Neurology_Adams

Neurology_Adams. The postictal state in patients with temporal lobe epilepsy rarely incorporates a protracted paranoid-delusional or amnesic psychosis lasting for days or weeks. The EEG during this period may show no seizure discharge, although this does not exclude repeated seizures in temporal lobe structures that are remote from the recording electrodes. This disorder, virtually indistinguishable from psychosis, may also present in the interictal period.


Neurology_Adams

Neurology_Adams. It had been observed that some patients with temporal lobe seizures may exhibit a number of personal peculiarities. It was stated that they are slow and rigid in their thinking, verbose, circumstantial and tedious in conversation, inclined to mysticism, and preoccupied with rather naive religious and philosophical ideas. Obsessionalism, humorless sobriety, emotionality (mood swings, sadness, and anger), and a tendency to paranoia are other frequently described traits. Diminished sexual interest and potency in men and menstrual problems in women, not readily attributable to antiepileptic drugs, are common among patients with complex partial seizures of temporal lobe origin. Geschwind proposed that a triad of behavioral abnormalities—hyposexuality, hypergraphia, and hyperreligiosity—constitutes a characteristic syndrome but this has been disputed.


Neurology_Adams

Neurology_Adams. Bear and Fedio suggested that certain personality traits were more common with right temporal lesions, and that anger, paranoia, and cosmologic or religious conceptualizing are more characteristic of left temporal lesions. However, Rodin and Schmaltz found no features that would distinguish foci on either side and they found no behavioral changes that would distinguish patients with temporal lobe epilepsy from other groups of epileptics. The problem of personality disturbances in epilepsy has not been clarified and many modern clinicians no longer identify these traits as parts of the epileptic syndrome, having in the past been imputed to these patients by societal and medical biases (see review by Trimble) but even this is open to other interpretation.


Neurology_Adams

Neurology_Adams. In the past few decades, sudden death has been emphasized as an underappreciated problem in the epileptic population. Certainly, the mortality in individuals with epilepsy is increased ostensibly from accidents, suicide, and the underlying cause of seizures. However, the main contributor to the increased mortality rate in otherwise healthy people with epilepsy is unexpected death outside of circumstances such as drowning, trauma from a fall, myocardial infarction, and automobile accidents during the seizure. It is to this group that the acronym “SUDEP,” or sudden unexplained death in epilepsy, has been applied. Surprisingly, unexpected death is predominantly an issue of adulthood more than of childhood. The rate of unexpected death increases with the duration and severity of epilepsy and several population studies suggest that the rate may be as high as several-fold higher than in age matched individuals in the general population. The rate of this entity is generally given as


Neurology_Adams

Neurology_Adams. and several population studies suggest that the rate may be as high as several-fold higher than in age matched individuals in the general population. The rate of this entity is generally given as approximately 0.35 cases per 1,000 person years but with severe epilepsy, and as high as 3 to 9 per 1,000 person years, as summarized by Leestma and colleagues. Most patients affected have a history of generalized tonic-clonic seizures and die in bed. In children, those with treatment resistant epilepsy, developmental delay and several syndromes such as tuberous sclerosis are at particular risk.


Neurology_Adams

Neurology_Adams. Several factors have emerged as risks from population-based and cohort case controlled studies; the postictal period immediately after a tonic clonic seizure, increasing seizure frequency (including three generalized seizures in the preceding year), lack of successful treatment (i.e., patients not in remission as documented in a 40-year follow-up of childhood epilepsy by Sillanpää and Shinnar), or subtherapeutic levels of antiepileptic drugs, the period of early adulthood, long-standing epilepsy, and mental retardation.


Neurology_Adams

Neurology_Adams. Most instances of SUDEP occur when the patient is unattended or during sleep. Although respiratory difficulty and cardiac changes including asystole and ventricular arrhythmias are known to occur during and immediately after seizures, none of these has been a consistent factor and usually, the precise mechanism of death has been difficult to determine. A postictal “shutdown” of brainstem activity resulting in hypercapnia or hypoxemia has been suggested but there may be various causes operative in different cases. One approach to preventing sudden death is adequate treatment with antiepileptic drugs. The risk of sudden death is as high as 20 times greater for untreated patients. Some specialists in the field of epilepsy have suggested that an open conversation be undertaken about the problem with patients and their families. More often, neurologists raise the issue only in high risk patients or when specifically asked. A review of this subject has been provided by Devinsky.


Neurology_Adams

Neurology_Adams. There remain to be considered several epileptic syndromes and other seizure states that cannot be readily classified with the usual types of generalized or partial seizures. Many of these, particularly the first four entities discussed below, have been found to have a genetic basis, typically involving an ion channel disorder. Benign Epilepsy of Childhood With Centrotemporal Spikes (Rolandic Epilepsy, Sylvian Epilepsy) This common focal motor epilepsy is unique among the focal epilepsies of childhood in that it is self-limiting despite a very abnormal EEG pattern. It is usually transmitted in families as an autosomal dominant trait and begins between 5 and 9 years of age. It typically announces itself by a nocturnal tonic-clonic seizure with focal onset. Thereafter, the seizures take the form of clonic contractions of one side of the face, less often of one arm or leg, and the interictal EEG shows high-voltage spikes in the contralateral lower rolandic or centrotemporal area.


Neurology_Adams

Neurology_Adams. Seizures are readily controlled by a single anticonvulsant drug and gradually disappear during adolescence. The relation of this syndrome to developmental dyslexia is unsettled. Epilepsy with Occipital Spikes (Panayiotopoulos Syndrome)


Neurology_Adams

Neurology_Adams. Epilepsy with Occipital Spikes (Panayiotopoulos Syndrome) A similar type of epilepsy, usually benign in the sense that there is no intellectual deterioration and the seizures often cease in adolescence, has been associated with spike activity over the occipital lobes as identified by Panayiotopoulos. Visual hallucinations, while not invariable, are the most common clinical feature, according to the review by Taylor and colleagues; sensations of movements of the eyes, tinnitus, or vertigo are also reported in cases of occipital epilepsy. These authors point out symptomatic causes of the syndrome, mainly cortical heterotopias. Autonomic overactivity is prominent with the seizures in some children. In both of these types of childhood epilepsy the observation that spikes are greatly accentuated by sleep is a useful diagnostic feature.


Neurology_Adams

Neurology_Adams. This term is applied to a special and particularly dramatic form of epilepsy of infancy and early childhood. West, in the mid-nineteenth century, described the condition in his son in great detail. This disorder, which in most cases appears during the first year of life, is characterized by recurrent, single or brief episodes of gross flexion movements of the trunk and limbs and, less frequently, by extension movements (hence the alternative terms infantile spasms or salaam or jackknife seizures). Most but not all patients with this disorder show major EEG abnormalities consisting of continuous multifocal spikes and slow waves of large amplitude. However, this pattern, named by Gibbs and Gibbs as hypsarrhythmia (“mountainous” dysrhythmia), is not specific for infantile spasms, being frequently associated with other developmental or acquired abnormalities of the brain. As the child matures, the seizures diminish and usually disappear by the fourth to fifth year. If MRI and CT scans are


Neurology_Adams

Neurology_Adams. associated with other developmental or acquired abnormalities of the brain. As the child matures, the seizures diminish and usually disappear by the fourth to fifth year. If MRI and CT scans are more or less normal, the usual pathologic findings according to Jellinger are cortical dysgeneses. Both the seizures and the EEG abnormalities may respond dramatically to treatment with adrenocorticotropic hormone (ACTH), corticosteroids, or the benzodiazepine drugs, of which clonazepam is probably the most widely used. A type of West syndrome that is caused by tuberous sclerosis also responds dramatically to gamma-aminobutyric acid (GABA)-inhibiting drugs such as vigabatrin, as noted below. However, most patients, even those who were apparently normal when the seizures appeared, are left mentally impaired. Infantile spasms may later progress to the Lennox-Gastaut syndrome, a seizure disorder of early childhood of graver prognosis as discussed in a previous section.


Neurology_Adams

Neurology_Adams. The well-known uncomplicated febrile seizure, specific to infants and children between 6 months and 5 years of age (peak incidence ages 9 to 20 months) and with a strong inherited tendency, is generally regarded as a benign condition. The frequency has been estimated to be approximately 4 per 1,000 children under the age of 5 but reportedly twice as high in Japanese children. It usually takes the form of a single, generalized motor seizure occurring as the patient’s core temperature rises or reaches its peak. Seldom does the seizure last longer than a few minutes and by the time an EEG can be obtained, there is no abnormality and recovery is complete. The seizures do not recur during the same episode of fever. The temperature is usually above 38°C (100.4°F).


Neurology_Adams

Neurology_Adams. Any viral or bacterial illness, or, rarely, an immunization, may be the precipitant of the fever; herpesvirus 6 is one of the common precipitants, probably because of its tendency to cause high fever. Prophylactic antiepileptic drugs have not been found to be helpful in preventing febrile seizures. Except for a presumed genetic relationship with benign epilepsy of childhood (Luders et al), which in itself is transient in nature, these patients’ risk of developing epilepsy in later life is only slightly greater than that of the general population. In some families, such as those studied by Nabbout and colleagues, febrile seizures alone, without generalized epilepsy, have been associated with a particular gene by linkage analysis. Presumably, when the gene products are identified, some insight into the nature of defects that lower the seizure threshold will be forthcoming.


Neurology_Adams

Neurology_Adams. This benign type of febrile seizure should not be confused with more serious illnesses in which a febrile acute encephalitic or encephalopathic state causes focal or prolonged seizures, generalized or focal EEG abnormalities, and repeated episodes of febrile convulsions during a febrile illness (complex febrile seizures). In these cases, these seizures may recur not only with infections but also at other times. When patients with both types are combined together under the rubric of febrile convulsions, it is not surprising that a high percentage are complicated by later atypical petit mal, atonic, and astatic spells followed by tonic seizures, mental retardation, and partial complex epilepsy. In a study of 67 patients with medial temporal lobe epilepsy by French and colleagues, 70 percent had a history of complex febrile seizures during the first 5 years of life, although many did not again develop seizures until their teens. Bacterial meningitis was an important risk factor; head and


Neurology_Adams

Neurology_Adams. had a history of complex febrile seizures during the first 5 years of life, although many did not again develop seizures until their teens. Bacterial meningitis was an important risk factor; head and birth trauma were less-common factors. Epidemiologic studies have substantiated this clinical point of view. Annegers and colleagues observed a cohort of 687 children for an average of 18 years after their initial febrile convulsion. Overall, these children had a fivefold excess of unprovoked seizures in later life. Among the children with simple febrile convulsions, the risk was only 2.4 percent. By contrast, children with what Annegers and colleagues called complex febrile convulsions (focal, prolonged, or repeated episodes of febrile seizures) had a greatly increased risk—8, 17, or 49 percent, depending on the association of one, two, or three of the complicating features.


