Epilepsy is a frequent neurological condition characterized by an enduring predisposition of the brain to develop unprovoked seizures. Epilepsy must be differentiated from acute symptomatic seizures.
A careful history is essential for the diagnosis of seizures and epilepsy. Electroencephalography (EEG) is often the most useful diagnostic test to confirm the diagnosis and classify seizures and epilepsy. Brain magnetic resonance imaging (MRI) is indicated in the absence of a well-defined genetic etiology. Identification of a specific epilepsy syndrome, when possible, guides medical treatment and prognosis.
Epileptic seizures are often misdiagnosed. Patients with uncertain diagnosis and/or pharmaco-resistant seizures should be referred to an epilepsy center for long-term video-EEG evaluation to confirm the diagnosis and assess patients as potential candidates for epilepsy surgery.
Selection of antiepileptic drugs (AEDs) is mainly based on seizure-type classification. There are currently more than 20 AEDs. Focal seizures may respond to practically any AED with the exception of ethosuximide. Generalized seizures respond better to a much more restricted group of AEDs (broad-spectrum drugs) including lamotrigine, levetiracetam, topiramate, valproate, and zonisamide. Other factors influencing drug selection include efficacy, toxicity, ease of use (determined by its pharmacokinetic profile and drug–drug interaction potential), and cost. Patient-related factors include age, gender, comorbidities, co-medications, and genotype.
Surgical therapy should be considered in patients with medication-resistant epilepsy and disabling seizures. Temporal lobectomy is the most commonly utilized surgical procedure and may result in complete seizure freedom in 60–70% of patients. Vagus nerve stimulation (VNS) is a palliative procedure, effective in a wide variety of epileptic syndromes. The ketogenic diet may be very effective, especially in pediatric patients.
Epilepsy is one of the most frequent neurological disorders, affecting between 0.5 and 1% of the population in the United States. Epilepsy has a predilection for children and the elderly. Approximately 200,000 new cases are diagnosed each year, a number expected to grow at a faster rate as the population ages. It is estimated that between 3 and 10% of Americans experience some kind of seizures during their lifetime.
A neurohospitalist or any physician providing inpatient care frequently interacts with seizure patients in five different situations: new-onset seizures; patients admitted for another illness; patients admitted via the emergency department (ED) for possible seizures; patients with known epilepsy admitted for another condition that may interfere with their seizures; and patients electively admitted for long-term video-EEG monitoring. The neurohospitalist should also familiarize themselves with their state laws regarding driving restriction after first seizures, recurrence of seizure, and major changes to medications.
Epilepsy is characterized by an “enduring predisposition of the brain to generate epileptic seizures.” Epilepsy has been classically defined as at least two unprovoked seizures more than 24 hours apart. Newer practical definitions have been proposed by a task force of the International League Against Epilepsy (ILAE) in 2014 to take into account the possibility of predicting recurrent seizures after a first episode and the possibility of resolution of epilepsy over time (Table 31-1). This new definition of epilepsy complements the earlier definition, but does not replace it.1
Definitions
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In the following sections, we detail the approach to the epilepsy patient and the steps needed to diagnose and treat the patient. These steps are informed by history and examination as well as testing (EEG, video-EEG, labs, MRI, and genetic testing):
Differentiating epileptic from nonepileptic seizures
Diagnosing the seizure type
Diagnosing the seizure syndrome
Starting rational monotherapy
If resistant, combining medications
Other last-resort therapies including surgical and dietary interventions
The first step for a neurohospitalist is to make an accurate diagnosis of epileptic versus nonepileptic seizures, as a misdiagnosis has serious repercussions for patients, and is not infrequent in clinical practice. Approximately one third of patients evaluated for seizures in our Epilepsy Monitoring Unit did not have epileptic seizures, and were diagnosed with either psychogenic nonepileptic seizures (PNES) or physiologic nonepileptic seizures, for example syncope.
Differential diagnosis of epileptic seizures is broad and age dependent, as illustrated in Table 31-2.2 The diagnosis is typically easier when patients present with a generalized tonic-clonic seizure where the differential is limited to convulsive syncope or PNES.
Seizures Differential Diagnosis
ADULTS Syncope Cardiogenic Vasovagal Reflex Hypotensive Transient ischemic attacks Transient global amnesia Vertigo Toxic and metabolic disorders Sleep disorders Paroxysmal dyskinesia PNES Panic attacks Hyperventilation syndrome Acute confusional state CHILDREN Basilar migraine |
The term pseudo-seizures is often used but should be avoided, as it is often interpreted as “fake seizures.” In most instances, there is no evidence for secondary gain. Patients often present with a dissociative disorder and cannot control these clinical events. These episodes are often just as disruptive to the patient’s life as “true” epileptic seizures.
