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The EEG is sometimes of value in localizing pathologic processes. When a collection of fluid overlies a portion of the cortex, activity over this area may be damped. This fact may aid in diagnosing and localizing conditions such as subdural hematomas. Lesions in the cerebral cortex cause local formation of transient disturbances in brain activity, marked by high-voltage abnormal waves that can be recorded with an EEG. Seizure activity can occur because of increased firing of neurons that are excitatory (eg, release of glutamate) or decreased firing of neurons that are inhibitory (eg, release GABA).
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CLINICAL BOX 14–2 Sleep Disorders
Narcolepsy is a chronic neurologic disorder caused by the brain’s inability to regulate sleep–wake cycles normally. The affected individual experiences a sudden loss of voluntary muscle tone (cataplexy), an eventual irresistible urge to sleep during daytime, and possibly brief episodes of total paralysis at the beginning or end of sleep. Narcolepsy is also characterized by a sudden onset of REM sleep, unlike normal sleep that begins with NREM, slow-wave sleep. The prevalence of narcolepsy ranges from 1 in 600 in Japan to 1 in 500,000 in Israel, with 1 in 1000 Americans being affected. Narcolepsy has a familial incidence strongly associated with a class II antigen of the major histocompatibility complex on chromosome 6 at the HLA-DR2 or HLA-DQW1 locus, implying a genetic susceptibility to narcolepsy. The HLA complexes are interrelated genes that regulate the immune system (see Chapter 3). Compared to brains from healthy persons, the brains of persons with narcolepsy often contain fewer hypocretin (orexin)-producing neurons in the hypothalamus. It is thought that the HLA complex may increase susceptibility to an immune attack on these neurons, leading to their degeneration.
Obstructive sleep apnea (OSA) is the most common cause of daytime sleepiness due to fragmented sleep at night and affects about 24% of middle-aged men and 9% of women in the United States. Breathing ceases for more than 10 s during frequent episodes of obstruction of the upper airway (especially the pharynx) due to reduction in muscle tone. The apnea causes brief arousals from sleep in order to reestablish upper airway tone. An individual with OSA typically begins to snore soon after falling asleep. The snoring gets progressively louder until it is interrupted by an episode of apnea, which is then followed by a loud snort and gasp as the individual tries to breathe. OSA is not associated with a reduction in total sleep time, but individuals with OSA experience a much greater time in stage 1 NREM sleep (from an average of 10% of total sleep to 30–50%) and a marked reduction in slow-wave sleep (stages 3 and 4 NREM sleep). The pathophysiology of OSA includes both a reduction in neuromuscular tone at the onset of sleep and a change in the central respiratory drive.
Periodic limb movement disorder (PLMD) is a stereotypical rhythmic extension of the big toe and dorsiflexion of the ankle and knee during sleep lasting for about 0.5–10 s and recurring at intervals of 20–90 s. Movements can actually range from shallow, continual movement of the ankle or toes, to wild and strenuous kicking and flailing of the legs and arms. Electromyograph (EMG) recordings show bursts of activity during the first hours of NREM sleep associated with brief EEG signs of arousal. The duration of stage 1 NREM sleep may be increased and that of stages 3 and 4 may be decreased compared to age-matched controls. PLMD is reported to occur in 5% of individuals between the ages of 30 and 50 years and increases to 44% of those over the age of 65. PLMD is similar to restless leg syndrome or Willis-Ekbom disease in which individuals have an irresistible urge to move their legs while at rest all day long.
Sleepwalking (somnambulism), bed-wetting (nocturnal enuresis), and night terrors are referred to as parasomnias, which are sleep disorders associated with arousal from NREM and REM sleep. Episodes of sleepwalking are more common in children than in adults and occur predominantly in males. They may last several minutes. Somnambulists walk with their eyes open and avoid obstacles, but when awakened they cannot recall the episodes.
THERAPEUTIC HIGHLIGHTS Excessive daytime sleepiness in patients with narcolepsy can be treated with amphetamine-like stimulants, including modafinil, methylphenidate (Ritalin), and methamphetamine. Gamma hydroxybutyrate (GHB) is used to reduce the frequency of cataplexy attacks and the incidences of daytime sleepiness. Cataplexy is often treated with antidepressants such as imipramine and desipramine, but these drugs are not officially approved by the US Federal Drug Administration for such use. The most common treatment for OSA is continuous positive airflow pressure (CPAP), a machine that increases airway pressure to prevent airway collapse. Drugs have generally proven to have little or no benefit in treating OSA. Dopamine agonists, which are used to treat Parkinson disease, also can be used to treat PLMD and Willis–Ekbom disease.
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Epilepsy is a condition in which there are recurring, unprovoked seizures that may result from damage to the brain. The seizures represent abnormal, highly synchronous neuronal activity. Epilepsy is a syndrome with multiple causes. In some forms, characteristic EEG patterns occur during seizures or between attacks; however, abnormalities are often difficult to demonstrate. Seizures are divided into partial (focal) seizures and generalized seizures.
