Searching for Seizure-Precipitating Factors

Seizure-precipitating factors are not always reported by patients spontaneously and so must be specifically sought. In the most common type of photosensitive epilepsy, the identification of a triggering stimulus may be trivial in some situations, such as stroboscopic lightning at a dance party or a video game session, but can be harder to detect in the case of alternating sun exposure when driving along a line of trees or looking at an object characterized by a pattern of repetitive high-contrast figures. Similarly, in the much rarer primary reading epilepsy, an affected adolescent or young adult will not necessarily recognize the role played by reading aloud until several seizures occur under similar circumstances. Detailing patient activity prior to seizure onset offers the best opportunity for a physician to detect a seizure-triggering factor.

Apart from these examples, a variety of other sensory or cognitive stimuli may occasionally precipitate partial or generalized seizures. These include sudden unexpected noise responsible for startle-induced seizures, listening to specific pieces of music, playing chess, performing mental arithmetic, programming a particular gesture, and virtually any other mental process. One of our patients used to experience temporal lobe seizures when he heard or saw something related to the “past,” like an old song or a movie from the 1950s, regardless of their relation to his personal memories. Although patients may feel reluctant to consider or report such odd stimuli, physicians should equally be prepared for such oddities that primarily reflect the potential for any cortical neural network to generate seizures, including those involved in allocating times and dates to events in living experience.

One general rule applies to epilepsy—The more odd the experiential or behavioral phenomena, the more likely that they are of epileptic origin provided the presence of core features of an epileptic seizure are present (see later). Although counterintuitive, the “theatrical” semiology of psychogenic attacks usually proves less dramatic than that of partial seizures.

Validating the Core Features of Epileptic Seizures

Once the context of a seizure episode has been ascertained, and prior to its detailed description, one should confirm the presence of the core features that characterize almost all epileptic fits, such as an abrupt onset, a short duration of several seconds to a few minutes, and a stereotyped sequence of ictal signs and symptoms.

“Desperately Seeking” a Witness to the Seizure(s)

Witnessed accounts of seizures often provide essential information, complementary to that reported by patients. Even in simple partial seizures characterized by a rising epigastric sensation, witnesses can notice subtle oroalimentary automatisms (chewing or lip-smacking) of which patients are unaware. This example is particularly striking because the sole presence of oroalimentary automatisms allows a firm conclusion about the epileptic origin of a condition that might otherwise be considered an anxiety disorder, inasmuch as the scalp-electroencephalogram is usually normal in such types of limbic seizure.

Spontaneous narrative by nonmedical observers can be inadequate, so direct questioning is also needed. Efforts should always be made to directly question witnesses. A single telephone call can prove much more fruitful than costly medical examinations. The critical questions relate to the first detectable abnormal sign witnessed and whether there was any warning from the patient. Was there any detectable blush or pallor, change in respiration rate or facial expression, or head deviation? Were the eyes open with a fixed orientation or responsive to external stimulation (in favor of partial seizures), closed (in favor of nonepileptic seizures), or rolled upward (suggesting GTCS or syncope)? Were the arms still, or in a peculiar posture or gesture, or were they rhythmically moving? If a patient fell, was the fall abrupt or progressive, forward or backward, with legs bent or stretched, and was the fall followed by general hypotonia or hypertonia?

If “convulsions” are reported, their duration, type, and the amplitude of limb movements must be specified to distinguish GTCS from convulsive syncope and psychogenic attacks. In GTCS, clonic movements are characterized by tonic contractions of moderate amplitude that last approximately 30 seconds. In convulsive syncope, only one to five irregular clonic movements are observed during a few seconds. In psychogenic “convulsion-like” episodes, rhythmic limb movements typically resemble a large-amplitude tremor developing in the context of neutral or decreased muscular tone and often lasting several minutes.

If a seizure is primarily characterized by a lack of responsiveness, particular attention should be paid to the presence of automatisms, which, though often noticed, are infrequently reported spontaneously by witnesses. The diagnostic value of oroalimentary automatisms has been mentioned, the same is true for manual, pedal, and verbal automatisms, which all strongly suggest an epileptic origin for seizures. These automatic activities tend to imitate seemingly natural or purposeful gestures or speech, although they usually appear meaningless or inappropriate during a seizure. They must be distinguished from elementary motor activity leading to posture, change in muscle tone, clonic jerk, or a scream. In the 1989 classification of seizures and epilepsies, automatisms are specifically associated with complex partial seizures. In fact, as previously described, subtle automatisms may also occur during simple partial seizures and, at times, during absence seizures.

Seizures Associated With Complete Loss of Consciousness, a Fall, and Convulsive Features

This category includes “primary” GTCS, secondary generalized partial seizures, and the much less frequent generalized tonic, atonic, or clonic seizures. Distinction between primary and secondary generalized tonic-clonic seizures has important therapeutic consequences and can pose a difficult diagnostic problem. Differential diagnosis primarily includes syncope and psychogenic nonepileptic seizure.