Neurology_Adams

Neurology_Adams. It has been appreciated for a long time that seizures can be evoked in certain individuals by a discrete physiologic or psychologic stimulus. The term reflex epilepsy is reserved for this small subgroup. Forster classified these seizures in accordance with their evocative stimuli into five types: (1) visual—flickering light, visual patterns, and specific colors (especially red), leading to rapid blinking or eye closure; (2) auditory—sudden unexpected noise (startle), specific sounds, musical themes, and voices; (3) somatosensory—either a brisk unexpected tap or sudden movement after sitting or lying still, or a prolonged tactile or thermal stimulus to a certain part of the body; (4) writing or reading of words or numbers; and (5) eating.


Neurology_Adams

Neurology_Adams. Visually induced seizures are by far the most common type. The seizures are usually myoclonic but may be generalized and triggered by the photic stimulation of television or an EEG examination or by the photic or pattern stimulation of video games. In other types of reflex epilepsy, the evoked seizure may be focal (beginning often in the part of the body that was stimulated) or generalized and may take the form of one or a series of myoclonic jerks or of an absence or tonic-clonic seizure. Seizures induced by reading, voices, or eating are most often of the complex partial type; seizures induced by music are usually myoclonic, simple, or complex partial. A few such instances of reflex epilepsy have been caused by focal cerebral disease, particularly occipital lesions.


Neurology_Adams

Neurology_Adams. Many of the antiepileptic drugs are effective in controlling individual instances of reflex epilepsy. Some patients learn to avert the seizure by undertaking a mental task, for example, thinking about some distracting subject, counting, or by initiating some type of physical activity. Forster demonstrated that in certain types of reflex epilepsy, the repeated presentation of the stimulus may eventually render the trigger innocuous but this requires a great deal of time and reinforcement, which limits its therapeutic value.


Neurology_Adams

Neurology_Adams. This is a special type of focal motor epilepsy characterized by persistent rhythmic clonic movements of one muscle group—usually of the face, arm, or leg—which are repeated at fairly regular intervals every few seconds and continue for hours, days, weeks, or months without spreading to other parts of the body. Thus epilepsia partialis continua is, in effect, a highly restricted and very persistent focal motor status epilepticus. The distal muscles of the leg and arm, especially the flexors of the hand and fingers, are affected more frequently than the proximal ones. In the face, the recurrent contractions involve either the corner of the mouth or one or both eyelids. Occasionally, isolated muscles of the neck or trunk are affected on one side. The clonic activity may be accentuated by active or passive movement of the involved muscles and may be reduced in severity but not abolished during sleep.


Neurology_Adams

Neurology_Adams. First described by Kozhevnikov in patients with Russian spring-summer encephalitis, these ongoing partial seizures may be induced by a variety of acute or chronic cerebral lesions. In some cases the underlying disease is not apparent, and the clonic movements may be mistaken for some type of slow tremor or extrapyramidal movement disorder. Most patients with epilepsia partialis continua show focal EEG abnormalities, either repetitive slow-wave abnormalities or sharp waves or spikes over the central areas of the contralateral hemisphere. In some cases, the spike activity can be related precisely in location and time to the clonic movements (Thomas et al). In the series collected by Obeso and colleagues, there were various combinations of epilepsia partialis continua and cutaneous reflex myoclonus (cortical myoclonus occurring only in response to a variety of afferent stimuli).


Neurology_Adams

Neurology_Adams. As would be expected, a wide range of causative lesions has been implicated—developmental anomalies, encephalitis, demyelinative diseases, tumors, metabolic abnormalities, particularly hyperosmolarity, and degenerative diseases. Epilepsia partialis continua is particularly common in patients with the rare condition, Rasmussen encephalitis (see further on). Whether cortical or subcortical mechanisms are responsible for epilepsia partialis continua is an unresolved question. The electrophysiologic evidence adduced by Thomas and colleagues favors a cortical origin; the pathologic evidence is less definite. In each of eight cases in which the brain was examined postmortem, they found some degree of involvement of the motor cortex or adjacent cortical area contralateral to the affected limbs. However, all but one of these patients also had some involvement of deeper structures on the same side as the cortical lesion, on the opposite side, or on both sides.


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Neurology_Adams. It is characteristic of the disorder to be resistant to treatment, often leading to the use of several antiepileptic drugs and still finding them to be ineffectual. At times, it is preferable to reduce the medications and their number in favor of producing fewer side effects. These judgments must be made in view of the disruption of daily life. Although exceptional cases may persist for a year or more, most resolve, leaving variable neurologic defects.


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Neurology_Adams. In 1958, Rasmussen described three children in whom the clinical problem consisted of intractable focal epilepsy (the epilepsia partialis continua described above) in association with a progressive hemiparesis. The cerebral cortex disclosed a mild meningeal infiltration of inflammatory cells and an encephalitic process marked by neuronal destruction, gliosis, neuronophagia, some degree of tissue necrosis, and perivascular cuffing. Many additional cases were soon uncovered and Rasmussen was able to summarize the natural history of 48 personally observed patients (see the often cited monograph by Andermann and the more recent review by Bien and colleagues 2005). Adult cases are known and they tend to have a milder and more protracted course as noted by Villani and coworkers. Some have focal cortical myoclonus.


Neurology_Adams

Neurology_Adams. An expanded view of the syndrome has added several interesting features. The affected children are typically ages 3 to 15 years, more girls than boys. Half of them have epilepsia partialis continua. The progression of the disease leads to hemiplegia or other deficits and focal brain atrophy, and even total hemiatrophy, in most cases. The neuropathology of five cases revealed extensive destruction of the cortex and white matter with intense gliosis and lingering inflammatory reactions.


Neurology_Adams

Neurology_Adams. The CSF shows a pleocytosis and sometimes oligoclonal bands but these are not uniform findings. Focal cortical and subcortical lesions are usually visualized by MRI and are bilateral in some cases. The finding of antibodies to glutamate receptors (GluR3) in a proportion of patients with Rasmussen encephalitis has raised interest in an immune causation (see review by Antel and Rasmussen). The autoimmune hypothesis has been supported by the findings of Twyman and colleagues that these antibodies cause seizures in rabbits and lead to the release of the neurotoxin kainate in cell cultures. However, Wendl’s group and others have found these antibodies and many others various types of focal epilepsy and have questioned their specificity.


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Neurology_Adams. The unrelenting course of the disease had in the past defied medical therapy. In some patients the process eventually burns out, but in those with continuous focal epilepsy the seizures continued despite all antiepileptic drugs. The use of high doses of corticosteroids, when started within the first year of the disease, proved beneficial in 5 of the 8 patients treated by Chinchilla and colleagues. Repeated plasma exchanges and immune globulin have also been tried, but the results are difficult to interpret. When the disease is extensive and unilateral, neurosurgeons have resorted to partial hemispherectomy. PSYCHOGENIC NONEPILEPTIC SEIZURES (PNES, PSEUDOSEIZURES)


Neurology_Adams

Neurology_Adams. These common episodes, which simulate convulsive or nonconvulsive seizures, are not the result of a paroxysmal neuronal discharge. They are termed psychogenic nonepileptic seizures (PNES) and comprise a heterogeneous group of disorders that are easily mistaken for epileptic spells. Moreover, they comprise a large proportion of treatment resistant epilepsy and often are treated with multiple antiepileptic drugs, to which they are unresponsive. It has been estimated that 70 percent of people diagnosed with PNES have been previously diagnosed and treated for epilepsy. In large series, nonepileptic seizures comprise 4 percent of cases of transient loss of consciousness, 20 percent of referrals to specialist epilepsy services, and 50 percent of apparent status epilepticus. It should be emphasized that patients with true epileptic seizures can exhibit psychogenic ones as well, making the distinction between the two particularly difficult. It is this population that proves most vexing (and


Neurology_Adams

Neurology_Adams. that patients with true epileptic seizures can exhibit psychogenic ones as well, making the distinction between the two particularly difficult. It is this population that proves most vexing (and common) in specialty epilepsy services.


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Neurology_Adams. Our current conceptualization is that the condition arises as a behavioral response to underlying emotional or psychological distress. Episodes may be derived from traumatic experiences in early life, particularly physical, sexual, and mental abuse during childhood but such is not always the case. Many experts consider them to be allied with hysteria (Briquet disease, conversion disorder, as discussed in Chap. 47) or malingering. Recent studies suggest that a conversion-hysterical disorder accounts for most cases, and that malingering is rare but this is difficult to prove.


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Neurology_Adams. Three broad categories of psychogenic states seem to generate pseudoseizures: (1) panic disorder that is itself common in people with epilepsy; (2) dissociative disorders, in which convulsions are typically prolonged, resembling generalized tonic-clonic seizures, or alternatively, swooning as in a faint or presyncopal spell, or blank spells that closely simulate absence seizure; and (3) malingering, the deliberate feigning of seizures to avoid certain situations, for example, imprisonment.


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Neurology_Adams. Usually, the unconventional motor display in the course of a nonepileptic seizure is sufficient to identify it as such: completely asynchronous thrashing of the limbs and repeated side-to-side movements of the head; striking out at a person who is trying to restrain the patient; hand-biting, kicking, trembling, and quivering; pelvic thrusting and opisthotonic arching postures; and screaming or talking during the ictus. It is helpful to observe that the eyes are kept quietly or forcefully closed in pseudoseizure whereas the lids are open or show clonic movement in epilepsy. Psychogenic spells are likely if attacks are prolonged (many minutes, even hours), if there is rapid breathing (whereas apnea is typical during and after a seizure), or if there is tearfulness after an episode. Psychogenic seizures tend to occur in the presence of observers, to be precipitated by emotional factors. With few exceptions, tongue-biting, incontinence, hurtful falls, or postictal confusion are lacking


Neurology_Adams

Neurology_Adams. seizures tend to occur in the presence of observers, to be precipitated by emotional factors. With few exceptions, tongue-biting, incontinence, hurtful falls, or postictal confusion are lacking but if the tongue is bitten in one of these spells it is usually the front, compared to the lateral tongue injury that is characteristic of an epileptic attack. Incontinence does not assist in making a clear distinction from epileptic seizures.


