Page 423 - Basic _ Clinical Pharmacology ( PDFDrive )

24
A
P
H
R
C
T
E
Antiseizure Drugs

Roger J. Porter, MD, &
Michael A. Rogawski, MD, PhD

C ASE STUD Y

A 23-year-old woman presents to the office for consultation was unchanged, and levetiracetam was gradually increased to
regarding her antiseizure medications. Seven years ago, this 1000 mg bid. The patient had no significant adverse effects
otherwise healthy young woman had a tonic-clonic seizure from this dosage. At age 21, she had a second tonic-clonic
at home. She was rushed to the emergency department, at seizure while in college; further discussion with her room-
which time she was alert but complained of headache. A mate at that time revealed a history of two recent episodes of
consulting neurologist placed her on levetiracetam, 500 mg 1–2 minutes of altered consciousness with lip smacking (focal
bid. Four days later, electroencephalography (EEG) showed impaired awareness seizure, formerly complex partial seizure).
rare right temporal sharp waves. Magnetic resonance imaging A repeat EEG showed occasional right temporal spikes. What
(MRI) was normal. One year after this episode, a repeat EEG is one possible strategy for controlling her present symptoms?

Epilepsy is a chronic disorder of brain function characterized by the The antiseizure drugs described in this chapter are usually used
recurrent and unpredictable occurrence of seizures. Approximately chronically to prevent the occurrence of seizures in people with
1% of the world’s population has epilepsy, which is the fourth most epilepsy. These drugs are also, on occasion, used in people who do
common neurologic disorder after migraine, stroke, and Alzheim- not have epilepsy—to prevent seizures that may occur as part of
er’s disease. Seizures that occur in people with epilepsy are transi- an acute illness such as meningitis or in the early period following
tory alterations in behavior, sensation, or consciousness caused by either neurosurgery or traumatic brain injury. In addition, certain
an abnormal, synchronized electrical discharge in the brain. Many antiseizure drugs are used to terminate ongoing seizures such as in
cases of epilepsy are the result of damage to the brain, as occurs status epilepticus or prolonged febrile seizures or following expo-
in traumatic brain injury, stroke, or infections, whereas in other sure to seizure-inducing nerve toxins. Seizures are occasionally
cases, the epilepsy is caused by a brain tumor or developmental caused by an acute underlying toxic or metabolic disorder, such
lesion such as a cortical or vascular malformation; these epilepsies as hypocalcemia, in which case appropriate therapy should be
are referred to as “symptomatic.” In other cases, genetic factors are directed toward correcting the specific abnormality.
believed to be the root cause. Genetic epilepsies are often called
idiopathic. In most cases, the inheritance is complex (polygenic).
Rarely, a single gene defect can be identified. A wide diversity of DRUG DEVELOPMENT FOR EPILEPSY
genes may be affected, including (1) those encoding voltage-gated
receptors, Most antiseizure drugs have been identified by tests in rodent (rat
ion channels and synaptic receptors such as GABA A
(2) components of the neurotransmitter release machinery includ- or mouse) models. The maximal electroshock (MES) test, in
ing syntaxin binding protein (STXBP1), (3) neural adhesion which animals receive an electrical stimulus, with tonic hindlimb
molecules such as PCDH19, and (4) proteins involved in synapse extension as the end point, has been the most productive model.
development such as leucine-rich glioma inactivated-1 (LGI1). The MES test led to the identification of many of the sodium

409