Differential Diagnoses

Syncope can result from various pathophysiological mechanisms with a common endpoint being a decrease in cerebral perfusion responsible for acute cerebral and brainstem dysfunction. Vasovagal syncope is the most frequent and can be mistaken for GTCS. It typically occurs in adolescents and young adults following emotionally salient stimuli (pain, sight of blood during venous puncture, warm and enclosed atmosphere) or after standing motionless for prolonged periods (related to progressive venous blood sequestration in the lower limbs). Thus, vasovagal syncope usually occurs in the standing position and often aborts if a patient lies down in the early phase of an attack. More rarely, vasovagal syncope will occur in a seated patient at the end of a meal, triggered by digestion-induced splanchnic blood sequestration. Prodromes include vertigo, visual and auditory disturbances, nausea, sweating, and the feeling of an imminent fainting or death. Intense pallor and general hypotonia follow, resulting in a progressive nontraumatic fall and loss of consciousness, with eyes closed or rolled upward. At times, syncope might progress to brief axial hypertonia associated with a few irregular clonic limb movements (fewer than six), “convulsive syncope.” Urination and biting of the tip of the tongue can occur, but normal consciousness is restored much more rapidly than in GTCS. Thus, detailed analysis of all signs and symptoms usually results in a clear distinction of syncope from GTCS, even in the presence of clonic movements, urination, and tongue biting. When necessary, a tilt test can be used to confirm the diagnosis of vasovagal syncope. Cardiogenic syncope represents a less frequent form of attack, observed in older patients with cardiovascular pathology but no other precipitating factors. It is characterized by a more abrupt loss of consciousness and fall.

Psychogenic nonepileptic seizures (psychogenic nonepileptic seizures) can mimic several seizure types including GTCS. They can be precipitated by a stressful event, typically in a patient with a history of child abuse. They can also occur in epileptic patients making the differential diagnosis more difficult. In psychogenic nonepileptic seizures resembling GTCS, patients are unlikely to report an aura and are usually evasive regarding activity prior to seizure onset. A nontraumatic fall can be seen in standing patients, but psychogenic nonepileptic seizures occur more frequently in patients who are seated or lying down. No tonic phase is observed (nor is vocalization, apnea, or cyanosis), and clonic movement proper is not seen. Abnormal movements typically consist of erratic movements of the limbs associated with pelvic thrusts or tremor like agitation of the entire body, while the eyes remain closed and characteristically show active resistance to opening. The movements often last several minutes with a waxing and waning evolution. In the postictal period, patients may be calm, motionless, and unresponsive with closed eyes, or they break into tears and are distressed. No postictal confusion, urinary incontinence, or tongue biting are observed. The triggers for and termination of psychogenic nonepileptic seizures are both highly suggestible.

Simulated seizures are distinguished from psychogenic nonepileptic seizures by the intention to mislead others. Secondary benefits should be obvious to evoke this diagnosis, which is nevertheless difficult unless acknowledged by a patient explicitly.

Seizures Primarily Characterized by an Impairment of Consciousness

Seizures predominantly characterized by an impairment of consciousness, or lack of responsiveness, are often referred to as “absences.” The term is easily understood but carries a risk of misclassification of seizure type and, in turn, epileptic syndrome. An isolated impairment of consciousness can be a generalized absence seizure or a complex partial seizure, evoking diagnoses of idiopathic generalized epilepsy and partial epilepsy, respectively. This distinction parallels that between primary GTCS and secondary generalized seizures. Psychogenic nonepileptic seizures can also mimic this form of attack.

To describe seizures primarily characterized by an impairment of consciousness, without inferring their mode of onset, the term “dialeptic” has been proposed, the use of which is to be encouraged within the medical community. In its original definition, based on detailed observations of video-recorded attacks, dialeptic seizure excludes episodes where lack of responsiveness is associated with marked automatisms or other abnormal motor activity (the latter being referred to as motor seizures with several subtypes). In real life, however, seizure descriptions rely on witnesses who usually place more emphasis on the lack of responsiveness than on associated motor signs, describing these episodes also as absences.

The duration of impairment of consciousness and accompanying symptoms can provide clues about the underlying seizure type, although this criterion has many exceptions. The distinction between the two main forms of dialeptic seizure often relies on other features, in particular, the age at onset, seizure frequency, and electroencephalographic findings.

Absence seizures are included in the category of generalized seizure and primarily encountered in childhood absence epilepsy. Typical absence seizures are characterized by an abrupt impairment of consciousness lasting 5 to 30 seconds, followed by immediate and full restoration of normal consciousness. Decreased attention or alertness, emotion, and hyperventilation are predisposing factors. Patients usually remain motionless without change in muscular tone, gait, or stance if standing. Subtle eyelid or perioral 3-Hz myoclonus can be observed, as can manual automatisms during longer lasting episodes (more rarely, autonomic signs or axial hypotonia). Most characteristically, typical absences recur from ten to several hundred times a day in childhood absence epilepsy. They can be overlooked by teachers and parents who conclude that a child is simply inattentive. Absence seizures are less frequent in the juvenile form of absence epilepsy and in other idiopathic generalized epilepsies such as juvenile myoclonic epilepsy. Atypical absence seizures represent a less frequent form of generalized absence seizure usually encountered in the epileptic encephalopathies. They are less abrupt, of longer duration, and associated with more marked tonic, atonic, or myoclonic features than typical absences. Motor signs are often asymmetrical and can result in atraumatic falls.