Neurology_Adams

Neurology_Adams. Another clue to nonepileptic seizures has been highly resistant epilepsy in an individual with normal cognitive function and normal brain imaging. Sometimes there has been a background of unexplained medical problems, previous psychological problems (depression, panic disorder, overdose, self harm, addiction), and a life story that includes intense emotional trauma. Prolonged fugue states usually prove to be manifestations of hysteria or a psychopathy, that is, a dissociative state, even in a known epileptic. The serum creatine kinase levels are normal after nonepileptic seizures; this may be helpful in distinguishing them from epilepsy. Where doubt remains, a recording of the ictal or postictal EEG or prolonged combined video and EEG recording of an attack may settle the issue. The treatment of these patients requires a patient, nonjudgmental and multidisciplinary approach with the goal of reducing disability and hospital admission and eliminating unnecessary medications.


Neurology_Adams

Neurology_Adams. Physiologically, the epileptic seizure has been defined as a sudden alteration of central nervous system (CNS) function resulting from a paroxysmal high-frequency or synchronous low-frequency, high-voltage electrical discharge. This discharge arises from an assemblage of excitable neurons in any part of the cerebral cortex and possibly in secondarily involved subcortical structures as well. In the proper circumstances, a seizure discharge can be initiated in an entirely normal cerebral cortex, as when the cortex is activated by ingestion of drugs, or by withdrawal from alcohol or other sedative drugs. A special mechanism that ostensibly creates a secondary seizure focus, “kindling,” is the result of repeated stimulation with subconvulsive electrical pulses from an established focus elsewhere; it is known to occur in animal models but is a controversial entity in humans.


Neurology_Adams

Neurology_Adams. Viewed from a larger physiologic perspective, seizures require three conditions: (1) a population of pathologically excitable neurons; (2) an increase in excitatory, mainly glutaminergic, activity through recurrent connections in order to spread the discharge; and (3) a reduction in the activity of the normally inhibitory GABAergic projections. Each of these has been challenged but is supported by considerable data and together they serve as a reasonable model, as noted below. Understanding of the initial discharges and their spread has been advanced by the identification of several rare forms of familial epilepsy that are the result of mutations in sodium, potassium, acetylcholine receptor, or GABA channels on neurons. These are discussed further on under “Role of Genetics.”


Neurology_Adams

Neurology_Adams. Just why the neurons in or near a focal cortical lesion discharge spontaneously and synchronously is not fully understood. Some of the electrical properties of a cortical epileptogenic focus suggest that its neurons have been deafferented. Neurons in these circumstances are hyperexcitable, and they may chronically remain in a state of partial depolarization, able to fire irregularly at rates as high as 700 to 1,000 per second. The cytoplasmic membranes of such cells have an increased ionic permeability, which renders them susceptible to activation by hyperthermia, hypoxia, hypoglycemia, hypocalcemia, and hyponatremia, as well as by repeated sensory (e.g., photic) stimulation and during certain phases of sleep (where hypersynchrony of neurons occurs).


Neurology_Adams

Neurology_Adams. As a model of spontaneous discharges, epileptic foci induced in the animal cortex by the application of penicillin are characterized by spontaneous interictal discharges, during which the neurons of the discharging focus exhibit large, calcium-mediated paroxysmal depolarizations (depolarizing shifts), followed by prolonged after-hyperpolarizations. The latter are caused in part by calcium-dependent potassium currents, but enhanced synaptic inhibition also plays a role. The depolarizing shifts occur synchronously in the penicillin focus and summate to produce surface-recorded interictal EEG spikes; the after-polarizations correspond to the slow wave of the EEG spike-and-wave complex (see Engel). The neurons surrounding an experimental epileptogenic focus are hyperpolarized and release inhibitory GABA. The spread of seizures depends on factors that activate neurons in the focus or inhibit those surrounding it. Beyond this, the precise mechanism that governs the transition from a


Neurology_Adams

Neurology_Adams. inhibitory GABA. The spread of seizures depends on factors that activate neurons in the focus or inhibit those surrounding it. Beyond this, the precise mechanism that governs the transition from a circumscribed interictal discharge to a widespread seizure state is not understood.


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Neurology_Adams. Biochemical studies of neurons from a seizure focus have not greatly clarified the problem. Levels of extracellular potassium are elevated in glial scars near epileptic foci, and a defect in voltage-sensitive calcium channels has also been postulated. Epileptic foci are known to be sensitive to acetylcholine and to be slow in binding and removal of the neurotransmitter. A deficiency of the inhibitory neurotransmitter GABA, increased glycine, decreased taurine, and either decreased or increased glutamic acid have been variously reported in excised human epileptogenic tissue, but whether these changes are the cause or result of seizure activity has not been determined. The interpretation of reported abnormalities of GABA, biogenic amines, and acetylcholine in the cerebrospinal fluid (CSF) of epileptic patients poses similarly great difficulties.


Neurology_Adams

Neurology_Adams. Concurrent EEG recordings from an epileptogenic cortical focus and subcortical, thalamic, and brainstem centers in the animal model have enabled investigators to construct a sequence of electrical and clinical events that characterize an evolving focal seizure. Firing of the involved neurons in the cortical focus is reflected in the EEG as a series of periodic spike discharges, which increase progressively in amplitude and frequency. Once the intensity of the seizure discharge exceeds a certain point, it overcomes the inhibitory influence of surrounding neurons and spreads to neighboring cortical regions via short corticocortical synaptic connections.


Neurology_Adams

Neurology_Adams. A provocative finding, based on sophisticated mathematical analysis of EEG tracings, indicates that subtle electrographic changes arise several minutes before the ictal discharge (see LeVan Quyen et al). This suggests that seizures could be triggered either by a change in central thalamic rhythm generators or a subtle alteration in the electrical activity in the region of a focal lesion. Of interest are the findings by Litt and colleagues that in a small number of patients there are prolonged bursts of seizure-like activity detected by sophisticated techniques even days before the onset of temporal lobe seizures. Their proposal is that these events cause a cascade of electrophysiologic changes that very gradually culminate in a seizure.


Neurology_Adams

Neurology_Adams. If unchecked, cortical excitation spreads to the adjacent cortex and to the contralateral cortex via interhemispheric pathways, and also to anatomically and functionally related pathways in subcortical nuclei (basal ganglionic, thalamic, and brainstem reticular nuclei). It is at this time that the clinical manifestations of the seizure begin. The excitatory activity from the subcortical nuclei is conceived to feed back to the original focus and to other parts of the cerebrum, a mechanism that serves to amplify their excitatory activity and to give rise to the characteristic high-voltage polyspike discharge in the EEG. The spread of excitation to the subcortical, thalamic, and brainstem centers corresponds to the tonic phase of the seizure and to loss of consciousness as well as to the signs of autonomic nervous system overactivity (mydriasis, tachycardia, hypertension) and to arrest or respiration. The development of unconsciousness and the generalized tonic contraction of muscles are


Neurology_Adams

Neurology_Adams. of autonomic nervous system overactivity (mydriasis, tachycardia, hypertension) and to arrest or respiration. The development of unconsciousness and the generalized tonic contraction of muscles are reflected in the EEG by a diffuse high-voltage discharge pattern appearing simultaneously over the entire cortex. There is little evidence to support the conjecture made by Penfield that seizure activity originates in the thalamus; thus his term centrencephalic seizure is no longer used.


Neurology_Adams

Neurology_Adams. Soon after the spread of excitation, a diencephalic inhibition begins and intermittently interrupts the seizure discharge, changing it from the persistent tonic phase to the intermittent bursts of the clonic phase. In the surface EEG, a transition occurs from a continuous polyspike to a spike-and-wave pattern. The intermittent clonic bursts become decreasingly frequent and finally cease altogether, leaving in their wake an “exhaustion” (paralysis) of the neurons of the epileptogenic focus and a regional increase in permeability of the blood–brain barrier and regional edema in magnetic resonance images. An excess of these inhibitory mechanisms and metabolic exhaustion are thought to be the basis of Todd’s postepileptic paralysis and of postictal stupor, sensory loss, aphasia, hemianopia, headache, and diffuse slow waves in the EEG. Plum and associates observed a twoto threefold increase in cerebral glucose utilization during seizure discharges and suggested that the paralysis that


Neurology_Adams

Neurology_Adams. headache, and diffuse slow waves in the EEG. Plum and associates observed a twoto threefold increase in cerebral glucose utilization during seizure discharges and suggested that the paralysis that follows might be a result of neuronal depletion of glucose and an increase in lactic acid. The exact roles played by each of these factors in postictal paralysis of function are not settled.


Neurology_Adams

Neurology_Adams. Insights to absence seizures have been obtained from animal models of bilaterally synchronous 3-per-second high-voltage spike-and-wave discharges. The spike-and-wave complex, which represents brief excitation followed by slow-wave inhibition, is the type of EEG pattern that characterizes the clonic (inhibitory) phase of the focal motor or grand mal seizure. By contrast, this strong element of inhibition is present diffusely throughout an “absence” attack, a feature that perhaps accounts for the failure of excitation to spread to lower brainstem and spinal structures (tonic-clonic movements do not occur). Earlier mentioned is the work by Blumenfeld’s group, suggesting that the interruption of consciousness in this syndrome can be linked with electrophysiologic changes in the thalamus, comparable to what is described for types of generalized seizure.


Neurology_Adams

Neurology_Adams. Of theoretical importance is the observation that a seizure focus may establish, via commissural connections, a persistent secondary focus in the corresponding cortical area of the opposite hemisphere (mirror focus). The nature of this phenomenon is obscure; it may be similar to the “kindling” phenomenon mentioned earlier in animals, where a repeated nonconvulsive electrical stimulation of normal cortex induces a permanent epileptic focus. No morphologic change is visible in the mirror focus, at least by light microscopy. The mirror focus may be a source of confusion when trying to identify the side of the primary discharging lesion by EEG. However, there is only limited evidence that mirror foci related to the kindling phenomenon produce seizures in humans (see Goldensohn).


