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Epilepsy


Epilepsy

What is epilepsy? 
Epilepsy is a disorder characterized by a wide spectrum of seizures. I will describe the seizure types later, but they range from very brief staring spells to the much stereotyped jerking and flexing of the arms and legs. A diagnosis of epilepsy is made after more than one unprovoked seizure. About 1% of the population has epilepsy.

What is a seizure? 
The definition of "seizure" is not completely agreed upon. What we do know is that a seizure consists of a change in brain activity that results in a disruption of our normal behavior. If you give any more detail than that, then people start to argue. Generally speaking, however, people agree that a seizure has elements of "synchrony" and "hyper-excitation". 

Normally, brain activity is "chaotic". When you hook someone up to an electroencephalogram (EEG, a machine that measures brain waves) you see very random looking, unpredictable activity (does anyone else find it ironic that chaotic activity is required to generate "normal" behavior**). Synchrony occurs when groups of neurons (called "networks") begin to fire together. "Why" and "how" our neurons become synchronous is not known. It is one of the many mysteries of a very complex system that is being studied by epilepsy researchers.

Seizures are also said to involve hyper-excitation. Brain activity consists of excitatory and inhibitory signals. The analogy often used is that of a car. A car has both an accelerator (excitatory) and brakes (inhibitory). For normal driving, a combination of accelerating and braking is necessary. During a seizure, however, this balance is lost and the brain becomes hyper-excitable. This is where the analogy falls apart because someone having a seizure isn't the same as someone driving off the road and crashing. Rather, they show the behavior of whatever brain region is over-excitable. If the seizure is in a motor area of the brain, then they have a seizure involving motor actions- such as arm and leg movements. If the seizure is in the visual area of the brain, then they may see flashing lights or odd visual patterns. 

Types of Epilepsy

Symptomatic Epilepsy
Approximately 30-40% of patients with epilepsy have "symptomatic” seizures. These are seizures associated with a specific structural abnormality in the brain. Such abnormalities can include tumours, brain injury, infections, scars, and blood vessel malformations (Browne & Holmes, 2001). Symptomatic epilepsies are the hardest to treat and are often drug-resistant (Kwan & Brodie, 2000).

Idiopathic Epilepsy
Sixty to seventy percent of patients with epilepsy have "idiopathic” seizures. These are seizures that occur in an apparently normal brain. Idiopathic seizures are thought to be caused by a subtle biochemical or ionic imbalance, probably inherited. These seizures tend to respond favourably to anticonvulsant drugs.


Types of Seizure
Seizures are classified as "partial” (focal, local) or "generalized” (global).

Partial Seizures
Partial seizures, initially, involve only a portion of the brain. The three forms of partial seizures are simple partial, complex-partial and partial seizures that secondarily generalize.

Simple partial seizures are usually non-motor seizures that involve certain sensations (e.g. flashing lights, odd smells, strong anxiety). Those who experience a simple partial seizure remain conscious and alert throughout the seizure. These seizures typically last less than two minutes. Simple partial seizures may secondarily generalize (spread) to other brain structures.

Complex-partial seizures begin as a focal or "partial” seizures and spread to become partially generalized, which causes impairment of consciousness. The patient is not unconscious, but is unaware of the environment around him. Impairment of consciousness is what makes the seizure "complex”. Complex-partial seizures are often preceded by an "aura”, that warns the patient the seizure is going to occur. The aura is actually the simple partial seizure that triggers the complex-partial attack. During the seizure, "automatisms” may occur. These non-reflex movements can involve oral automatisms (e.g. chewing, lip smacking, and swallowing) or "ambulatory automatisms” (e.g. rubbing or picking hand movements, running or walking). Patients have no memory for the period of the seizure. Complex-partial seizures typically last between 30 seconds and 2 minutes but can leave the patient mentally hazy or confused for hours.

Generalized Seizures

Generalized seizures involve the entire brain. There are various types of generalized seizures, including absence seizures, myoclonic seizures and tonic-clonic seizures.

Absence seizures are characterized, behaviourally, by a sudden loss of consciousness accompanied by brief staring spells. Electrographically (ie, the pattern you see on the EEG), absence seizures are characterized by a three-per-second spike and wave discharge. Absence seizures tend to be very short (3-10 seconds) and they can occur many times in a day.

Myoclonic seizures involve a sudden jerking movement of the body. These seizures only tend to last a second or two but can recur frequently.

Tonic-clonic seizures are what many people think of when they hear the word "epilepsy”. They are seizures where the individual is unconsciousness and experiencing a convulsions (full body involuntary motor movements). The words "tonus” and "clonus” apply to the muscle actions involved in the convulsions. Clonus refers to a rapid succession of muscle contraction and relaxation, leading to jerking-like movements. Tonus refers to a constant state of contraction. This usually causes the limbs to stiffen and to flex or extend. Tonic-clonic seizures tend to last between one and two minutes, although they may last longer.

Anticonvulsant Drugs, Antiseizure Drugs or Antiepileptic Drugs?
I am seldom picky over words, but I really dislike the term "antiepileptic drug". It sounds like a pill you take if you don't like people with epilepsy. Some rogue, pill-popping gang wandering the streets with a score to settle against those who have epilepsy. Whoever coined this term obviously didn't eat their Wheaties.