Complex partial seizures can resemble absence seizures in a minority of patients, especially when originating in prefrontal regions resulting in isolated dialeptic seizures of short duration. However, complex partial seizures can be easily distinguished from absences in the majority of patients because of the presence of one or more of the following ictal signs or symptoms:

Preceding aura (including all forms of simple partial seizures described further)

Patient warning (vocalization) at seizure onset

Partial responsiveness

Lack of motionless staring

Marked motor, verbal, or oroalimentary automatisms

Focal dystonic, tonic, clonic, or atonic motor manifestation

Clear-cut emotional or autonomic signs

Duration over 30 seconds

Postictal deficit, urinary urgency, thirst, nose wiping, or confusion

The large variety of ictal complex partial seizure manifestations cannot be detailed herein, nor the distinctive features of temporal, frontal, parietal, occipital, or insular seizures. These descriptions that are of relevance for localization of seizure onset zones in epilepsy surgery candidates are addressed in Chapters 54.

Differential Diagnosis (Psychogenic Nonepileptic Seizures, Parasomnia)

Psychogenic nonepileptic seizures can resemble dialeptic seizures especially in patients who have suffered or observed such seizures in others. Automatisms are very unlikely to occur in psychogenic nonepileptic seizures, but tremor-like focal limb movements can be associated with apparent impairment of consciousness. Eye closure with active resistance to opening remains a very suggestive sign of psychogenic nonepileptic seizures in this form of nonepileptic seizure.

Parasomnias can be confused with nocturnal seizures, although patients with somnambulism and nocturnal terror attacks typically remember their dreams once awoken, whereas patients with nocturnal seizures usually do not recollect psychic experiences associated with their ictal behavior. Misdiagnosis usually results from partial seizures being regarded as parasomnias; this is especially so in the three main types of attack described in nocturnal frontal lobe epilepsy—paroxysmal arousal, nocturnal paroxysmal dystonia, and episodic nocturnal wandering. The abrupt onset and termination of these seizures and the typical movements observed in nocturnal paroxysmal dystonia characterized by pelvic and bimanual or bipedal repetitive movements, including pelvic thrusts, bicycling, and kicking often associated with vocalizations, usually point to the epileptic origin of an attack.

Seizures Primarily Characterized by Abnormal Sensations with Preserved Consciousness

Simple partial seizures represent the main form of epileptic attack with preserved consciousness. Generalized myoclonic seizures are characterized by failure to recognize myoclonic jerks despite preserved consciousness to the extent that they may remain unreported by patients. The differential diagnoses range from generalized anxiety disorder with panic attack to presyncopal states, hypoglycemia, transient ischemic attacks, migraine with aura, and gastrointestinal disorders in children. Misdiagnosis is usually due to a failure to identify the epileptic origin of attacks rather than the opposite, but one should be aware of possible comorbidity.

Simple partial seizures can result in a great variety of sensory illusions and hallucinations (olfactory, gustatory, auditory, visual, somatosensory, vestibular) that can range from elementary to highly elaborated perceptions (music) including complex psychic experiences such as déjà vu, déjà vécu, and other dreamy states. Inner body sensations are also very frequent, especially rising epigastric and often distressing sensations, as well as pelvic, abdominal, thoracic, and throat manifestations. Emotional manifestations are usually negative, such as fear, and there can be various autonomic signs, including tachycardia, flushing, and breathing difficulties. Unlike automatisms, focal tonic or clonic movements can be recognized by patients during a simple partial seizure.

Among rare and odd symptoms that are misinterpreted by both patients and physicians, one should be aware of out-of-body experiences and heautoscopy (when patients see their own bodies from a distant visual perspective or mirror images of themselves); ecstatic seizures often compared with divine experiences, possibly at the origin of prophecies; orgasmic attacks most usually described as painful; and gelastic seizures characterized by unmotivated and irrepressible laughter that is often symptomatic of a hypothalamic hamartoma.

Differential Diagnoses of Simple Partial Seizures

Presyncopal states of vasovagal origin have been described in a previous section. The distinction from epileptic seizures relies on the presence of specific precipitating factors; progressive onset, intense pallor, and a combination of sensory and vegetative symptoms. Whereas many of these symptoms can occur together during seizures, the specific combination of vertigo, visual and auditory disturbances, nausea, sweating, and a feeling of imminent fainting or death is very unlikely to result from an epileptic fit.

Panic attacks are primarily characterized by the progressive onset of intense unmotivated fear and agitation associated with increased heart and respiratory rates, thoracic pain and feeling of an imminent death, paraesthesias, sweating, and nausea.

Hypoglycemia typically results in hunger, epigastric pain, pallor, and sweating at times associated with neurological deficits. In severe hypoglycemia, usually precipitated by drugs in diabetic patients, symptoms can be followed by an authentic epileptic seizure. A blood glucose assay readily identifies this disorder.

Transient ischemic attacks raise two potential sources of misdiagnosis: (1) Some partial seizures are characterized by an isolated ictal aphasia or focal limb deficit (negative motor manifestation) lasting from several seconds to a few minutes that can be wrongly diagnosed as a transient ischemic attack. These rare seizure types are usually symptomatic of an MRI-detectable brain lesion located in a specific cortical region (Broca’s area, inferior dorsolateral premotor cortex, mesial aspect of the precentral and postcentral regions). (2) Conversely, a transient ischemic attack can precipitate a seizure, leading to an erroneous diagnosis of postictal Todd’s paralysis and failure to diagnose the underlying ischemic etiology. In both of these circumstances, a vascular workup is recommended.