Neurology_Adams

Neurology_Adams. The origins of EEG activity of an epileptic focus and the generalization of seizures are discussed in Chap. 2 and earlier in this chapter. The EEG provides confirmation of Hughlings Jackson’s concept of epilepsy—that it represents a recurrent, sudden, excessive discharge of cortical neurons. The EEG is the most sensitive, indeed indispensable, tool for the diagnosis of epilepsy; but like other ancillary tests, it must be used in conjunction with clinical data. In patients with idiopathic generalized seizures, and in a high proportion of their relatives, interictal spike-and-wave abnormalities without any clinical seizure activity are common, especially if the EEG is repeated several times or taken over long periods. By contrast, a proportion of epileptic patients have a perfectly normal interictal EEG. Using standard methods of scalp recording, the EEG may even be normal during the experiential aura of a simple or complex partial seizure. Furthermore, interpretation of EEG


Neurology_Adams

Neurology_Adams. normal interictal EEG. Using standard methods of scalp recording, the EEG may even be normal during the experiential aura of a simple or complex partial seizure. Furthermore, interpretation of EEG abnormalities must take into account that a small number of healthy persons (approximately 2 to 3 percent) show paroxysmal EEG abnormalities.


Neurology_Adams

Neurology_Adams. A single EEG tracing obtained during the interictal state is abnormal to some degree in 30 to 50 percent of epileptic patients; this figure rises to 60 to 70 percent if patients are subjected to several recordings. Many EEG patterns are possible in seizures. One consistent observation, however, has been that the region of earliest spike activity corresponds best to the epileptogenic focus, a rule that has come to guide epilepsy surgery. The postseizure or postictal state also has an EEG correlate, taking the form of random generalized slow waves after generalized seizures and focal slowing following partial seizures. With clinical recovery, the EEG returns to normal or to the preseizure state.


Neurology_Adams

Neurology_Adams. A higher yield of abnormalities and a more precise definition of seizure types can be obtained by the use of several special EEG procedures, as described in Chap. 2. Here it is restated that activating procedures such as hyperventilation, photic stroboscopic stimulation, and sleep increase the yield of EEG recordings. EEG recording during sleep is particularly helpful because focal abnormalities, particularly in the temporal lobes, may become prominent in slow-wave and stage II sleep. Sphenoidal leads have been used to detect inferomedial temporal seizure activity, but they are uncomfortable and probably add little more information than can be obtained by the placement of additional subtemporal scalp electrodes. Nasopharyngeal electrode recordings are too contaminated by artifact to be clinically useful.


Neurology_Adams

Neurology_Adams. Beyond dependably identifying artifacts in the EEG recording, one of the main challenges for the electroencephalographer is to differentiate between normal patterns that simulate seizures and true epileptic or interictal discharges. These paroxysmal but ostensibly normal patterns appear mostly during sleep, each with a highly characteristic morphology. These include small sharp spikes, “14 and 6” polyspike activity, lambda and posterior occipital mu rhythm, and occipital sharp transients. These are pictured in most standard textbooks on the subject of EEG and discussed in Chap 2.


Neurology_Adams

Neurology_Adams. Several methods of long-term EEG monitoring are now in common use and are of particular value in the investigation of patients with surgically removable epileptogenic foci and of nonepileptic spells. The most common of these makes use of telemetry systems, in which the patient is attached to the EEG machine by cable or radio transmitter without unduly limiting freedom of movement. The telemetry system is joined to an audiovisual recording system, making it possible to record seizure phenomena (even at night, under dim or infrared light) and to synchronize them with the EEG abnormalities. An alternative is the use of a small digital recording device that is attached to a miniature EEG machine worn by the patient at home and at work (“ambulatory EEG”). The patient is instructed to push a button if he experiences an “event,” which can later be correlated with EEG activity.


Neurology_Adams

Neurology_Adams. Cerebral imaging has come to play a major role in the diagnosis of seizures. CT is able to demonstrate many of the typical underlying causes of seizures in adults but MRI is more sensitive for the detection of small structural abnormalities underlying epilepsy including tumor, stroke and traumatic lesions. Furthermore, more subtle abnormalities such as medial temporal sclerosis, heterotopias and other disorders of neuronal migration, and small glial scars can be clearly visualized with MRI. Advances in MRI field strength and techniques such as thin slice acquisition, continue to expose structural lesions in what were previously called cryptogenic cases and some of these lesions may be surgically remediable.


Neurology_Adams

Neurology_Adams. After a seizure, particularly one with a focal component, MRI sometimes discloses subtle focal cortical swelling and signal change in the FLAIR (fluid-attenuated inversion recovery) and diffusion-weighted sequences, or, if a contrast agent is administered, an ill-defined cortical blush may be visible. These changes are transient and are the effect of, rather than cause of, seizure and are thought to reflect disruption of the blood–brain barrier and metabolic changes in the cortex. There is an approximate relationship between the duration of seizure activity and the intensity and extent of these changes but they rarely persist for more than a day or two. Likewise, angiography or perfusion imaging performed soon after a seizure may show a focal area of enhanced blood flow or elevated blood volume. Less-well understood is the findings on MRI of increased T2 signal or restricted diffusion in the hippocampi and posterior thalamus after a prolonged seizure or status epilepticus. There are


Neurology_Adams

Neurology_Adams. volume. Less-well understood is the findings on MRI of increased T2 signal or restricted diffusion in the hippocampi and posterior thalamus after a prolonged seizure or status epilepticus. There are also imaging changes in the white matter, particularly the splenium of the corpus callosum that may occur soon after the withdrawal of certain antiepileptic medications as discussed in the later section on the use of these drugs and by Gürtler and colleagues.


Neurology_Adams

Neurology_Adams. The CSF after a seizure occasionally contains a small number of white blood cells (most often in the range of 10/mm3) in about 5 percent of patients. In a series of 309 individuals, Tumani and colleagues found up to 24 white blood cells but the median was far lower. A slight increase in protein is also possible. Like the imaging abnormalities these findings may lead to spurious conclusions about the presence of an active intracranial lesion, particularly if polymorphonuclear leukocytes predominate; a larger pleocytosis should always be construed as a sign of inflammatory or infectious disease.


Neurology_Adams

Neurology_Adams. Systemic (lactic) acidosis is a common result of convulsive seizures, and it is not unusual for the serum pH to reach levels near or below 7 if taken immediately after a convulsion. Of more practical value is the fact that almost all generalized convulsions produce a rise in serum creatine kinase activity that persists for hours, a finding that could be used to greater advantage in emergency departments to assist in distinguishing seizures from fainting. Of course, extensive muscle injury from a fall or prolonged compression during a period of unconsciousness can produce the same abnormality.


Neurology_Adams

Neurology_Adams. Concentrations of serum prolactin, like those of other hypothalamic hormones, rise for 10 to 20 min after all types of generalized seizures, including complex partial types, but not in absence or myoclonic types. An elevation may help differentiate a psychogenic seizure from a genuine one; however, serum prolactin may also be slightly elevated after a syncopal episode (Fisher et al). There is also a postictal rise in ACTH and serum cortisol, but these changes have a longer latency and briefer duration. If elevations in these hormonal levels are used as diagnostic tests, one must have information about normal baseline levels, diurnal variations, and the effects of concurrent medications. Changes in body temperature, which are said to sometimes precede a seizure, may reflect hypothalamic changes but are far less consistent and difficult to use in clinical work.


Neurology_Adams

Neurology_Adams. In most autopsied cases of primary generalized epilepsy of the genetic variety, the CNS is grossly and microscopically normal. Not surprisingly, there are also no visible lesions in the seizure states complicating drug intoxication and withdrawal, transient hyperand hyponatremia, and hyperand hypoglycemia, which presumably represent derangements at the cellular level.


Neurology_Adams

Neurology_Adams. In contrast, symptomatic epilepsies have definable lesions. MRI, which has been used as a surrogate for pathology, has improved matters by exposing some cortical heterotopias that had been previously difficult to detect, and to highlight the frequency of gliosis in the medial temporal lobes. Other lesions include zones of neuronal loss and gliosis (scars) or other lesions such as heterotopia, dysgenic cortex, hamartoma, vascular malformation, porencephaly, and tumor. Vascular malformations, hamartomas, ganglioneuromas and related dysembryoplastic neuroectodermal tumors (DNET), which are important causes of drug resistant epilepsy, and low-grade astrocytomas were less frequent; again, in a small number, no abnormalities could be found. Certainly the focal epilepsies are associated with the highest incidence of structural abnormalities, although in certain cases no morphologic change is visible.


Neurology_Adams

Neurology_Adams. It has not been possible to determine which component of the lesion is responsible for the seizures. Gliosis, fibrosis, vascularization, and meningocerebral cicatrix have all been incriminated, but they are found in nonepileptic foci as well. The Scheibels’ Golgi studies of neurons from epileptic foci in the temporal lobe showed distortions of dendrites, loss of dendritic spines, and disorientation of neurons near the scars, but these findings have dubious status because they were not usually compared with similar nonepileptic lesions. Once a gliotic focus of whatever cause becomes epileptogenic, it may remain so throughout the patient’s lifetime.


Neurology_Adams

Neurology_Adams. In several series of cases of temporal lobe excisions in prior decades, such as the often cited one described by Falconer, a specific pattern of neuronal loss with gliosis (sclerosis) in the hippocampal and amygdaloid region was found in the majority, and this abnormality is being increasingly recognized with MRI, as already noted (medial temporal sclerosis; see Fig. 15-4). The most common associated histologic finding is loss of neurons in the CA1 segment (Sommer sector) of the pyramidal cell layer of the hippocampus, often unilateral, extending into contiguous regions of both the pyramidal layer and the underlying dentate gyrus. It is still undetermined whether this neuronal loss is primary or secondary and, if the latter, whether it was incurred at birth or happened later as the consequence of recurrent seizures.