A remote history of abuse is reported in 75% of cases, but typically, there is no severe psychiatric disorder identified in these patients. PNES may be, at times, difficult to distinguish from epileptic seizures. PNES are usually less stereotyped and often last longer than epileptic seizures. In general, they frequently last half an hour or more, with on and off periods. Emotional changes may be seen. PNES can often be induced or controlled by suggestion. The ictal behavior is diverse, but eye closure during seizures, lateral head movements, and prominent pelvic movements suggest PNES. Seizures may occur during drowsiness, but not during sleep. Traumatic complications and even urinary incontinence may occur with PNES, but a bitten tongue is suggestive of epileptic seizures. Differential diagnosis with frontal lobe seizures can be challenging. Diagnosis of PNES should be confirmed with video-EEG monitoring whenever it is possible.
Syncope is a frequent consideration in the differential diagnosis of patients with new-onset seizures. In cases of syncope, the transient loss of consciousness reflects an abrupt reduction in blood flow and oxygen supply to the brain. Circumstances preceding the syncopal episode may include prolonged orthostasis, hypovolemia, or specific triggers (pain, injection, cough, etc.). Associated symptoms such as lightheadedness and nausea preceding the loss of consciousness may be suggestive of syncope. Pallor and hypotonia are frequently reported. Cardiac syncope is not always associated with palpitations. Myoclonic jerks and a brief stiffening are frequently seen, a condition known as convulsive syncope. The convulsions result from a lack of cortical control of the brainstem, rather than an epileptic phenomenon. The brevity of motor changes and the absence of prolonged postictal changes are consistent with syncope. Urine loss may occur with syncope. A bitten tongue is less frequent than with seizures, and limited to the tip of the tongue. A true epileptic seizure may occur in this context, but is rare.
A simple historical questionnaire proposed by Sheldon3 accurately diagnosed seizures with 94% sensitivity and specificity (Table 31-3).
Questionnaire Proposed to Determine Whether an Episode of Loss of Consciousness is Due to Seizure or Syncope3
| Questions | Points if Yes |
|---|---|
| At times, do you wake with a cut tongue after your spells? | 2 |
| At times, do you have a sense of “déjà vu” or “jamais vu” before your spells? | 1 |
| At times, is emotional stress associated with losing consciousness? | 1 |
| Has anyone ever noted your head turning during a spell? | 1 |
| Has anyone ever noted that you are unresponsive, have unusual posturing or have jerking limbs during your spells or have no memory of your spells afterwards? (Score as yes for any positive response) | 1 |
| Has anyone ever noted that you are confused after a spell? | 1 |
| Have you ever had lightheaded spells? | −2 |
| At times, do you sweat before your spells? | −2 |
| Is prolonged sitting or standing associated with your spells? | −2 |
TIAs typically present with an abrupt onset of negative symptoms and signs such as hemiparesis, dysphasia, and visual loss. In contrast, seizures typically present with positive signs such as jerking or stiffening with variable and evolving distribution. Alteration of awareness is unusual with patients with TIAs, and is suggestive of seizures. Diagnosis can be more challenging when frequent minor seizures or a focal nonconvulsive status epilepticus is clinically associated with focal deficits such as dyslexia or dysphasia. An EEG may be required under these circumstances.
“Limb shaking” TIAs associated with severe carotid artery stenosis can mimic motor seizures; a postural trigger is often reported, that is, it occurs after the patient gets up from a chair abruptly, for example.4
Progressive-onset, slow-progression “in waves” and a long duration of focal neurological symptoms, lasting more than 5–10 minutes are suggestive of migraines. Diagnosis is easier when patients have a positive personal and family history of migraines, and when a typical migraine headache with nausea and photophobia follows the aura. Confusion and even loss of consciousness may be associated with basilar migraine.
Epilepsy is more frequent in migraineurs, and the two conditions may be related. Headaches are frequent following seizures, and are typically migrainous in nature. Electroclinical studies have shown that a partial seizure may be effectively triggered during the aura in some patients (migralepsy).
Movement disorders typically last longer than seizures and are associated with preserved consciousness. Paroxysmal dyskinesias, which present as episodic hyperkinetic disorders, may be kinesigenic, nonkinesigenic, or exercise induced. Dystonia and tics may be occasionally confused with seizures.
Diagnosis may be more difficult among patients with toxic or metabolic encephalopathies, when alteration of awareness may be associated with various involuntary movements. Under those circumstances, the EEG can be difficult to interpret, as triphasic waves often associated with metabolic disorders can mimic epileptiform discharges. The normalization of the EEG after injection of a benzodiazepine confirms the diagnosis of epileptic seizures only if the patient’s behavior improves concomitantly. In contrast, triphasic waves are less responsive to benzodiazepine effects.
Parasomnias can, at times, be difficult to differentiate from nocturnal seizures. Sleep walking and night terrors are typically noted among children during the first half of the night, but may persist into adulthood when they become difficult to distinguish from ictus.
Rapid eye movement (REM) behavior disorder is associated with Parkinson disease (PD). The absence of paralysis during REM sleep allows the patient to “act out” his/her dreams with often a violent and frightening tone. Epileptic seizures may have similar symptomatology, and video-EEG monitoring with EMG may be necessary to rule out seizures.