Migraine with aura clearly differs from simple partial seizures by its progressive onset, slow propagation, and the long duration of aura reflecting spreading cortical depression whose speed approximates 3.5 mm/min within the visual cortex. The characteristics of visual migrainous auras also differ from those of occipital epileptic seizures, with noncolored hallucinations moving from peripheral to central portions of the visual field in migraine and colored hallucinations, static or growing from center to periphery, in epilepsy. Misdiagnosis can result from the fact that partial seizures; in particular, those originating in the occipital lobe, can be associated with severe postictal migraine.

Gastrointestinal disorders, and especially gastric reflux, can be wrongly diagnosed in young children with epileptic seizures primarily characterized by epigastric discomfort or vomiting. The lack of a clear-cut positional or feeding precipitating factor, the presence of associated automatisms or lack of responsiveness, and epileptiform electroencephalographic abnormalities prevent such misdiagnosis.

Generalized myoclonic seizures are described in this section because they are associated with fully preserved consciousness. However, due to their benign features, this type of seizure almost never leads to medical attention or to spontaneous complaint by patients interviewed after a first GTCS. They are primarily encountered in juvenile myoclonic epilepsy and characterized by single or repetitive brief bilateral and symmetrical jerks of proximal limb segments, typically the shoulders, leading to the release of held objects (most likely those used during washing and breakfast due to their morning time of occurrence). Falls may occur when the lower limbs are affected.

Biological Markers of Epileptic Seizures

Creatine kinase is typically elevated in the hours following a GTCS, reflecting muscular exhaustion resulting from sustained ictal hypertonia. The levels of the enzyme remain normal in syncope and psychogenic nonepileptic seizures.

Prolactin release peaks 15 minutes after the end of a GTCS or of a temporal lobe complex partial seizure, reflecting the propagation of ictal discharges into the hypothalamus. The relatively low magnitude of this release needs to be compared with a baseline value obtained in the same individual at the same hour on another day.

Electroencephalography

Electroencephalography is an essential and necessary tool to establish the diagnosis of epileptic syndromes once the epileptic origin of seizures has been ascertained. However, electroencephalography has several limitations for identification of seizure type:

The presence of interictal epileptiform electroencephalographic abnormalities (spikes, sharp waves, spikes and waves) favors an epileptic origin of a seizure but does not exclude a nonepileptic attack, because a few percent of normal individuals demonstrate incidental electroencephalographic findings of these types. Conversely, interictal electroencephalograms often prove normal in epileptic patients, of whom 15% will consistently fail to show epileptiform abnormalities on repeat investigation.

Ictal electroencephalography is very rarely obtained on a first recording unless the patient has very frequent absence seizures, or attacks precipitated by hyperventilation or intermittent photic stimulation, in which case it usually provides clear-cut evidence of seizure type. The electroencephalogram can also prove inconclusive in patients with epileptic foci that are localized on the mesial surface of the brain. These include two previously discussed forms of frequently misdiagnosed seizure type: simple partial seizures of mesial temporal origin giving rise to isolated epigastric sensations and nocturnal paroxysmal dystonia of mesial frontal origin.

In contrast to these limitations a postictal electroencephalogram has the advantage of being more readily obtained than an ictal electroencephalogram, while still demonstrating abnormalities such as postictal slow waves that are directly related to a preceding seizure (Fig. 52-1). When present, such slow waves strongly support an epileptic origin for attacks and may differentiate between generalized and focal seizures depending on the scalp distribution.

Figure 52-1 Postictal slow waves.

Familial History

The familial history can reveal various forms of genetic susceptibility to seizures and epilepsy. An autosomal dominant transmission is observed in rare and heterogeneous conditions such as nocturnal frontal lobe epilepsy, generalized epilepsy with febrile seizures plus, benign familial neonatal or infantile convulsions, a peculiar form of juvenile myoclonic epilepsy, and tuberous sclerosis. Recessive and maternal transmission occurs in various rare forms of progressive myoclonic epilepsy, whereas some abnormalities of neuronal migration are characterized by X-linked transmission.

Idiopathic generalized epilepsy is often found in several members of the same family; the basis for this is believed to be polygenic transmission. The affected members of the same family can present with different forms of idiopathic generalized epilepsy, or even other types of epileptic syndrome such as primary reading epilepsy.

Past History

A past history of perinatal insult, complicated febrile seizures, meningitis and other central nervous system infections, severe head trauma, and any other neurological disorders should be sought, for they might represent the etiology of nonidiopathic partial epilepsy.

Perinatal insults include all events that might have resulted in ischemic, hypoxic, or traumatic brain lesions, in particular, premature or prolonged delivery.

Complicated febrile seizures represent 5% of all febrile seizures, which themselves affect 4% to 5% of all children. Febrile seizures are complicated when one of the four following criteria is present: occurrence before the age of 9 months, duration longer than 20 minutes, unilateral or asymmetrical clonic movements, and postictal neurological deficit. The risk of developing temporal lobe epilepsy after a complicated febrile seizure is about 50%, whereas it is only 2.5% after a simple febrile seizure.