Neurology_Adams

Neurology_Adams. However, early life head trauma, infections, and a variety of less-common perturbations may also cause the combination of neuron loss and mild gliosis of medial temporal sclerosis. The cessation of seizures in many patients following surgical resection of the medial temporal lobe favors the first interpretation that the pathologic change is primary in most cases (see further on under “Surgical Treatment of Epilepsy”). Attesting to the uncertainty of cause or effect are numerous surgical series that favor one view or the other (see editorial by Sutula and Pitkänen). Role of Genetics


Neurology_Adams

Neurology_Adams. Role of Genetics Most primary epilepsies have a genetic basis and, as in many other diseases such as diabetes and atherosclerosis, the mode of inheritance is complex, that is, some are likely to be polygenic but increasingly, single mutations are being found. That a genetic factor is operative in the primary generalized epilepsies is suggested by a familial incidence in 5 to 10 percent of such patients and, in certain families, the inheritance of a seizure disorder through specific genes (Afawi et al). The importance of genetic factors in the primary epilepsies is also underscored by evidence from twin registries; the overall concordance rate has been up to 70 percent for monozygotic twins and, 30 percent for dizygotic pairs (Vadlamudi et al).


Neurology_Adams

Neurology_Adams. Of course, epilepsy is a component of many genetic syndromes that are defined by their dysmorphic appearance, neurocutaneous disorder, or maldevelopment of the cerebra with or without mental retardation. What we consider first the few idiopathic seizure disorders that are inherited by a simple (mendelian) pattern. These include a subgroup of benign neonatal familial convulsions inherited as an autosomal dominant trait (Leppert et al), and a similar disorder of infantile onset and a benign myoclonic epilepsy of childhood (autosomal recessive). Particularly informative are a special group of epileptic disorders in which monogenic genetic defects are related to abnormalities of ion channels or neurotransmitter receptors (Table 15-3). These were mentioned earlier in the discussion of the physiology of seizures and despite their rarity they suggest that idiopathic epilepsy may be caused by a disruption in the function of these same channels.


Neurology_Adams

Neurology_Adams. The consequences of almost all of these mutations are to enhance overall neuronal excitability. Examples include autosomal dominant nocturnal frontal lobe epilepsy, which may present as a partial seizure (in which the offending mutations are in subunits of the nicotinic acetylcholine receptor subunit); so-called “generalized epilepsy with febrile seizures plus” (subunits of a neuronal sodium channel associated with various combinations of uncomplicated febrile seizures, febrile seizures persisting beyond childhood, generalized, absence, myoclonic, atonic, and complex partial seizures); benign familial neonatal convulsions (two different potassium channels); and forms of juvenile myoclonic epilepsy and childhood absence epilepsy (subunits of the brain GABAA receptor).


Neurology_Adams

Neurology_Adams. Some of these are summarized in Table 15-3, and their number will almost certainly expand in the next few years. As with numerous other genetic neurologic disorders, a single mutation may produce different epilepsy and seizure types, and a single type may be the result of one of several different mutations. Also notable is the low penetrance of some monogenic epileptic disorders, particularly the autosomal dominant one associated with nocturnal frontal seizures.


Neurology_Adams

Neurology_Adams. Another group of epilepsies with mendelian inheritance has been ascribed to genetic defects that do not implicate ion channels. Most of these are primarily myoclonic disorders in which the epilepsy is one component. Two forms of progressive myoclonic epilepsy, Unverricht-Lundborg disease and Lafora body disease, are the result, respectively, of mutations in genes encoding cystatin B and tyrosine phosphatase. To these inherited forms of epilepsy may be added diseases such as tuberous sclerosis and ceroid lipofuscinosis (Chap. 36), which have a strong proclivity to cause seizures and genetically determined heterotopias such as FLN1 (this and other developmental aberrations are discussed in Chap. 37).


Neurology_Adams

Neurology_Adams. More complex genetic elements are identified in several childhood seizure disorders—absence epilepsy with 3-per-second spike-and-wave discharges and benign epilepsy of childhood with centrotemporal spikes—both of which are transmitted as autosomal dominant traits with incomplete penetrance or perhaps in a more complicated manner. In the partial, or focal, epilepsies the role of heredity is not nearly so clear. Yet in numerous studies there has been a greater-than-expected incidence of seizures, EEG abnormalities, or both among first-degree relatives. Among the familial cortical epilepsies, both a temporal and frontal lobe type, are inherited in a polygenic fashion or in an autosomal dominant pattern. Undoubtedly also inherited, is the tendency to develop simple febrile convulsions, though the mode of inheritance is uncertain. Finally, copy number variations probably play a role in approximately 5 percent of cases according to Olsen and colleagues.


Neurology_Adams

Neurology_Adams. The physician faced with a patient who seeks advice about an episodic disorder of nervous function must determine first, whether the episode in question is a seizure. In the diagnosis of epilepsy, history is the key; in many adult cases the physical examination is unrevealing. The examination in infants and children is of greater value, as the finding of dysmorphic and cutaneous abnormalities allow the diagnosis of a number of highly characteristic cerebral diseases that give rise to epilepsy.


Neurology_Adams

Neurology_Adams. Paramount in establishing that there has been a seizure is a description from a witness. A detailed account of the event is required and in particular, the type and duration of bodily movements, level of alertness and responsiveness during and immediately after the episode, skin color and breathing, and incontinence. If a witness is not available, then a telephone call to observers and family may give more information than does sophisticated laboratory testing. From the patient, information can be obtained regarding tongue biting, incontinence, and recollection of the event of the immediately preceding epoch. If the patient is able to provide information, previous events that may have been misinterpreted as other than a seizure, for example, brief losses of consciousness, myoclonic jerks, rumpled bedsheets with incontinence, unexplained falls with injury and so forth, may hint at preceding seizures. The family history, developmental milestones, neonatal events and the circumstances of


Neurology_Adams

Neurology_Adams. rumpled bedsheets with incontinence, unexplained falls with injury and so forth, may hint at preceding seizures. The family history, developmental milestones, neonatal events and the circumstances of birth are useful additional aspects of the evaluation of epilepsy.


Neurology_Adams

Neurology_Adams. In the category of genuine seizures, the diagnosis of temporal lobe epilepsy may be difficult to distinguish from imitators of epilepsy. These attacks are so variable and so often induce disturbances of behavior and psychic function—rather than overt interruptions or loss of consciousness—that they may be mistaken for temper tantrums in children, drug ingestion, hysteria, panic attacks, or acute psychosis. These seizures may include verbalizations that cannot be remembered, walking aimlessly, repetitive olfactory and gustatory hallucinations, stereotyped hand movements or automatism such as lip smacking. The nature of the patient’s report of a psychic experience is often helpful in distinguishing seizures from psychogenic events. In the former, patients attempt to focus with great effort on the description of the experience, although the term “indescribable” is often included in the report, whereas vague and imprecise descriptions of “something being wrong” or resorting to a friend or


Neurology_Adams

Neurology_Adams. the description of the experience, although the term “indescribable” is often included in the report, whereas vague and imprecise descriptions of “something being wrong” or resorting to a friend or family member to describe the event usually implicates a psychogenic seizure. We place emphasis on amnesia for the events of at least part of the seizure as an important criterion for the diagnosis of temporal lobe epilepsy. Hysterical fugues can cause substantial difficulty in diagnosis. They may be recognized by the loss of personal identity and by episodes that are longer than typical of seizures, sometimes up to a few days.


Neurology_Adams

Neurology_Adams. Absence attacks may be similarly difficult to distinguish from other brief disorders of consciousness. Helpful maneuvers are to have the patient hyperventilate to evoke an attack or to observe the patient counting aloud for several minutes. Those with frequent absence attacks will pause or skip one or two numbers. The conditions most likely to simulate an epileptic seizure are psychogenic nonepileptic seizures and other paroxysmal events such as panic attack and syncope but also, unexplained falls (drop attacks), transient ischemic attacks, particularly those associated with limb shaking, rapid eye movement (REM) sleep behavior disorder, subarachnoid hemorrhage, migraine, hypoglycemia, cataplexy, paroxysmal ataxia and choreoathetosis, and transient global amnesia. In emergency departments it is often difficult to differentiate the postictal effects of an unwitnessed seizure from the confusion and amnesia following cerebral concussion.


Neurology_Adams

Neurology_Adams. The clinical differences between a seizure and a syncopal attack are considered in Chap. 17; there it was emphasized that no single criterion stands inviolate. Particularly emphasized because of their potential gravity are episodes of cardiac syncope from a serious arrhythmia, especially ventricular tachycardia. Cardiac arrhythmias may present as episodes of unheralded loss of consciousness, sometimes with associated convulsive movements that simulate epileptic disorders and the failure to pursue the diagnosis of arrhythmia may have important consequences. Palpitations, previous myocardial infarction, ECG abnormalities, valvular disease, and thoracic trauma may direct attention to the proper diagnosis.


Neurology_Adams

Neurology_Adams. Migraine may be mistaken for a seizure. One feature of the focal neurologic disorder of typical migraine is particularly helpful—namely, the pace of the sequence of cerebral malfunction over a period of minutes rather than seconds, as in focal epilepsy. Even this criterion may fail occasionally, especially if both migraine and partial seizures are joined, for example, as expressions of a vascular malformation of the brain.


Neurology_Adams

Neurology_Adams. Identification of a TIA and its separation from focal epilepsy are aided by considering that most paroxysmal vascular disorders are characterized by loss of function that can be attributed to one area of the cortex such as paralysis, blindness, diplopia, or aphasia. If the ischemic attack is marked by an evolution of symptoms, they tend to develop more slowly than those of a seizure. The patient’s age and presence of vascular risk factors, evidence of disease of the heart and carotid arteries, and the lack of disorder of consciousness or amnesia may be supportive of the diagnosis of vascular disease. However, a “limb-shaking” TIA and convulsive phenomena at the outset of basilar artery occlusion may be nearly impossible to distinguish from epilepsy.


Neurology_Adams

Neurology_Adams. Regarding the distinction of seizures from odd disorders such as cataplexy, paroxysmal ataxia or choreoathetosis, transient global amnesia, it is sufficient to be aware of the diagnostic features for each of these conditions. REM sleep behavior disorder tend to occur later in the sleep cycle, as they require REM, whereas frontal epileptic seizures with violent motions or acts that might be mistaken for REM sleep behavior disorder, can occur at any time of the night and tend to be briefer than the sleep disorder. Drop attacks (falling to the ground without loss of consciousness as discussed in Chap. 6) remain an enigma. In most cases, it has not been possible to substantiate an association with circulatory disturbances of the vertebrobasilar system and seldom have we observed drop attacks to be an expression of atonic or myoclonic epilepsy.


