Epilepsy

Parkinsonism

Neurological Diseases

Epilepsy

Seizures that occur on a chronic, recurrent basis

Thought to be caused by damage to the network of cortical neurons that have become capable of sustaining an excessive discharge pattern for several seconds

The results of this excessive discharge pattern is a seizure

Question

If the damage to the cortical neurons is permanent, why don’t seizures occur all the time?

Answer

There is an interplay between environmental and internal brain factors

The normal neuronal control mechanisms that contain and control abnormal neuronal firing are overcome

Sometimes fatigue and sleep loss can trigger a seizure

Normally impossible to determine what sets off seizures in most patients with epilepsy

Non-Epilepsy Seizures

Isolated seizures caused by a number of potentially reversible problems CNS trauma, infection, or stroke

Blunt force trauma to the brain, concussions, damage to parts of brain, patients who had strokes

Hyponatremia and hypoglycemia Hypoxia Alcohol withdrawal Fever (mainly in children)

If underlying causes of seizures are not corrected, may lead to the development of recurrent seizures or epilepsy

Etiology

The cause of 80% of the seizures in patients with epilepsy are unknown

The most common causes of epilepsy include head trauma and stroke

CNS tumors and infections are also common causes

Epidemiology

2 million in US are afflicted Incidence is between 35-75 cases/100,000

persons About 8% of population will experience a

seizure during their lifetime New onset seizures occurs most frequently

in infants <1 month of age and in adults >55 years old More chances in very young and very old

Classification of Seizures

Partial seizures Simple partial seizures Complex partial seizures Secondary generalized

Generalized seizures

Simple Partial Seizures

Caused by a group of hyperactive neurons confined to a single locus in brain

Patient experiences abnormal sensations or uncontrolled muscle movements in a portion of their body

Patient does not lose consciousness

Complex Partial Seizures

Also caused by a group of hyperactive neurons confined to a single locus in brain

Patient may experience sensory hallucinations and mental distortions

Abnormal muscle movements may include chewing movements and loss of bowel or urine control

Patient may lose consciousness

Secondary Generalized

Generalized seizures that begin as simple or complex partial seizure and spread to involve the entire brain

Many patients complain of a “aura” Aura may be the beginning of the seizure

Generalized Seizures

Entire cortex is involved from the onset of the seizure Tonic-clonic seizures Absence seizures Myoclonic seizures Atonic seizures

Tonic-Clonic Seizures

Sudden loss of consciousness accompanied by tonic extension and rhythmic clonic contractions of all major muscle groups.

The duration of the seizure is usually 1 to 3 minutes.

This type of seizures are often called grand mal

Absence Seizures

Sudden and brief loss of consciousness without muscle movements.

These seizures are often described as daydreaming or blanking out episodes

Seizures often called petit mal

Myoclonic Seizures

Single and very brief jerks of all major muscle groups lasting 3-4 seconds

Patients with these may not lose consciousness

Patients describe seizures as shoulder shrugs or spinal chills.

May cluster and build into a generalized tonic-clonic seizures.

Atonic Seizures

The patient loses consciousness and muscle tone.

No muscle movements are typically noted

Patient falls if not sitting or lying down Often described as “falling out”

Overview of Treatment

Selecting appropriate therapy is dependent upon identifying and understanding the different seizure types

Selecting appropriate therapy is dependent mechanism of action, effectiveness, adverse effects, and potential for drug interactions

Doses must be individualized using titration to minimize adverse effects and maximize therapeutic benefits

Selecting appropriate therapy is based upon some knowledge, experience, luck and “black magic”

In many cases, no logical approach “black magic?” – wagner calls it this because in some cases there is

no logical approach to tx or seizures

Mechanisms of Action Glutamate is the major excitatory neurotransmitter in

the cerebral cortex Glutamate is released from presynaptic neurons and

attaches to cetain receptor sites on postsynaptic neurons.

This results in a opening of membrane channels allowing calcium or sodium to flow into the postsynaptic neurons thus depolarizing it and transmitting an excitatory signal

Phenytoin, carbamazepine, and lamotrigine interfere with this mechanism (interfere w/stimulatory mech)

Mechanisms of Action

GABA is the major inhibitory neurotransmitter in the cerebral cortex

GABA attaches to neuronal membranes and opens chloride channels

When chloride flows into the neuron, it becomes less excitable.

Mechanism causes seizure activity to be “shut off” by controlling excessive neuronal firing.