Severe head trauma results in post-traumatic epilepsy in 0.5% to 5% of cases. One should distinguish early post-traumatic seizures occurring during the first week from post-traumatic epilepsy that develops later, although the former is a risk factor for the latter. The delay between head trauma and the onset of post-traumatic epilepsy is less than 1 year in 60% of cases, less than 3 years in 80%, and less than 10 years in 95%. The severity of head trauma is assessed by the presence of the following criteria: penetrating open trauma (associated with a 30% risk of developing post-traumatic epilepsy), intracranial hematoma, any type of computed tomography (CT) scan or MRI-detectable brain lesion, prolonged neurological deficit, coma or post-traumatic amnesia greater than 24 hours, and depressed skull fracture.

Meningitis, meningoencephalitis, and brain abscess are frequent causes of partial epilepsy. Neurocysticercosis is the leading cause in Latin America. HIV infection is commonly associated with epileptogenic opportunistic brain infections in developing countries.

A great variety of other neurological disorders can give rise to epilepsy including stroke, brain tumors, vascular malformations, multiple sclerosis, and Alzheimer’s disease. Systemic autoimmune diseases also favor the development of epilepsy, including specific conditions such as Hashimoto’s and celiac diseases (see later).

Age at Onset

Age at onset is a major diagnostic criterion in the vast majority of idiopathic or generalized epilepsy syndromes. The main exceptions are cryptogenic and symptomatic partial epilepsies, which can occur at virtually any age. Table 52-1 provides an overview of the age-dependent syndromes by increasing age at onset.

TABLE 52-1 Overview of the Age-Dependent Syndromes by Increasing Age at Onset

Neurological and General Examinations

These examinations are normal in the great majority of patients with idiopathic and cryptogenic epilepsy. Conversely, children with epileptic encephalopathies usually show developmental delay, justifying a thorough neuropsychological assessment. Symptomatic epilepsies can be associated with any type of neurological dysfunction depending on the number, size, and location of any underlying brain lesion(s). Other physical findings, in particular, skin abnormalities, are also found in certain specific epileptogenic disorders such as tuberous sclerosis or Sturge-Weber syndrome.

Electroencephalography

Electroencephalography is a mandatory investigation in all epileptic disorders including first unprovoked seizure, where it helps determine the risk of subsequent attacks. As previously mentioned, a postictal electroencephalogram performed within 6 hours of a seizure is likely to be more informative than interictal electroencephalogram and should be obtained in patients hospitalized for de novo epilepsy.

Standard electroencephalography typically lasts 20 minutes, including periods of hyperventilation and intermittent photic stimulation. Hyperventilation favors the occurrence of all types of interictal electroencephalographic abnormalities and can precipitate absences as well as partial seizures. It also elicits physiological slow waves, at times of very high amplitude, in children and young adults. Intermittent photic stimulation can also be responsible for physiological photomyogenic electroencephalographic responses, which should be distinguished from the abnormal photoparoxysmal response, which is characterized by generalized spike-and-wave or polyspike-and-wave discharges that can culminate in a clinically overt seizure (Fig. 52-2). Photoparoxysmal response is observed mainly in juvenile myoclonic epilepsy and in the rare, purely photosensitive epilepsies. Photoparoxysmal response can also be seen in nonepileptic patients, especially in family members of juvenile myoclonic epilepsy probands.

Figure 52-2 Photoparoxysmal response with generalized polyspike and waves elicited by intermittent photic stimulation in juvenile myoclonic epilepsy.

In children, longer recordings are often needed to obtain essential information provided by sleep recordings at this age. Sleep stages 1 and 2 can facilitate the appearance of interictal abnormalities, especially in idiopathic partial and generalized epilepsies. Sleep recording is also mandatory to detect the syndrome of continuous spikes-and-waves during sleep as well as the tonic ictal discharges that characterize Lennox-Gastaut syndrome. In some instances, a 24-hour ambulatory electroencephalogram is needed to thoroughly investigate all states of vigilance, associated with polygraphic recording of muscle activity and respiratory rate when necessary. In-hospital video-electroencephalographic monitoring lasting several hours to 1 or 2 weeks may be needed to characterize some seizures fully, especially if electrical or clinical data are insufficient to permit classification of seizure type or the underlying syndrome.

Patients with epilepsy can show epileptiform abnormalities, including focal or generalized, symmetrical or asymmetrical spikes (duration less than 80 milliseconds), sharp waves (duration, 80 to 200 milliseconds), polyspike, spike-and-wave, and polyspike-and-wave complexes that can be isolated or assembled into rhythmic bursts or discharges of various durations, amplitudes, and frequencies (Fig. 52-3). When lasting more than a few second(s), these rhythmic epileptiform patterns constitute ictal discharges. Bilateral symmetrical generalized spike-and-wave discharges with a frequency that is equal to or higher than 3 Hz are characteristic of typical absence seizures and more generally of idiopathic generalized epilepsies (Fig. 52-4). Conversely, bilateral asymmetrical generalized spike-and-wave discharges with a frequency that is equal to or lower than 2.5 Hz are seen in atypical absence seizures and cryptogenic or symptomatic generalized epilepsies (Fig. 52-5). Generalized tonic or tonic-clonic seizures are characterized by a diffuse flattening of the electroencephalogram, reflecting a very high frequency discharge of low amplitude. Various types of focal ictal discharges are seen at the onset of partial seizures, including rhythmic spikes, sharp waves, or slow waves, as well as low-amplitude fast-activity discharges (Fig. 52-6). Patients with epilepsy can also show nonepileptiform, and thus less specific electroencephalographic findings, such as intermittent slow waves. Permanently abnormal background activity or a slow wave focus that is poorly or not reactive to external stimuli suggests an underlying encephalopathy or brain lesion.