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Partial seizures originate in a small group of neurons and can result from head injury, brain infection, stroke, or tumor, but often the cause is unknown. Symptoms depend on the seizure focus. They are further subdivided into simple partial seizures (without loss of consciousness) and complex partial seizures (with altered consciousness). An example of a simple partial seizure is localized jerking movements in one hand progressing to clonic movements of the entire arm lasting about 60–90 s. Auras typically precede the onset of a partial seizure and include abnormal sensations. The time after the seizure until normal neurologic function returns is called the postictal period.
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Generalized seizures are associated with widespread electrical activity and involve both hemispheres simultaneously. They are further subdivided into convulsive and nonconvulsive categories depending on whether tonic or clonic movements occur. Absence seizures (formerly called petit mal seizures) are one of the forms of nonconvulsive generalized seizures characterized by a momentary loss of consciousness. They are associated with 3/s doublets, each consisting of a typical spike-and-wave pattern of activity that lasts for about 10 s (Figure 14–9). They are not accompanied by auras or postictal periods. These spike and waves are likely generated by low threshold T-type Ca2+ channels in thalamic neurons.
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The most common convulsive generalized seizure is tonic-clonic seizure (formerly called grand mal seizure). This is associated with sudden onset of contraction of limb muscles (tonic phase) lasting about 30 s, followed by a clonic phase with symmetric jerking of the limbs as a result of alternating contraction and relaxation (clonic phase) lasting 1–2 min. There is fast EEG activity during the tonic phase. Slow waves, each preceded by a spike, occur at the time of each clonic jerk. For a while after the attack, slow waves are present.
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Recent research provides insight into a possible role of release of glutamate from astrocytes in the pathophysiology of epilepsy. Also, there is evidence to support the view that reorganization of astrocytes along with dendritic sprouting and new synapse formation form the structural basis for recurrent excitation in the epileptic brain. Clinical Box 14–3 describes information regarding the role of genetic mutations in some forms of epilepsy.
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TREATMENT OF SEIZURES
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Only about two-thirds of those suffering from seizure activity respond to drug therapies. Some respond to surgical interventions (eg, those with temporal lobe seizures), whereas others respond to vagal nerve stimulation (eg, those with partial seizures). Prior to the 1990s, the most common drugs used to treat seizures (anticonvulsants) included phenytoin, valproate, and barbiturates. Newer drugs have become available but, as is the case with the older drugs, they are palliative rather than curative. Clinical Box 14–3 describes mechanisms of actions of some drugs used to treat seizures.
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CLINICAL BOX 14–3 Genetic Mutations & Epilepsy
Epilepsy has no geographic, racial, gender, or social bias. It can occur at any age, but is most often diagnosed in infancy, childhood, adolescence, and old age. It is the second most common neurologic disorder after stroke. According to the World Health Organization, an estimated 50 million people worldwide (8.2 per 1000 individuals) experience epileptic seizures. The prevalence in developing countries (such as Colombia, Ecuador, India, Liberia, Nigeria, Panama, United Republic of Tanzania, and Venezuela) is more than 10 per 1000. Many affected individuals experience unprovoked seizures, for no apparent reason, and without any other neurologic abnormalities. These are called idiopathic epilepsies and are assumed to be genetic in origin. Mutations in voltage-gated potassium, sodium, and chloride channels have been linked to some forms of idiopathic epilepsy. Mutated ion channels can lead to neuronal hyperexcitability via various pathogenic mechanisms. Scientists have recently identified the mutated gene responsible for development of childhood absence epilepsy (CAE). Several patients with CAE were found to have mutations in a subunit gene of the GABA receptor called GABRB3. Also, SCN1A and SCN1B mutations have been identified in an inherited form of epilepsy called generalized epilepsy with febrile seizures. SCN1A and SCN1B are sodium channel subunit genes that are widely expressed within the nervous system. SCN1A mutations are suspected in several other forms of epilepsy.
THERAPEUTIC HIGHLIGHTS There are three broad mechanisms of action of new and old anticonvulsant drugs: enhancing inhibitory neurotransmission (increase GABA release), reducing excitatory neurotransmission (decrease glutamate release), or altering ionic conductance. Gabapentin is a GABA analog that acts by decreasing Ca2+ entry into cells and reducing glutamate release; it is used to treat generalized seizures. Topiramate blocks voltage-gated Na+ channels associated with glutamate receptors and potentiates the inhibitory effect of GABA; it is also used to treat generalized seizures. Ethosuximide reduces the low threshold T-type Ca2+ currents in thalamic neurons, and thus is particularly effective in treatment of absence seizures. Valproate and phenytoin block high frequency firing of neurons by acting on voltage-gated Na+ channels to reduce glutamate release.