Benzodiazepines work by enhancing action of GABA

Approach to Treatment

Type of seizures must be determined Determine if there is an underlying cause Risk of subsequent should be determined If it is determined that the patient has “real”

seizures and if there is a risk of subsequent seizures, drugs are given

Approach to Treatment

In the design of pharmacological plan, the patient Must be willing to take the medication Must be willing to monitor seizure

frequency Most be willing to monitor adverse

reactions

Selection of Treatment

Proper identification of seizure type is helpful in selecting appropriate therapy

Adverse reaction patterns and economic factors should be considered

Follow consensus recommendations for treatment by American Academy of Neurology

Effectiveness of Treatment

50% of patients with epilepsy can be completely controlled

Of the remaining 50% 25% have meaningful improvement with

treatment 25% of patients do not respond well

Generic Name Brand Name

Dose related Side Effects Idiosyncratic Side Effects

Divalproex sodium Depakote Drowsiness, nausea, tremor Hepatotoxicity

Lamotrigine Lamaictal Drowsiness, headache Rash

Levetiracetam Keppra Drowsiness, dizziness Depression

Phenytoin Dilantin Drowsiness, diplopia, ataxia Rash, others

Topiramate Topamax Drowsiness, ataxia, dizziness acute myopia and glaucoma

Carbamazepine Tegretol Drowsiness, nausea, diplopia Aplastic anemia

Oxycarbazepine Trileptal Drowsiness, diplopia Hyponatremia

Gabapentin Neurontin Drowsiness Edema

Pregabalin Lyrica Drowsiness, ataxia, diplopia Edema

General Consultation Take medication with a glass of water. Follow the directions on the prescription label. Take your doses at

regular intervals about the same time every day Do not take your medicine more often than directed. If you miss a dose, take it as soon as you can. If it is almost time for

your next dose, take only that dose. Do not take double or extra doses.

Visit your doctor or health care professional for a regular check on your progress.

Do not change brands or dosage forms of this medicine without discussing the change with your doctor

If you are taking this medicine for epilepsy do not stop taking it suddenly

Consultation

You should keep a record at home of how you feel and how your condition is responding to treatment

You should share this information with your doctor or health care professional at each visit.

You should contact your doctor or health care professional if your seizures get worse or if you have any new types of seizures

Many Problems

Many, many adverse effects Adverse frequently cause drug to be

discontinued Dose related Idiosyncratic

Many drug interactions

Generic Name Brand Name

Dose related Side Effects Idiosyncratic Side Effects

Divalproex sodium Depakote Drowsiness, nausea, tremor Hepatotoxicity

Lamotrigine Lamictal Drowsiness, headache Rash

Levetiracetam Keppra Drowsiness, dizziness Depression

Phenytoin Dilantin Drowsiness, diplopia, ataxia Rash, others

Topiramate Topamax Drowsiness, ataxia, dizziness acute myopia and glaucoma

Carbamazepine Tegretol Drowsiness, nausea, diplopia Aplastic anemia

Oxcarbazepine Trileptal Drowsiness, diplopia Hyponatremia

Gabapentin Neurontin Drowsiness Edema

Pregabalin Lyrica Drowsiness, ataxia, diplopia Edema

Idiosyncratic Side Effects

Rash including Stevens-Johnson Syndrome

Hepatotoxicity Bone marrow toxicity These side effects are potentially life-

threatening

Drugs Associated with most Idiosyncratic Reactions

Carbamezepine Phenytoin Valproate Lamotrigine

Parkinson’s Disease (PD)

Overview

Patients display motor and non-motor symptoms

The most useful diagnostic tool is the clinical history

Therapy is begun when the disease affects quality of life

Disease is progressive Late stages of the disease may be associated

with dementia

Epidemiology

Affects 1 million Americans Average age of onset is >60 years old Genetics may play a role in that 15%

of patients with PD have a first-degree relative with the disease

Etiology

Cause is unknown Deterioration and eventual death of nerve cells in the substantia nigra Neurotransmitters needed for normal fx

are reduced

Motor Symptoms – “TRAP”

T = Tremor at rest ("pill rolling") R = Rigidity A = Akinesia or bradykinesia P = Postural instability and gate

abnormalities

Non-Motor Symptoms – “SOAP”

S = Sleep disturbances insomnia, rapid eye movement sleep behavioral disorder, restless legs syndrome