Figure 52-3 Generalized 3-Hz spike and wave discharge during an absence seizure in childhood absence epilepsy.

Figure 52-4 Left frontal spikes and sharp waves (F3) in cryptogenic frontal lobe epilepsy.

Figure 52-5 Bilateral asymmetrical generalized spike-and-wave discharges with a frequency lower than 2.5 Hz during an atypical absence seizure in Lennox-Gastaut syndrome.

Figure 52-6 Right temporal lobe discharge during a temporal lobe seizure.

Neuroimaging

Neuroimaging must be performed in the majority of patients with epilepsy, unless clinical and electroencephalographic data have allowed a confident diagnosis of an idiopathic partial or generalized epileptic syndrome.

Although CT scanning is much less sensitive than MRI in the identification of epileptogenic brain lesions such as hippocampal sclerosis, malformations of cortical development, cavernous angiomas, and low-grade tumors, it has two important applications:

CT remains the method of choice for investigating newly diagnosed patients in an emergency setting. Indeed, based on the fact that 1% of de novo seizures are symptomatic of brain lesions requiring rapid neurosurgical management, including subdural and intracerebral hematomas and brain abscess, a CT scan without contrast enhancement is recommended in the immediate management of patients with newly diagnosed seizures associated with any of the following criteria: a partial seizure, age greater than 40, a focal neurological abnormality, persisting headache or confusion, fever, HIV infection, recent head trauma, anticoagulant treatment, and cancer.

In addition, CT scanning may be more sensitive than MRI in detecting calcifications, such as those observed around the ventricles in tuberous sclerosis, or the occipital calcifications associated with celiac disease (Fig. 52-7).

Figure 52-7 Bilateral occipital calcifications in celiac disease with occipital lobe epilepsy.

MRI is the gold standard for neuroimaging of the nonidiopathic epilepsies. It should be performed at 1.5 T or higher, by a radiologist familiar with the special sequences and slices orientations for optimal investigation of epileptic disorders. A standard epilepsy protocol should typically include a three-dimensional 1-mm³ resolution T1-weighted sequence as well as T2-weighted and FLAIR images in the axial and coronal planes, the latter perpendicular to the long axis of the hippocampus. Provided such a protocol, MRI can detect abnormalities in up to 80% of patients with temporal lobe epilepsy and approximately two thirds of patients with nonidiopathic epilepsies. The most frequently encountered epileptogenic brain lesions are hippocampal sclerosis (Fig. 52-8), gliotic scars following various cerebral insults, low-grade tumors, and, in particular, dysembryoplasic neuroepithelial tumors, gangliogliomas, oligodendrogliomas, cavernous angiomas, and malformations of cortical development, including cortical dysplasia, heterotopia, and polymicrogyria.

Many other investigations can occasionally be useful for the identification of a specific disease underlying an epileptic disorder, including biochemical and ophthalmological tests, as well as skin or muscle biopsy.

Figure 52-8 MRI sign of hippocampal sclerosis with atrophy and increased T2 signal of the left hippocampus.

Epileptic Syndromes in Neonates, Infants, and Children Younger Than 6 Years

Epilepsies occurring before the age of 6 include a great variety of rare disorders, many of which are associated with a grave prognosis. The very benign syndromes of neonatal convulsions that remit spontaneously and rapidly after a few days stand apart, provided an underlying metabolic dysfunction has been ruled out, The majority of epileptic syndromes encountered in infancy and early childhood, in particular, those manifesting with a generalized myoclonic or tonic component, lead to severe epilepsy associated with encephalopathy or developmental delay of varying severity. These include early myoclonic encephalopathy, early-infantile epileptic encephalopathy with suppression burst (Otahara’s syndrome), severe myoclonic epilepsy of infancy (Dravet’s syndrome), infantile spasms (West’s syndrome), and Lennox-Gastaut syndrome. These conditions necessarily require the expertise of a child neurologist or epileptologist and are not dealt with further in this chapter. The same expertise is needed to distinguish these disorders from less severe forms of epilepsy such as myoclonic-astatic epilepsy (Doose’s syndrome), benign myoclonic epilepsy in infants, and all forms of cryptogenic or symptomatic partial epilepsies that might occur at this age.

Many of these disorders, including Otahara’s, West’s, and Lennox-Gastaut syndromes, can result from surgically treatable brain lesions and thus require expert MRI investigation.

Idiopathic Epilepsies of Late Childhood and Adolescence

The idiopathic epilepsies, in particular, childhood absence epilepsy, juvenile myoclonic epilepsy, and benign childhood epilepsy with centrotemporal spikes,¹ represent the most prevalent epileptic syndromes of childhood and adolescence. They should be identifiable by any physician involved in the care of patients with epilepsy, inasmuch as specific treatments exist for these syndromes.

Idiopathic epilepsies are typically age related and characterized by a benign evolution. In addition, the generalized forms of idiopathic epilepsy are usually associated with familial history of idiopathic generalized epilepsy, although not necessarily a similar epileptic syndrome, and a favorable response to valproate.

