Epilepsy and Seizures

Epilepsy

• CNS disease characterized by recurrent seizures
• There is abnormal (excessive) neuronal activity, resulting in a power surge in the brain
• This activity is disordered and not part of normal functioning or synchronous rhythmic firing of neurons
• Seizures may or may not involve convulsions, which manifest as uncontrolled limb movements
• Excessive discharge during a seizure can be localized or spread into both hemispheres

Classification of Seizures

• Seizures are classified as either generalized or focal (partial)

Generalized Seizures

• Tonic-clonic (grand mal) seizures involve a phase lasting less than 1 minute
• Exhibit maximum involvement of both hemispheres
• Begin with a rigid (tonic) phase, followed by jerking of limbs (clonic)
• End with a post-ictal state, where the person may be unconscious and drowsy
• Absence (petit mal) seizures last 15-20 seconds and often happen 100 times per day
• Occur mainly in childhood
• Involve abrupt interruption in consciousness, person just stares straight ahead ("zones out")
• May involve a blank stare, lip-smacking, or rapid blinking
• Myoclonic seizures manifest as brief (about 1 second), rapid jerking of the arms
• Occur quickly and can be mistaken for nervousness or clumsiness
• Atonic seizures involve sudden loss of muscle tone, causing the person to become limp and appear to pass out
• Wearing a helmet may be required

Focal Seizures

• Focal seizures are partial seizures that occur in one hemisphere
• Types include:
• Without altered mental awareness:
• Confined to one area of the brain that serves a basic function (small area)
• Twitching in one arm may be experienced, but consciousness is preserved
• Symptoms depend on the location of the seizure and can spread ipsilaterally
• With altered mental awareness (brain fog):
• Involves a brain region that serves a complex function (hippocampus, frontal lobe)
• Consciousness is impaired and preceded by an aura (subjective emotion)
• Secondary generalization is when the seizure starts in one area and can progress to a generalized seizure

Three Steps of a Focal Seizure

• Initiation: There is an increase in electrical activity at the cellular level
• Synchronization: Electrical activity is synchronized in surrounding neurons
• Spread: Electrical activity spreads to adjacent regions, and if it goes to the other hemisphere, the seizure becomes secondarily generalized

Anticonvulsants - Mechanisms

• Problem: excessive neuronal activity
• Solutions:
• Decrease excitatory (go signal) transmission in the brain
• Increase inhibitory (stop signal) transmission in the brain
• Mechanisms of Action:
• Prolong the inactive conformation of voltage-gated Na+ channels (generation of action potentials), making neurons less likely to fire
• Increase GABA activity (inhibitory neurotransmitter), boosting natural stop signals
• Block T-type Ca2+ channels, which helps treat absence seizures
• Enhance K+ channels, which helps repolarize after action potential, dampening neuronal excitability
• Inhibit glutamate activity, blocking the go signal

Status Epilepticus

• Repeated seizures are so prolonged that they appear to be one continuous seizure lasting longer than 30 minutes
• The person does not regain consciousness between seizures
• Diazepam or lorazepam IV are the first drugs used because they penetrate the BBB quickly and can stop seizures rapidly
• Once things calm down, a loading dose of longer acting medication (phenytoin, phenobarb, or carbamazepine) is administered
• A loading dose of anticonvulsants prevents reoccurrence

Metabolism of Anticonvulsants

• Enzyme Induction:
• Increases activity 2-4 weeks AFTER continuous dosing
• Increases activity AFTER drug discontinuation
• Enzyme Inhibition:
• Decreases activity whenever the drug is present
• Presence of inhibition follows the drug’s kinetics

Importance of Drug Interactions

• The most important mechanisms resulting in a drug interaction with anticonvulsants are induction and inhibition of hepatic enzymes
• Patients may experience loss of efficacy or signs of toxicity when drugs are added or removed

Anticonvulsants & Bone Density

• Phenytoin, phenobarbital, and carbamazepine increase the metabolism of vitamin D (crucial for calcium absorption)
• Valproic acid increases bone resorption, leading to bone loss
• Recommendations include:
• Daily supplements of Ca2+ and vitamin D
• Regular weight-bearing exercise
• Avoiding smoking and excess alcohol
• Regular bone density testing

Anticonvulsants in Pregnancy

• There is a link between anticonvulsants and birth defects
• It is best to avoid discontinuing anticonvulsants abruptly
• The lowest dose and fewest drugs (monotherapy) should be used along with blood monitoring
• Valproic acid and phenytoin are the most teratogenic (Cat D)
• Carbamazepine, phenobarbital, and clonazepam are also Cat D
• All other anticonvulsants are Cat C