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Seizures may be due to
congenital defects, hypoxia at birth, head trauma, brain tumors, metabolic disorders or alcohol withdrawal
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idiopathic seizures
They can also occur without any known cause
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partial seizure
When the electrical discharge is limited to only adjacent areas (in the cerebral cortex
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generalized seizure.
when it spreads outside the cerebral cortex or through distant parts of brain
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PARTIAL, Simple:
no loss of consciousness, limited to one part of the body (e.g. convulsions of a single limb).
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Partial, Complex:
impairment of consciousness, confused or bizarre behavior.
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GENERALIZED, Tonic-Clonic
(Grand mal) consists of alternating periods of synchronous muscle jerks (clonic) and muscle rigidity (tonic phase) with impairment of consciousness; followed by a period of CNS depression.
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Generalized, Absence Seizures
(Petit mal)is a brief, frequent losses of consciousness with staring and fluttering eyelids that last 10-30 seconds.
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Generalized, Status Epilepticus
(SE) is a persistent general seizure (>30 minutes) which can be life threatening if not stopped.
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MIXED TYPES
A seizure may start as a partial seizure and progress into a generalized seizure.
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BIOCHEMICAL BASIS OF ANTI-SEIZURE MEDICATIONS
Anti-seizure medications prevent either the initial discharge or the spread of electrical discharge. At a molecular level there are several ways that anti-seizure medications may act.
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Anti-Seizure can act by
They may act by inhibiting Na influx through gated pores across the neural membrane, thus inhibiting depolarization. The two most commonly prescribed anti-seizure medications, phenytóin (Dilantin) and carbamazepine (Tegretol), act by this mechanism. Delay of the depolarization process prevents the neuron from rapid repeated depolarization (a characteristic of epileptic seizures) without preventing slower normal depolarization.
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Anti-Seizure can act by B
They may act by enhancing the effect of inhibitory pre-synaptic neurons. Inhibitory neurons in the brain often have GABA as their neurotransmitter. GABA binds to ion transport proteins embedded in the post-synaptic membrane and enhances chloride transport into the neuron and potassium ion out of the neuron, thus stimulating hyperpolarization of the post-synaptic neuron, making it more difficult for the neuron to fire.
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Anti-Seizure can act by C
C. Anti-seizure medications may act by inhibiting excitatory pre-synaptic neurons. Pre-synaptic excitatory neurons commonly release an amino acid, glutamate or glycine, as their neurotransmitter. Glutamate can bind to NMDA receptors in the post-synaptic neuron (NMDA = N-methyl D aspartate). Binding to these receptors 3 stimulate Na+ and Ca+2 channels to open and to depolarize the post-synaptic neuron. Drugs which act to inhibit glutamate release will inhibit the firing of post-synaptic neurons
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Anti-Seizure can act by D
D. Drugs that are effective against absence seizures, such as valproic acid (Depakote), inhibit the depolarization of T-type Ca+2 channels. Rapid firing of T-type Ca+2 channels in the hypothalamus appears to be responsible for absence seizures. Delaying depolarization of these hypothalamic neurons alleviates absence seizures.
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Phenytóin (Dilántin)
Phenytóin (Dilántin) acts to inhibit the sodium channels in the post-synaptic neuron, but only when repeat frequent firing of the neuron has occurred so that the neuron has not had time to completely repolarize. It appears to have little effect on normally discharging neurons. It works on all types of seizures except absence seizures.
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Adverse effects of phenytóin:
1. sedation, ataxia(incoordination), cognitive impairment 2. gingival hyperplasia (approximately 20-40%) 3. dermatitis (2-5%) is extremely severe in rare cases(Steven-Johnson syndrome) 4. teratogenicity (cleft palate, heart defects). Patients on phenytoin have 4-6% incidence of birth defects (cleft lip particularly common) vs. 2% in general population; this may be due to inhibition of folic acid absorption; folic acid supplements are recommended in all pregnant women. 5. sudden withdrawal may produce status epilepticus (SE)
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Fosphenytoin (Cerebyx)
is a new drug related to phenytóin. It is more water soluble, less alkaline (pH 8.8), easier on veins when used for IV control of status epilepticus.
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Topiramate(Topomax)
Topiramate(Topomax) appears to work to inhibit Na channels and to augment the action of the GABA receptors. It is most commonly used in the treatment of partial complex seizures. It has official FDA approval for prevention of migraines, off label use for neuropathic pain (e.g. burning sensations in feet), and drug withdrawal. It has recently been FDA approved for weight loss. It is now off patent.
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Carbamázepine (Tégretol)
Carbatrol and Tegretol XL are long acting forms of carbamazepine. 5 Carbamazepine (Tegretol) is used primarily in the treatment of grand mal and complex seizures. It has also shown efficacy in the treatment of neuralgia and bipolar disorder.