Childhood absence epilepsy occurs in school-aged children of normal intelligence and is characterized by very frequent typical absence seizures, up to several hundred per day, that can be elicited by hyperventilation. Electroencephalography demonstrates generalized 3-Hz spike-and-wave discharges and otherwise normal background activity. Evolution is usually benign under appropriate treatment, with disappearance of absences during adolescence, but breakthrough GTCS might occur at that age in 40% of patients.

Juvenile myoclonic epilepsy has a peak incidence between 12 and 17 years but can occur more rarely in younger children and adults. Generalized myoclonic seizures, described in detail in a previous section of this chapter, are an invariant feature of this epileptic syndrome. Bilateral myoclonic jerks are typically experienced on awakening without associated loss of consciousness and are often not reported spontaneously by patients. GTCS are seen in 90% of patients often preceded by repetitive myoclonic jerking. From 10% to 15% of patients also suffer absence seizures. Clinical or electroencephalographic photosensitivity is present in 30% to 40% of patients. Sleep deprivation and alcohol intake can be triggering factors, especially for GTCS. Interictal electroencephalography shows generalized or asymmetrical polyspike-and-wave discharges at 3 Hz or faster. In contrast to most other idiopathic epilepsies, juvenile myoclonic epilepsy remains drug dependent during adulthood, with seizure relapse in 90% of patients who withdraw treatment.

Benign childhood epilepsy with centrotemporal spikes is the most frequent epileptic syndrome of childhood with an age at onset ranging between 3 and 13 years. Seizures are typically sleep-related and characterized by tonic-clonic contraction of one side of the face and ipsilateral tongue and pharyngeal-laryngeal muscles, ictal anarthria, and profuse dribbling at times preceded by somatosensory symptoms in the same body parts, and preserved consciousness. Secondary involvement of the ipsilateral upper limb can also be seen, as well as secondary generalization. Interictal electroencephalography shows typical high-amplitude, slow biphasic centrotemporal spikes, with a characteristic tangential dipolar distribution (Fig. 52-9). Spikes greatly increase in frequency and often become bilateral during sleep. Antiepileptic drug treatment can be avoided if seizures are brief and appear only during sleep.

Figure 52-9 Typical high-amplitude slow biphasic right centrotemporal spikes in benign childhood epilepsy with centrotemporal spikes.

Nonidiopathic Partial Epilepsies

Nonidiopathic partial epilepsies represent between 50% and 60% of all epilepsies and occur across the entire life span. The seizure type varies greatly as a function of the cortical regions involved by an ictal discharge and often provides information about the most likely side and lobe of onset. Such information is useful in interpretation of the relationship between an MRI-detected abnormality and associated seizures or can help in detection of subtle brain lesions or malformations of cortical development. The multiple forms of nonidiopathic partial epilepsies need to be distinguished because specific management issues arise in this frequent disorder. For instance, mesial temporal lobe epilepsy with MRI changes of hippocampal sclerosis is characterized by a high rate of pharmacoresistance that is estimated to lie between 60% and 90% and shows an excellent response to epilepsy surgery in 80% of operated patients (Fig. 52-9). Despite these figures, the majority of patients with mesial temporal lobe epilepsy are referred for presurgical evaluation after an average delay of 15 to 20 years, primarily because the epileptic syndrome has not been properly assessed.

Mesial temporal lobe epilepsy often develops in children, adolescents, or young adults with a past history of complex febrile convulsions. Among the many different signs and symptoms that can occur during temporal lobe seizures, the following ictal sequence is the most suggestive of mesial temporal lobe epilepsy: initial distressing, rising epigastric sensation sometimes associated with déjà vu or a dreamy state, early oroalimentary automatism followed by loss of awareness, upper limb motor automatisms ipsilateral to seizure onset with contralateral arm dystonia and ipsilateral head deviation, postictal nose wiping, and confusion with no or rare secondary generalization. Ictal verbal automatisms and postictal aphasia can also occur depending on the side of ictal onset. Hippocampal sclerosis can be readily detected on MRI provided that the appropriate sequences, slice thickness, and orientation are used to show clear-cut atrophy and an increased T2 and FLAIR signal within the hippocampus. Interictal electroencephalography often demonstrates anterior temporal spikes and intermittent slow waves but may also be normal.

Occasional Seizures

Occasional seizures must be distinguished from all of the above conditions as they usually do not require antiepileptic treatment but rather control of a provocative agent or situation.² The latter includes intake of excessive alcohol; of illicit drugs such as cocaine, codeine, amphetamines, and phencyclidine; and of many psychotropic drugs including antipsychotics, antidepressants, and lithium. Abrupt abstinence of alcohol, benzodiazepines, and barbiturates in chronic abusers can also precipitate a seizure. In contrast to alcohol-related seizures, alcohol-related epilepsy is characterized by relapsing partial or generalized seizures appearing in a chronic alcohol-abuser, independent of acute alcohol toxicity or sudden abstinence. It usually requires antiepileptic drug treatment.

Sleep deprivation can also elicit seizures. Similarly, patients with obstructive sleep apnea syndrome can have nocturnal seizures that are better controlled by treatment of sleep apnea than by antiepileptic drugs.