Neurology_Adams

Neurology_Adams. Several laboratory studies are usually included in the initial diagnostic evaluation—complete blood count (CBC), blood chemistries, ECG, EEG, and imaging of the brain, preferably MRI. CT gives some information on major problems that may underlie epilepsy but MRI is superior in detecting the various structural causes of epilepsy. If blood is tested after the episode in question, elevation in creatine kinase (persistent for hours) and formerly, elevation of prolactin (for up to 10 min) may occur after an unwitnessed convulsive seizure but the test is not specific enough to be useful in general practice. Other forms of testing—for example, cardiac stress tests, Holter monitor, tilt-table testing, long-term cardiac rhythm monitors, and sleep studies—are sometimes indicated in order to exclude some of the nonepileptic disorders listed earlier. Some patients may need prolonged EEG monitoring, either in the hospital or with portable equipment at home. In all forms of epilepsy, prolonged EEG


Neurology_Adams

Neurology_Adams. some of the nonepileptic disorders listed earlier. Some patients may need prolonged EEG monitoring, either in the hospital or with portable equipment at home. In all forms of epilepsy, prolonged EEG and video monitoring in a hospital unit may prove diagnostic.


Neurology_Adams

Neurology_Adams. (Table 15-4 and Fig. 15-5) Having concluded that the neurologic disturbance under consideration is one of seizure, the next issue is to identify its type. Indeed, in most cases this determines the nature of treatment. Because there are so many seizure types, especially in childhood and adolescence, each one tending to predominate in a certain age period, a clinical advantage accrues to considering seizures from just this point of view. A broader approach includes consideration of the neurologic and EEG findings, the response to drugs, etiology, and prognosis. Figure 15-5 displays the frequency of each seizure type and the main causes of seizures by age group. These data are assembled from various sources and are approximate, but they highlight several points of clinical importance.


Neurology_Adams

Neurology_Adams. The neonatologist is often confronted by an infant who begins to convulse in the first days of life. In most instances, the seizures are fragmentary—an abrupt movement or posturing of a limb, stiffening of the body, rolling up of the eyes, a pause in respirations, lip-smacking, chewing, or bicycling movements of the legs. Even the experienced observer may have difficulty at times in distinguishing seizure activity from the normal movements of the neonate. If manifest seizures are frequent and stereotyped, the diagnosis is less difficult. The seizures correlate with focal or multifocal cortical discharges; however, as is the case with most EEG changes in neonates, these are poorly formed and less distinct than seizure discharges in later life. Presumably the immaturity of the cerebrum prevents the development of a fully organized seizure pattern, and the incomplete corticocortical myelination prevents bihemispheric spread. The EEG is nonetheless helpful in diagnosis. For example,


Neurology_Adams

Neurology_Adams. prevents the development of a fully organized seizure pattern, and the incomplete corticocortical myelination prevents bihemispheric spread. The EEG is nonetheless helpful in diagnosis. For example, periods of EEG suppression may alternate with sharp or slow waves, or there may be discontinuous theta activity that represents electrographic seizure activity. Conversely, electrical seizure activity in the neonate may be unattended by clinical manifestations.


Neurology_Adams

Neurology_Adams. An early onset of myoclonic jerks, either fragmentary or massive, with an EEG pattern of alternating suppression and complex bursts of activity is particularly ominous. Ohtahara described another unfavorable form of neonatal seizure evolving in infancy into infantile spasms (West syndrome) and Lennox-Gastaut syndrome and leaving in its wake severe brain damage. Most reported patients have been left developmentally delayed.


Neurology_Adams

Neurology_Adams. Neonatal seizures occurring within 24 to 48 h of a difficult birth are usually indicative of severe cerebral damage, usually anoxic, either antenatal or parturitional. Such infants often succumb, and about half of the survivors are seriously handicapped. Seizures having their onset several days or weeks after birth are more often an expression of acquired or hereditary metabolic disease. In the latter group, hypoglycemia is the most frequent cause; another, hypocalcemia with tetany, has become infrequent. A hereditary form of pyridoxine deficiency is a rare but treatable cause, sometimes also inducing seizures in utero and characteristically responding promptly to massive doses (100 mg) of vitamin B6 given intravenously. Biotinidase deficiency is another rare but correctable cause. Nonketotic hyperglycemia, maple syrup urine disease, as well as other metabolic disorders may lead to seizures in the first week or two of life and are expressive of a more diffuse encephalopathy.


Neurology_Adams

Neurology_Adams. In contrast, benign forms of neonatal seizures have also been identified. For example, Plouin described a form of benign neonatal clonic convulsions beginning on days 2 and 3, up to day 7, (“fifth day seizures”) in which there were no specific EEG changes. The seizures then remit and have a good prognosis. The inheritance is autosomal dominant. There are other nonfamilial cases with onset on days 4 to 6, wherein the partial seizures may even increase to status epilepticus; the EEG consists of discontinuous theta activity. In both these groups, the outlook for normal development is good and seizures seldom recur later in life. There are also benign forms of polymyoclonus without seizures or EEG abnormality in this age period. Some occur only with slow-wave sleep or feeding. They disappear after a few months and require no treatment. A form of benign nocturnal myoclonus in the neonate is also well known.


Neurology_Adams

Neurology_Adams. Neonatal seizures may continue into the infantile period, or seizures may begin in an infant who seemed to be normal up to the time of the first convulsive attack. While the most common type of convulsion is the febrile seizure, not strictly a type of epilepsy, the most characteristic epilepsy at this age is the massive sudden myoclonic jerk of head and arms leading to flexion or, less often, to extension of the body (infantile spasms, salaam spasms). This form, which characterizes the West syndrome as described earlier, has many underlying causes. The same seizure type occurs in infants with tuberous sclerosis (diagnosed in infancy by the presence of hypopigmentated macules, or “ash-leaf spots”), phenylketonuria, or Sturge-Weber angiomatosis, but most often it is associated with other diseases beginning in this age period. Infantile spasms cease by the end of the second year and are replaced by focal and secondarily generalized seizures. They do not respond well to the usual


Neurology_Adams

Neurology_Adams. other diseases beginning in this age period. Infantile spasms cease by the end of the second year and are replaced by focal and secondarily generalized seizures. They do not respond well to the usual antiepileptic medications. Some instances of infantile spasms may be due to a metabolic encephalopathy of unknown type or, a cortical dysgenesis (Jellinger). West syndrome is characterized by an EEG picture of large bilateral slow waves and multifocal spikes (hypsarrhythmia).


Neurology_Adams

Neurology_Adams. The Dravet syndrome, which includes myoclonic and focal seizures, occurs in this age group but is also relevant to adult practice as patients are recognized with persistence of resistant epilepsy of several types. In the past this form of epilepsy and developmental delay were attributed to a febrile illness or vaccination in infancy but it has become clear that the syndrome is the result of a loss of function mutation in a sodium channel gene (SCN1A in most cases). The initial seizures in these cases have been bought forward by a febrile episode or other neonatal event but they are subsequently characterized by unprovoked and treatment resistant episodes.


Neurology_Adams

Neurology_Adams. Febrile seizures represent a challenging problem in this age period. When febrile seizures are prolonged, focal, or accompanied by a neurologic deficit, they are referred to as complicated febrile seizure. These are distinguished from the benign familial febrile seizure syndrome discussed earlier in the chapter. While myoclonic activity with seizures in this age group raises concern of a serious condition, there is a common benign form with a heritable component and does not lead to developmental delay.


Neurology_Adams

Neurology_Adams. A number of focal epilepsies may appear for the first time during this age period and carry a good prognosis, that is, the neurologic and intellectual capacities remain relatively unimpaired and seizures may cease in adolescence. These disorders begin between 3 and 13 years of age and there is often a familial predisposition. Most are marked by distinctive focal spike activity that is accentuated by sleep (see earlier, in reference to benign childhood epilepsy with centrotemporal or occipital spikes). Several of these have been discussed earlier under the “Special Epileptic Syndromes.” In one form, benign childhood epilepsy with centrotemporal spikes, unilateral tonic or clonic contractions of the face and limbs recur repeatedly with or without paresthesia; anarthria may follow the seizure. There are central and temporal spikes in the EEG interictally. Less commonly, the focus originates in an occipital lobe with EEG spiking on eye closure. An acquired aphasia characterizes another


Neurology_Adams

Neurology_Adams. There are central and temporal spikes in the EEG interictally. Less commonly, the focus originates in an occipital lobe with EEG spiking on eye closure. An acquired aphasia characterizes another disorder that was described by Landau and Kleffner to mark the beginning of an illness in which there are partial or generalized motor seizures and multifocal spike or spike-and-wave discharges in the EEG and deterioration of language function.


Neurology_Adams

Neurology_Adams. As in any age group, there are structural causes of seizures that include medial temporal sclerosis, described in several places in this chapter, tumor and arteriovenous malformation. The special case of Rasmussen encephalitis and intractable seizures has already been discussed under the “Special Epileptic Syndromes.” Among the generalized idiopathic epilepsies, the typical absence disorder, with its regularly recurring 3-per-second spike-and-wave EEG abnormality, begins in this age period (rarely before age 4 years) and carries a good prognosis. This seizure disorder responds well to medications, as indicated further on. Its features are fully described in “Absence Variants.”


Neurology_Adams

Neurology_Adams. Convulsions in this age group may present around the age of 4 years as focal myoclonus with or without astatic seizures, atypical absence, or generalized tonic-clonic seizures. The EEG, repeated if initially normal, is most helpful in diagnosis; it reveals a paroxysmal 2to 2.5-per-second spike-and-wave pattern on a background of predominant 4to 7-Hz slow waves. Many of these cases qualify as the Lennox-Gastaut syndrome, are difficult to treat, and are likely to be associated with developmental delay. At this age, perhaps more than any other, the first burst of seizures may take the form of status epilepticus and, if not successfully controlled, may end fatally.


