontinue; weeks or months may be required, with very gradual dosage decrements

Toxicity of antiseizure drugs:

Toxicity of antiseizure drugs Overdose Causes respiratory depression, which may be potentiated by agents like alcohol

Management of Status Epilepticus :

Management of Status Epilepticus Status epilepticus refers to continuous seizures or repetitive, discrete seizures with impaired consciousness in the interictal period. Status epilepticus has numerous subtypes, including generalized convulsive status epilepticus (GCSE) (e.g., persistent, generalized electrographic seizures, coma, and tonic- clonic movements), and nonconvulsive status epilepticus (e.g., persistent absence seizures or partial seizures, confusion or partially impaired consciousness, and minimal motor abnormalities). The duration of seizure activity is 15–30 min.

Status Epilepticus:

Status Epilepticus GCSE is an emergency and must be treated immediately , since cardiorespiratory dysfunction, hyperthermia, and metabolic derangements can develop as a consequence of prolonged seizures, and these can lead to irreversible neuronal injury. Furthermore, CNS injury can occur even when the patient is paralyzed with neuromuscular blockade but continues to have electrographic seizures. The most common causes of GCSE are anticonvulsant withdrawal or noncompliance, metabolic disturbances, drug toxicity, CNS infection, CNS tumors, refractory epilepsy, and head trauma

Status Epilepticus:

Status Epilepticus Initial management includes maintenance of the airway and 50% dextrose (25–50 mL ) intravenously in case hypoglycemia is responsible. If seizures continue, an intravenous bolus of lorazepam , 4 mg, is given and repeated once after 10 minutes if necessary; alternatively, 10 mg of diazepam is given intravenously over the course of 2 minutes, and the dose is repeated after 10 minutes if necessary. This is usually effective in halting seizures for a brief period but occasionally causes respiratory depression. Phenobarbitone (100-200 mg im /iv) or phenytoin (25mg/min iv max ig ) à substituted to diazepam after the convulsions have been controlled

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