Finally, seizures can be provoked by acute metabolic dysfunction, including, hypoglycemia, hyponatremia, hypocalcemia, and hepatic and renal failure.

Nonketotic hyperglycemia is one particular such disorder that can complicate preexisting diabetes but also often occurs in patients without prior history of hyperglycemia. This specific metabolic disorder is responsible for reflex motor seizures triggered by active or passive posture or movements that can progress to epilepsia partialis continua. Biochemical testing shows hyperglycemia of varying severity without associated ketosis. MRI is normal. Antiepileptic treatments are ineffective, whereas normalization of glycemia by insulin rapidly leads to seizure control.

Progressive Myoclonic Epilepsies

Progressive myoclonic epilepsies include a variety of rare genetic seizure disorders associated with progressive neurological impairment, primarily characterized by action myoclonus and cerebellar dysfunction.³ They are thus of special interest to neurologists despite their rarity. Progressive myoclonic epilepsies at an early stage are often mistakenly diagnosed as juvenile myoclonic epilepsy, due to seemingly comparable age and seizure types at onset. However, a detailed analysis of the myoclonic jerks and neurological examination differentiate the two forms of myoclonic epilepsy, allowing anticipation of the far more severe prognosis of progressive myoclonic epilepsies. Various types of seizures can occur in these disorders, including generalized myoclonic seizures but also GTCS, atypical absences, and partial seizures that predominantly originate in the occipital lobe. However, the main clinical feature of progressive myoclonic epilepsy is the presence of action myoclonus that needs to be actively searched for. This movement disorder progressively worsens over years, together with the development of cerebellar dysfunction and cognitive impairment of varying severity, depending on the underlying etiology. Five diseases account for the great majority of progressive myoclonic epilepsies: Unverricht-Lundborg disease, myoclonic epilepsy with ragged red fibers, adult neuronal ceroid-lipofuscinosis (Kufs’ disease), Lafora’s disease, and sialidosis.

Unverricht-Lundborg disease is the most common cause of adult progressive myoclonic epilepsy with the highest prevalence around the Baltic and Mediterranean seas. Evolution is slow and cognitive impairment is usually mild or absent, but the condition can be significantly aggravated by phenytoin. The diagnosis is confirmed by detection of the EMP1 mutation in the cystatin B gene on chromosome 6.

Myoclonic epilepsy with ragged red fibers occurs at every age and results in progressive myoclonic epilepsy of varying severity, at times associated with neuropathy, extrapyramidal or pyramidal signs, and cardiac or hepatic dysfunction. Increased lactate can be observed in blood and cerebrospinal fluid, and muscle biopsy shows ragged red fibers in 90% of cases. The diagnosis is confirmed by detection of the MTTK mutation on mitochondrial DNA, accounting for the maternal line transmission. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes is another mitochondrial disorder that is more rarely associated with a progressive myoclonic epilepsy phenotype.

Lafora’s disease is primarily characterized by rapid neurological deterioration, leading to death within 10 years of onset. Transient blindness associated with occipital seizures is often described. Lafora bodies can be observed on skin biopsy, and the EMP2A mutation of the laforin gene is detected in 80% of cases.

Kufs’ disease is the adult form of neuronal ceroid lipofuscinosis and can be associated with a variety of nonspecific clinical patterns. Skin biopsy shows intracellular lipofuscin inclusion, whereas an important genetic heterogeneity hinders the detection of the underlying mutations in clinical practice.

Sialidosis has a juvenile or adult onset and is often responsible for a relatively pure and slowly progressive action myoclonus. However, GTCS, ataxia, and visual impairment associated with a characteristic cherry-red spot in the fundus can be observed. The diagnosis is confirmed by detection of a mutation on the NEU 1 gene.

Autoimmune and Endocrinological Seizure Disorders

These disorders are infrequent conditions whose special interest lies in the fact that they are diagnosed by specific biochemical tests and need specific treatment.

Celiac disease is associated with epilepsy in 3.5% to 5.5% of cases. Seizures typically originate in the occipital lobe, where bilateral calcifications are often observed (see Fig. 52-8). It is to be distinguished from Sturge-Weber syndrome, where the calcified occipital pial angiomata are usually unilateral. Epilepsy is often the presenting manifestation of this disorder, before the occurrence of intestinal symptoms. Diagnosis is confirmed by the detection of IgA endomysial antibodies. A gluten-free diet is then required, although its impact on epilepsy remains controversial.

Hashimoto’s disease can be responsible for an encephalopathy that combines seizures, myoclonus, and varying degrees of progressive cognitive impairment, confusion, and pyramidal signs. It usually manifests in the fifth decade. Partial seizures, most often arising from the temporal lobe, GTCS, and absence status might occur. MRI frequently shows hyperintense T2 lesions. The diagnosis is confirmed by positive anti-thyroid G and P antibodies, whereas thyroid function is normal in 66%. Corticosteroids are often spectacularly effective in this condition.

Several other rare forms of autoimmune limbic encephalitis have been described based on the demonstration of specific antibodies, including anti-Hu, which is found in paraneoplastic syndromes and those directed toward voltage-gated potassium channels, or the more recently discovered anti-neuropil antibodies. Recognizing these conditions has important therapeutic consequences as they can respond dramatically to corticosteroids.⁴