Neurology_Adams

Neurology_Adams. These represent a common problem in practice but present a special difficulty because this is the age at which syncope and psychogenic seizures begin to occur and alcohol and drug abuse may begin. In this age period in particular, as the adolescent strives for independence, the social disruption caused by seizures are likely to take a toll on the relationships and educational progress of the emerging adult. Here, we also face the frequent issue relating to the nature and management of the first seizure in an otherwise normal young person. As in other age groups, the history often discloses the likely provocation of seizures, as for example, in young person has been sleep deprived or imbibing alcohol or one of many abused drugs and has a first seizure. A search for a cause of the first seizure in this age group is necessary by MRI, ECG, and EEG but these tests less frequently disclose an underlying lesion than in other age groups. Often, there has only been a single event and no


Neurology_Adams

Neurology_Adams. seizure in this age group is necessary by MRI, ECG, and EEG but these tests less frequently disclose an underlying lesion than in other age groups. Often, there has only been a single event and no clinical or EEG features to define the nature of the seizure disorder. However, the type of seizure that first brings the child or adolescent to medical attention is most likely to be a generalized tonic-clonic convulsion and may mark the beginning of idiopathic generalized epilepsy or juvenile myoclonic epilepsy, as described earlier sections.


Neurology_Adams

Neurology_Adams. A few patients have had a history of absence in which the EEG shows a characteristic polyspike pattern, about one-third with a photomyoclonic response. When the seizures are an expression of a congenital epileptic focus that is associated with developmental delay or scholastic failure, the diagnostic and therapeutic problem becomes demanding. In the special group of younger individuals with long-standing seizures, nearly half have temporal lobe epilepsy. Huttenlocher and Hapke, in a follow-up study of 145 infants and children with intractable epilepsy, found that the majority had developmental delay.


Neurology_Adams

Neurology_Adams. Opinion is divided on whether treatment is required for the older child or adolescent who comes to medical attention because of a first seizure that appears to be idiopathic. Age, sex, and the circumstances of the seizure (withdrawal from drugs or alcohol, myoclonic episodes, family history) all figure into the risk of subsequent seizures. What is apparent is that the early use of antiepileptic drugs has little effect on the occurrence of later seizures, as summarized in guidelines authored by Krumholz and colleagues as discussed further on. When such cases have been observed without treatment, such as in the series reported by Hesdorfer and colleagues, the risk of another seizure over 10 years was 13 percent unless the first episode was status epilepticus, in which case the risk was 41 percent. Attention is given to regularizing sleep and minimizing alcohol and stimulants.


Neurology_Adams

Neurology_Adams. Hauser and Kurland reported an increase in the incidence of seizures as the population ages—from 11.9 per 100,000 in the 40to 60-year-old age group to 82 per 100,000 in those 60 years of age or older. Often, these individuals live alone so there is no witness to the event, they have multiple medical problems, they may have cognitive difficulty that impedes an accurate history, multiple medications are almost the rule, and cerebral imaging is likely to show abnormalities that may not be referable to the problem at hand.


Neurology_Adams

Neurology_Adams. A person in this age group who begins to have seizures of either focal or generalized type may harbor a primary or secondary tumor, a past cerebral infarct, or a traumatic cortical scar that had not declared itself clinically. For example, according to Sung and Chu, previous infarcts are by far the most common lesions underlying status epilepticus in late adult life. Probably the nature of the population in a given clinic determines the relative frequency of underlying causes. In any case, cerebral imaging usually settles the issue. However, many seizure-like events in this age group are the result of a cardiac arrhythmia, particularly ventricular tachycardia but also cardiac disorders not related to rhythm such as aortic stenosis. Therefore, ECG and long-term monitoring of heart rhythm are useful ancillary tests if the episode remains unexplained.


Neurology_Adams

Neurology_Adams. Cortical and subcortical lesions, the result of previous traumatic contusions, are a particularly important cause of seizures; the lesions are revealed by brain imaging and are typically located in the anterior frontal and temporal lobes. Brain abscess and other inflammatory and infectious illnesses remain common causes of adult seizures in tropical regions. In the elderly, seizures as a result of advanced Alzheimer and other degenerative diseases occur in up to 10 percent of cases; moreover, these patients are subject to falls, subdural hematoma, and all other illnesses of old age, such as cancer, that secondarily affect the brain. In individuals with cancer, cerebral metastasis is certainly a common cause of a first seizure.


Neurology_Adams

Neurology_Adams. In the common case of an adult with a first unexplained seizure, it has been our practice not to administer an antiepileptic medication unless there is an underlying structural lesion or an abnormality on a single EEG or with prolonged monitoring and to reevaluate the situation in 6 to 12 months. The decision regarding starting treatment in an older adult is informed by a number of factors including occupation, need for driving, safety of home environment, use of alcohol and other sedatives, anticipated compliance, and drug interactions. Usually, a second MRI and EEG are performed to exclude focal abnormalities that were not appreciated during the initial evaluation, but often these studies are again unrevealing. This approach has been prompted by data such as those of Hauser and colleagues, who found that about one-third of patients with a single unprovoked seizure will have another seizure within 5 years; the risk is even greater if there is a history of seizures in a sibling, a


Neurology_Adams

Neurology_Adams. who found that about one-third of patients with a single unprovoked seizure will have another seizure within 5 years; the risk is even greater if there is a history of seizures in a sibling, a complex febrile convulsion in childhood, or a spike-and-wave abnormality in the EEG. Moreover, the risk of recurrence is greatest in the first 24 months. In patients with two or three unexplained seizures, a far higher proportion, about 75 percent, have further seizures in the subsequent 4 years.


Neurology_Adams

Neurology_Adams. Seizures due to Underlying Medical Disease Several diseases announce themselves by an acute convulsion. Here we focus on generalized medical disorders as causes of single and episodic seizures, in contrast to structural lesions of the brain that cause focal or generalized epilepsy.


Neurology_Adams

Neurology_Adams. The possibility of abstinence seizures in patients who abuse alcohol or use benzodiazepine and related sedative drugs, must be considered when seizures occur for the first time in adult life or in adolescence. Suspicion is raised by the stigmata of alcohol abuse or a history of prolonged anxiety requiring sedative drugs. Also, sleep disturbance, tremulousness, disorientation, illusions, and hallucinations can be associated with the convulsive phase of the withdrawal syndrome. Seizures in this setting may occur singly, but as often, in a brief flurry, the entire convulsive period lasting for several hours and rarely for a day or longer, during which time the patient may display twitchiness or myoclonus and be unduly sensitive to photic stimulation. Chapter 41 discusses alcohol and other drug-related seizures in detail.


Neurology_Adams

Neurology_Adams. An outburst of seizures is also a prominent feature of all varieties of bacterial meningitis, more so in children than in adults. Fever, headache, and stiff neck provide the clues to diagnosis, and lumbar puncture yields the salient data. In endemic areas and in individuals who have traveled from these areas, cysticercosis and tuberculous granulomas of the brain are very common causes of epilepsy. Myoclonic jerking and seizures may appear early in acute herpes simplex encephalitis and other forms of viral, treponemal, and parasitic encephalitis, including those derived from HIV infection, both directly and indirectly such as toxoplasmosis and brain lymphoma; and in subacute sclerosing panencephalitis. Seizure(s) without fever or stiff neck may be the initial manifestation of syphilitic meningitis, a fact worth noting as this process reemerges in AIDS patients.


Neurology_Adams

Neurology_Adams. A variety of autoimmune encephalitides may cause seizures as, for example, with the anti-NMDA receptor antibody that is associated with ovarian and other teratomas and other paraneoplastic conditions such as the antibody syndrome directed at the voltage-gated potassium channel complex (see Chap. 30).


Neurology_Adams

Neurology_Adams. Uremia has a strong tendency to produce convulsions. Of interest is the relation of seizures to the development of acute anuric renal failure, generally from acute tubular necrosis but occasionally due to glomerular disease. Total anuria may be tolerated for several days without the appearance of neurologic signs, and then there is an abrupt onset of twitching, trembling, myoclonic jerks, and brief generalized motor seizures; acute hypertension probably plays a role. The entire motor constellation, one of the most dramatic in medicine, lasts several days until the patient sinks into terminal coma or recovers by dialysis. When this twitch-convulsive syndrome accompanies lupus erythematosus, seizures of undetermined cause, or generalized neoplasia, one should suspect its basis in renal failure.


Neurology_Adams

Neurology_Adams. Other acute metabolic illnesses and electrolytic disorders complicated by generalized and multifocal motor seizures are hyponatremia and its opposite, the hypernatremic, hyperglycemic and other hyperosmolar states, hypoglycemia, thyrotoxicity, porphyria, hypomagnesemia, and hypocalcemia. In all these cases, rapidly evolving electrolyte abnormalities are more likely to cause seizures than those occurring gradually. For this reason it is not possible to assign absolute levels of sodium, blood urea nitrogen (BUN), osmolarity, or glucose concentrations above or below which seizures are likely to occur. Lead (in children) and mercury (in children and adults) are the most frequent of the metallic poisons, still rare as a group, that cause convulsions. The presence of these heavy metals in homeopathic treatments should not be overlooked.


Neurology_Adams

Neurology_Adams. Generalized seizures, with or without twitching, occur in the advanced stages of many other illnesses, such as hypertensive encephalopathy, the posterior reversible encephalopathy syndrome from various drugs (PRES, as discussed in Chap. 33), sepsis—especially gram-negative septicemia with shock—and hepatic coma. Usually, seizures in these circumstances can be traced to an associated metabolic abnormality and are revealed by appropriate studies of the blood. Seizures are a central feature of the eclamptic syndrome as discussed in a separate section below. In most cases of seizures caused by metabolic and withdrawal states, treatment with antiepileptic drugs is not necessary as long as the underlying disturbance is rectified. Indeed, antiepileptic drugs are usually ineffective in halting the seizures if the metabolic disorder persists. Medications and Other Drugs as Causes of Seizures


Neurology_Adams

Neurology_Adams. Medications and Other Drugs as Causes of Seizures In addition to the withdrawal states, a large number of medications are themselves capable of causing seizures, usually when toxic blood levels are attained. The antibiotic imipenem and excessive doses of other penicillin congeners as well as linezolid may be responsible, particularly if renal failure leads to drug accumulation. Cefepime, a fourth-generation cephalosporin, widely used for the treatment of gram-negative sepsis, can result in status epilepticus, if given in excessive dosage (Dixit et al). Renal dysfunction, preexisting brain lesions and previous epilepsy have been emphasized as features associated with antibiotic-induced seizures in a review by Sutter and colleagues (2015), and they emphasize that the evidence for associations between seizures and specific antibiotics are often based on limited evidence.