Two more acceptable terms are "antiseizure drugs" and "anticonvulsant drugs". Strictly speaking, a seizure is an electrographic event. It is the disruption of brain activity that we can measure using an EEG (see "What is a Seizure" below). A seizure may or may not be associated with a convulsion. A convulsion is the movement/behavior caused by a seizure. For example, tonic-clonic* (formerly called grand mal) seizures cause tonic-clonic movements therefore it is a convulsive seizure. Other seizures, however, do not cause convulsions. For example, simple partial seizures that do not affect motor areas of the brain will not cause any movement- therefore they are non-convulsive seizures. I tend to use the terms "anticonvulsant drugs" and "antiseizure drugs" interchangeably. 

*Tonus is continuous contraction of the muscles, causing the limbs to straighten and become stiff. Clonus is the repeated contraction and relaxation of the muscles which results in a jerking movement.

The Drugs.
Upon being diagnosed with epilepsy, the first course of treatment is generally the drugs. 

Until the mid 1990s, the "traditional" anticonvulsants were the most commonly prescribed (drugs listed by generic name with trade name in parentheses). These include phenobarbital (Luminal®), primidone (Mysoline®), phenytoin (Dilantin®), carbamazepine (Tegretol®), ethosuximide (Zarontin®), clonazepam (Rivotril®) and valproate (Depakene®). These "first-line" anticonvulsant drugs are only effective in 60-70% of patients. They may also be associated with severe side effects.

In the past decade, a number of new drugs have been introduced to the market. These include felbamate (Felbatol®), fosphenytoin sodium (Cerebyx®), oxcarbazepine (Trileptal®), gabapentin (Neurontin®), lamotrigine (Lamictal®), zonisamide (Zonegran®), levetiracetam (Keppra®), tiagabine (Gabitril®), pregabalin (Lyrica®) and topiramate (Topamax®). Although these newer drugs have fewer side effects, they do not appear to be more effective at stopping seizures than the traditional drugs- meaning 20-30% of patients will not gain adequate seizure control on these meds.

How the Drugs Work.
The new anticonvulsant drugs may not be more effective than the old anticonvulsant drugs because they tend to work in very similar ways. Anticonvulsant drugs generally work to decrease excitation or increase inhibition in the brain. This is usually accomplished by one of three mechanisms: enhancing GABA activity, decreasing sodium channel activity, or decreasing T-type calcium channel activity.

GABA Drugs.
GABA (also know by the less cuddly name: gamma-aminobutyric acid) is the major inhibitory chemical in the brain. It works by slamming on the proverbial brakes (see car analogy under "What is a Seizure" below). The GABA drugs elevate levels of GABA in the brain. Slamming on the brakes will make the brain less excitable and less prone to seizures. It will also make it harder to remember things and stay alert/energetic. This is because these drugs raise GABA levels all over the brain, and not just in the area(s) that cause the seizure. 

A number of the anticonvulsants enhance the activity of GABA, often indirectly. Examples of such drugs are: phenobarbital (Luminal®), primidone (Mysoline®), topiramate (Topamax®), diazepam (Valium®) and tiagabine (Gabitril®).

Sodium Channel Blockers.
Sodium channels (specifically, voltage-gated sodium channels) are responsible for the firing of neurons in the brain. Think of a neuron as a water hose. The hose is full of little gates, however, that prevent the water from flowing through it. When the gates "sense" that water is coming, they open and allow the water to flow through. This is a rough analogy of how the voltage gated sodium channels work- only instead of water they allow the passage of positively charged ions (like sodium) into the cell which allows the signal to carry on. 

Drugs that work on sodium channels in the brain tend to delay these channels, causing neurons to fire a tiny bit slower than normal. Examples of voltage-gated sodium channel drugs are phenytoin (Dilantin®), carbamazepine (Tegretol®), felbamate (Felbatol®), lamotrigine (Lamictal®), oxcarbazepine (Trileptal®), pregabalin (Lyrica®), topiramate (Topamax®) and zonisamide (Zonegran®).

Calcium Channel Blockers.
T-type calcium channels are thought to cause rhythmic neuronal firing associated with absence seizures. Similar to sodium channels, calcium channels open and allow positively charged ions to enter the cell -- only this time it's calcium and not sodium. Calcium channel blockers tend to be most effective in treating absence seizures. Examples of drugs acting on calcium channels are ethosuximide (Zarontin®), felbamate (Felbatol®), lamotrigine (Lamictal®), topiramate (Topamax®) and zonisamide (Zonegran®). 

Drugs for the Treatment of Status Epilepticus.
Status epilepticus is a seizure that does not end on its own. Generally, someone is said to be in status if their seizure lasts longer than 5 minutes. This is when it's important to get to a hospital/call 911 as special drugs will be required to stop these seizures (see "Seizure First Aid" below). These include diazepam (Valium®), lorazepam (Ativan®) and sometimes general anesthetics such as propofol (Diprivan®). 
 
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