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Adverse Effects of Carbamazepine include:
1. sedation, ataxia, vertigo (common) 2. agranulocytosis (absence of a class of white blood cells called granulocytes); 3. aplastic anemia (absence of both red and white blood cells) (very rare but potentially life threatening) – blood counts commonly administered for first year 4. birth defects (Category C) 5. Rare instances of severe rash (Steven Johnson syndrome)
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Phenobarbital
works as an anti-seizure medication by increasing sensitivity of GABA receptors. Sedation may be a problem. It is effective against all forms except absence seizures. It’s use is decreasing.
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Adverse Effects of phenobarbital:
1. sedation, lethargy, and ataxia (some children have idiosyncratic hyperactivity) 2. anorexia 3. CNS depression if taken in large doses 4. induction of liver enzymes results in inactivation of other drugs including oral contraceptives and oral anticoagulants 5. probably teratogenic
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Valpróic Acid (Depakene)
Divalproex (Depakote) is an enteric coated form of Depakene. Depakote XL is an enteric coated extended release form Valpróic acid is believed to stimulate GABA receptors; it may also inhibit sodium channel depolarization and T-type Ca channel depolarization and hence Cl-1 entry into the axon. It is the only drug effective against all types of seizures. Many patients have fewer side effects than with Dilantin. The most common problem of valproic acid, nausea, has been greatly reduced by the use of an enteric-coated extended release form of the drug (Depakote). Unfortunately Depakote is under patent and considerably more expensive than Depakene. It is also available IV as Depacon.
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Adverse Effects of Valpróic Acid (Depakene)
1. nausea, vomiting, and indigestion are common (16% of patients) – reduced by using enteric coated Depakote weight gain 2. weight gain 3. bleeding 4. hepatotoxicity (1 in 30,000 total) especially in babies 5. teratogenicity (spina bifida) 6. increased risk of pancreatitis 7. bone marrow suppression
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Lamotrigine (Lamictal)
Used primarily in treatment of partial seizures and tonic-clonic seizures. It is also being used for the depressive stages of bipolar disorder. Adverse effects include ataxia, headache, nausea, and rash, rarely a life-threatening rash called Stevens-Johnson syndrome. It is seeing increased use in recent years.
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Levetiracetam(Keppra)
is seeing increased use as an adjunct drug in the treatment of partial and tonic-clonic seizures.
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BENZODIAZEPINES FOR SEIZURES
The benzodiazepines stop the current seizure, but do not prevent return of seizure once the benzodiazepine is metabolized. Both diazepam (Valium) and clonazepam (Klonopin) work by enhancing GABA receptor sensitivity.
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Lorazepam (Ativan) Diazepam (Valium)
are both commonly used for stopping status epilepticus. They are given IV or as a rectal suppository (in children).
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Clonazepam (Klonopin)
Clonazepam (Klonopin) is commonly used in treatment of absence seizures.
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Gabapentin (Neurontin
Gabapentin (Neurontin) acts to inhibit calcium channels in the brain neurons, thus reducing activity. It is approved for use as adjunct therapy in partial and secondarily generalized seizures, to be added when older drugs are not giving satisfactory control. It is also FDA approved for reducing postherpetic pain(shingles). It has a larger therapeutic index than most other anti-seizure medications (phenytóin 3, Tegretol 8, valproate 1.7), and the least number of adverse effects. Extensive (and illegal) promotion has resulted in 80% of prescriptions being for unlabelled uses such as mood swings in bipolar disorder, neuralgic pain (diabetic neuralgic pain, shingles), nystagmus, Parkinson’s disease, and schizophrenia. Pfizer paid a $450 million dollar settlement for illegal advertising of off-label used of Neurontin. Adverse effects are relatively mild, as anti-seizure medications go. They include sedation and ataxia.
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Pregabalin(Lyrica)
Pregabalin(Lyrica) is a newer version of gabapentin which is FDA approved for partial seizures as well as treating neurological pain associated with diabetes and shingles. Expensive! It has also been approved for treating fibromyalgia.
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ALTERNATIVE TREATMENTS
1) Extreme ketogenic diets (high fat, low carb like the Atkin’s diet) reduce seizures for some people (usually children) who are unresponsive to the various antiseizure medications. This very high fat diet can cause substantial elevation in blood cholesterol with potential acceleration of atherosclerosis. 2) Vagus nerve stimulation (e.g. 30 seconds every 5 minutes with a small device under the skin) reduces frequency and severity of complex seizures in some patients. A small magnet placed over the device can manually activate the device when a seizure starts.
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