0 = Other miscellaneous symptoms nausea

fatigue, speech, pain, dysesthesias, vision, seborrhea A = Autonomic symptoms drooling, constipation, sexual

dysfunction, urinary problems, sweating, orthostatic

hypotension, dysphagia P = Psychological symptoms anxiety, psychosis, cognitive

impairment, depression Psychological impairment Cognitive impairment, depression,

dimensia

Response Fluctuations - MAD

M= Motor fluctuations A = Akathisia D = Dyskinesias

Approach to Treatment Three phases

Lifestyle changes, nutrition, exercise Helps in early stages

Pharmacological treatment with drugs that enhance dopamine concentrations Want to decrease progression of disease, but majority of the

time it’s not possible

Surgical treatment take pt, do NOT anesthetize open up patient’s skull(do

use SOME anesthetic) expose the brain(brain has no pain receptors)

Take electrodes and put on parts of brain that theoretically is controlling abnormal movements Apply electrical stimulation to those areas, if you hit electrical impulses,

everything stops

Classification of Drugs

2 types of drugs for tx:1. Drugs which increase dopamine

concentration or activity

2. Drugs which block acetylcholine1. Theoretically better, but in reality are A LOT

less effective, used as an adjunct (NOT as primary tx)

Levodopa DOPA is metabolic precursor to dopamine Restores dopamine levels in substantia

nigra Levodopa must be converted to dopamine in dopamanergic neurons

As disease progresses(more dopramanergic neurons are destroyed in brain) response to L-Dopa declines less dopamanergic neurons are present to convert DOPA to dopamine

Results of Treatment with L-DOPA

Must use high doses Causes significant nausea and vomiting Causes significant orthostatic hypotension (especially in

elderly)– most of time elderly has it)

With chronic treatment, patients often complain that drug effects wears off resulting in development of motor fluctuation

Relief provided by levodopa is only symptomatic and temporary Does not halt progression of disease

Carbidopa

Carbidopa is a dopa decarboxylase inhibitor Decreases metabolism of levodopa in GI tract

and peripheral tissues Used in combination with levodopa (Sinemet

combo of L-dopa and carbidopa) Can use a lot less L-dopa

Increases available of levodopa in CNS May decrease dose of levodopa five-fold and

thus decrease incidence of side effects

Consultation Take orally with water at least 30 minutes before

eating or 1 hour after meals to maximize absorption May be taken with a small non-protein snack, such as fruit

or a cracker, to avoid nausea. Administering with food may decrease absorption.

***Causes orthostatic hypotension **Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells Good advice for any pt that causes orthostatic

hypotension

Consultation

Visit your doctor or health care professional for regular checks on your progress.

It may be several months before you feel the full benefits of this medicine.

Continue to take your medicine on a regular schedule You may experience a wearing of effect of this medication You may also experience an on-off effect where the medicine

apparently stops working Tell your doctor or health care professional if any of these

symptoms happen to you. Your dose may need to be changed.

Psychiatric disturbances

Psychiatric disturbances can occur including agitation, anxiety, confusion, dizziness, headache, euphoria, insomnia, memory loss, nightmares, toxic delirium, hallucinations, paranoid delusion, psychosis, and hypomania and depression

Sinemet’s psychiatric effects tend to be progressive and frequently a compromise must be reached between psychiatric effects and control of parkinson symptoms.

Dopamine Agonists

Pramipexole Mirapex Ropinirole Requip Directly stimulate dopamine receptor

sites in brain Actions similar to levodopa Severe side effects limit usefulness

Consultation

Take this medicine with a glass of water. Take it with or without food but if it upsets

your stomach, take it with food. Do not stop taking this medicine except on

your doctor's advice. Do not stand or sit up quickly, especially if

you are an older patient. This reduces the risk of dizzy or fainting spells. (orthostatic hypotension)

Antimuscarinic Drugs

Much less effective that other drugs Used as an adjunct to

levodopa/carbidopa Adverse effects similar to high doses

of atropine Benztropine Cogentin

(on top 200)

Consultation

May be administered without regard to meals Your mouth may get dry. Chewing sugarless gum or sucking

hard candy, and drinking plenty of water may help This medicine may cause dry eyes and blurred vision. If you

wear contact lenses you may feel some discomfort. Lubricating drops may help.

You may sweat less than usual while you are taking this medicine. As a result your body temperature could rise to a dangerous level.

Be careful not to get overheated during exercise or in hot weather. You could get heat stroke.

Avoid taking hot baths and using hot tubs and saunas.