Neurology_Adams

Neurology_Adams. The tricyclic antidepressants, bupropion, and lithium may cause seizures, particularly in the presence of a structural brain lesion. Lidocaine and aminophylline are known to induce an unheralded single convulsion if administered too quickly or in excessive doses. The use of the analgesic tramadol has also been associated with seizures. Curiously, the anesthetic propofol, which is discussed further on as a potent anticonvulsant in the treatment of status epilepticus, has caused marked myoclonic phenomena in some patients and, rarely, seizures. These may occur during induction or emergence from anesthesia or as a delayed effect (Walder et al).


Neurology_Adams

Neurology_Adams. The list of medications that at one time or another have been associated with a convulsion is long and, if no other explanation for a single seizure is evident, the physician is advised to look up in standard references the side effects of the drugs being administered to the patient. In a few of our otherwise healthy adult patients, extreme sleep deprivation coupled with ingestion of large doses of antibiotics or adrenergic medications or other remedies that are used indiscriminately for the symptomatic relief of colds has been the only plausible explanation for a single or doublet seizure. Furthermore, many illicit drugs of several varieties may cause seizures. Among the most prominent are cocaine, high-potency synthetic cannabinoids, abuse of amphetamines, phencyclidine, psilocibin, lysergic acid and related compounds. Some of these cause convulsions through an intermediate of extreme hypertension of vasculopathy but others seem to have a direct neurotoxic effect.


Neurology_Adams

Neurology_Adams. Global Arrest of Circulation Cardiac arrest, suffocation or respiratory failure, carbon monoxide poisoning, or other causes of hypoxic encephalopathy tend to induce diffuse myoclonic jerking and generalized seizures as cardiac function resumes. The myoclonic-convulsive phase of this condition may last only a few hours or days, in association with coma, stupor, and confusion; or it may persist indefinitely as an intention myoclonus state (Lance-Adams syndrome). These movements are to be distinguished from the convulsive movements of syncope discussed earlier in the chapter and in Chap. 17.


Neurology_Adams

Neurology_Adams. Convulsive seizures are quite uncommon in the acute or evolving phases of an arterial stroke. The ischemic convulsive phenomena of a “limb-shaking TIA” and a burst of generalized clonic motor activity during basilar artery occlusion have been mentioned earlier, but are uncommon and are not truly epileptic phenomena. Embolic infarcts involving the cortex become epileptogenic in fewer than 10 percent of cases and only after an interval of several months or longer. It has been stated in texts that thrombotic infarcts involving the cortex are almost never convulsive at their onset. Lacunar infarction, being deep and not involving the cortical surface, of course, does not produce convulsions.


Neurology_Adams

Neurology_Adams. In contrast, cortical venous thrombosis with underlying ischemia and infarction acts as a highly epileptogenic lesion (see Chap. 33). The same is true for hypertensive encephalopathy [including the above mentioned posterior reversible encephalopathy (PRES) and eclampsia] and thrombotic thrombocytopenic purpura (TTP), which has a strong tendency to cause nonconvulsive status epilepticus. The rupture of a saccular aneurysm is sometimes marked by one or two generalized convulsions that are not epileptic in nature and are probably predicated on the arrest of cerebral circulation. Cerebral hemorrhages, spontaneous or traumatic, that extend near the cortex, also may present with seizures acutely or become sources of recurrent focal seizures as a delayed consequence.


Neurology_Adams

Neurology_Adams. The use of anticonvulsants as prophylaxis for seizures after a typical cortical stroke of embolic or thrombotic type or nontraumatic cerebral hemorrhage is not necessary. The rate of such seizures has been estimated to be 3 percent or less in the first year. This subject is addressed further in Chap. 33.


Neurology_Adams

Neurology_Adams. It is not uncommon for severe concussion to be attended by brief convulsive movements (see Chap. 34). The appearance is in most cases of clonic twitching but may include a momentary tonic phase. Rarely, a prolonged clonic convulsion occurs. The nature of this event, whether originating in the reticular formation as a component of concussion, or from some disruption of cortical activity, is not clear. Almost invariably in our experience, the EEG recorded hours or a day later is normal, and imaging studies are likewise normal or show a small contusion. There is little to guide one in treatment of these patients; we tend to give a course of antiepileptic medications for several weeks but it is not established if this is the correct approach. Aside from penetrating brain trauma, the risk of delayed seizures is low. Further details on this subject, particularly seizures that occur as a late effect of traumatic brain injury can be found in Chap. 34.


Neurology_Adams

Neurology_Adams. Here one contends with two scenarios: the woman with epilepsy who becomes pregnant and the woman who has her first seizure during pregnancy. According to the extensive EURAP study, about two-thirds of epileptic women who become pregnant have no change in seizure frequency or severity (the majority remain seizure free); the remainder are evenly split between those in whom the frequency increases and in an equal number, it lessens. A systematic review has indicated that almost 90 percent of women who were seizure-free for a year before becoming pregnant, have no seizures during pregnancy.


Neurology_Adams

Neurology_Adams. Many antiepileptic medications also seem to be safe for the baby during breast-feeding in that only small amounts are excreted in lactated milk. The degree of penetration into breast milk is dependent on the extent of protein binding. Highly bound drugs do not appear in substantial concentrations and the converse is true. Relatively safe agents include carbamazepine, which is found to be 40 percent of the mother’s serum concentration, resulting in a neonatal blood level that is below the conventionally detectable amount. Phenytoin is excreted at 15 percent of maternal serum concentration, and valproate, being highly protein bound, is virtually absent in breast milk. No adverse effects have been attributed to these small amounts of these drugs. Those that appear in intermediate concentrations include levetiracetam, oxcarbazepine, tiagabine, vigabatrin, gabapentin, and topiramate. Drugs considered risky for the infant because of high concentrations in breast milk include phenobarbital,


Neurology_Adams

Neurology_Adams. include levetiracetam, oxcarbazepine, tiagabine, vigabatrin, gabapentin, and topiramate. Drugs considered risky for the infant because of high concentrations in breast milk include phenobarbital, primidone, ethosuximide, zonisamide, and benzodiazepines. The risks of using this last group of drugs in the postpartum period must be weighed against the sedating effects of the medication on the neonate.


Neurology_Adams

Neurology_Adams. In the past, issues regarding a coagulopathy in the fetus exposed to phenobarbital (now infrequently used for adult seizure disorders) and certain of the other drugs are well known to obstetricians and pediatric specialists and are treated with the oral administration of vitamin K, 20 mg/d during the eighth month or 10 mg IV 4 h before birth and 1 mg IM to the neonate. Teratogenic Effects of Antiepileptic Medications


Neurology_Adams

Neurology_Adams. Teratogenic Effects of Antiepileptic Medications Because it is important to prevent major convulsions in the pregnant epileptic woman, antiepileptic medication should not be discontinued or arbitrarily reduced, particularly if there have been recent convulsions. The conventional drugs (phenytoin, carbamazepine, levetiracetam, lamotrigine) are all tolerated in pregnancy comparably to their use before pregnancy. Plasma levels of most of these drugs, both the free and protein-bound fractions, fall slightly in pregnancy in part because they are cleared more rapidly from the blood but there is considerable inter-individual variability. It is important to monitor the drug levels so that adjustments can be made. The main issue, however, pertains to the potential teratogenicity of most of the drugs with valproate having more risk than the others, and a slight reduction in verbal IQ in children born of mothers who had been exposed to valproate during pregnancy.


Neurology_Adams

Neurology_Adams. The most common teratogenic effects have been cleft lip and cleft palate, but infrequently also a subtle facial dysmorphism (“fetal anticonvulsant syndrome”), similar to the fetal alcohol syndrome. In general, the risk of major congenital defects is low; it increases to 4 to 5 percent in women taking antiepileptic drugs during pregnancy, in comparison to 2 to 3 percent in the overall population of pregnant women. These statistics have been essentially confirmed in the large study by Holmes and colleagues, conducted among several Boston hospitals. When all types of malformations were included, both major and minor, 20 percent of infants born to mothers who took antiepileptics during pregnancy showed abnormalities, compared to 9 percent of mothers who had not taken medications. These authors identified “midface hypoplasia” (shortened nose, philtrum, or inner canthal distance) and finger hypoplasia as characteristic of anticonvulsant exposure; these changes were found in 13 and 8 percent


Neurology_Adams

Neurology_Adams. identified “midface hypoplasia” (shortened nose, philtrum, or inner canthal distance) and finger hypoplasia as characteristic of anticonvulsant exposure; these changes were found in 13 and 8 percent of exposed infants, respectively. However, it should be emphasized that in large surveys, major malformations have occurred in only 5 percent of infants exposed to antiepileptic drugs. The infants born of a group of women with epilepsy who had not taken anticonvulsants during pregnancy showed an overall rate of dysmorphic features comparable to that in control infants, but there was still a 2 to 3 percent rate of facial and finger hypoplasia. This risk is shared more or less equally by all the major antiepileptics again, with valproate associated with a higher rate. Aggregating eight databases, Jetnik and colleagues found a number of malformations of the nervous and somatic systems to be increased in comparison to other antiepileptic drugs.


Neurology_Adams

Neurology_Adams. Of equal or greater concern has been the findings by Meador and colleagues that in utero exposure to valproate was associated with lower IQs (by 9 points) compared to lamotrigine in children at the age of 4. It is not clear if the effect persists after this age. Children who had been exposed to phenytoin or to carbamazepine also had slightly lower IQs but this difference was ostensibly accounted for by lower maternal IQ. Some studies, including the one by Meador and colleagues suggest that folate may have an ameliorating effect on this detrimental effect at age 3, whereas there is an uncertain benefit of folate in preventing fetal malformations due to the drugs.


Neurology_Adams

Neurology_Adams. The risk of neural tube defects is also slightly increased by anticonvulsants during pregnancy, and greatest for the use of valproate. It had been considered to be reduced by giving folate before pregnancy has begun (it is not clear if this is true for valproate), but epilepsy experts avoid the use of valproate during pregnancy altogether. These risks are greater in women taking more than one anticonvulsant, so that monotherapy is a desirable goal. Furthermore, the risk is disproportionately increased in families with a history of these defects. Some of the newer anticonvulsants should probably be used cautiously until greater experience has been obtained. As each new drug has been introduced over the years, there has usually been a tentative claim of reduced teratogenic effects, often proven later to be incorrect. Claims have been made of safety in this regard for lamotrigine, causing many specialists to change from the more conventional drugs to this one in women who anticipate