Variations in the level of vigilance during the day associated with a sleep disorder, such as sleep apnea or periodic limb movements, may have an abrupt onset. Patients typically have their eyes closed, and are easily arousable. In younger patients, the association with cataplexy and sleep paralysis may indicate narcolepsy.
CASE 31-1
The patient is a 24-year-old woman followed up for 4 years by a psychiatrist for bipolar disorder and anxiety. She has been treated with lamotrigine for mood stabilization, and is taking alprazolam for anxiety attacks. After discussing her symptoms with a friend who was a physician, she decided to consult a neurologist.
What elements in the history and the examination may point to seizures being the cause of these spells?
A thorough history is essential for the diagnosis. History should include personal and family data, epilepsy risk factors, potential triggering factors, ictal behavior, and recovery stage, associated signs such as tongue biting, and if multiple events were reported, whether these were stereotyped.
The initial phase of a seizure is the most informative. The aura, in particular, can provide evidence for epileptic seizures and valuable information regarding the area of possible seizure onset.
The neurological examination is often normal in patients with epilepsy. Particular attention is given on the level of vigilance and transient focalization that may indicate ictal and postictal changes. Skin evaluation may find evidence for a neurocutaneous disorder.
CASE 31-1 (continued)
In addition to anxiety attacks, she described stereotyped episodes with rising epigastric sensations and “déjà-vu” feelings concerning for simple partial seizures, which were exacerbated during periods of stress.
What is the next step in the diagnostic workup of this patient?
Serum chemistry with attention to serum sodium, calcium, magnesium, glucose, and renal and liver profile should be obtained systematically. Serum levels of some medications including AEDs may be useful. Blood and urine toxic screen are often obtained.
Serum prolactin levels may also be useful, as they may be raised 2- to 3-folds above baseline levels within 15–20 minutes following a generalized seizure, and in some instances of partial seizures, before returning to baseline after 60 minutes. Of note, serum prolactin levels may also be elevated following syncope.
EEG is the most useful test to evaluate patients with seizures. It may support the diagnosis of epileptic seizures and epilepsy, and is often essential for characterizing a specific epileptic syndrome (see Chapter 9).
Epileptiform discharges are hallmarks of epilepsy. Sharp waves and spikes found on routine EEG are strongly suggestive of clinical seizures. In most published series, only a very small percentage of adult patients without a history of seizures have epileptiform discharges on their EEG. The incidence of epileptiform discharges on EEG in patients with no clinical seizures is higher in the pediatric population and in patients with autism spectrum disorder.
Epileptiform discharges are identified on routine EEG in 35–50% of cases following a first unprovoked seizure. The epileptiform discharges may be brought out by hyperventilation and intermittent photic stimulation, which are used routinely. The probability of capturing epileptiform discharges may be increased when the EEG is recorded within 24 hours following the index seizure, after sleep deprivation, when sleep occurs during the recording, and in selected cases when additional electrodes are used. The probability of a positive study is considerably higher in patients younger than 20 years of age at the time of the recording and in patients with idiopathic generalized epilepsy. When the EEG is unrevealing, it may be repeated. The cumulative yield to identify epileptiform discharge increases to 70% after a third EEG. The probability of finding additional information after 3 negative EEGs is low.5
It is essential to realize that routine EEG(s) are persistently normal in approximately 30% of patients with seizures. Thus, a normal routine EEG does not rule out the diagnosis of seizures.
The gold standard to diagnose seizures and epilepsy is to record a seizure on video-EEG in order to demonstrate that a given behavioral change is associated with electrographic seizures. Long-term video EEG monitoring increases dramatically the yield of obtaining a recorded seizure, particularly when provocation techniques are used. In our Epilepsy Unit, one seizure or more is observed in about 80% of our patients. Similarly, the probability of recording interictal epileptiform discharges in patients with epilepsy is considerably increased. Video-EEG is the test of choice to diagnose nonepileptic seizures, particularly PNES (see Chapter 9).
Ideally, video-EEG monitoring is obtained in a specialized unit where technicians and specialized nurses are trained to interact with these patients. When not available, portable video-EEG machines may be used at the bedside.
Brain imaging should be obtained in most patients with new-onset seizures with the exception of patients with well-defined genetic epilepsies such as absence epilepsy, juvenile myoclonic epilepsy (JME), or benign rolandic epilepsy.
Magnetic resonance imaging (MRI) is preferred to brain computed tomography (CT) due to the higher sensitivity to detect epileptogenic lesions. CT is typically used in emergency cases. Particular attention is directed to the temporal lobes that are poorly evaluated with CT. A temporal lobe epilepsy protocol with thin T1 coronal cuts obtained perpendicularly to the long axis of the hippocampus and use of FLAIR sequences are requested when hippocampal sclerosis is a consideration.
When patients are potential candidates for epilepsy surgery, functional neuroimaging including ictal single photon emission computed tomography (SPECT) and interictal positron emission tomography (PET) are used for localizing the seizure focus, complementing EEG and anatomic neuroimaging.
CASE 31-1 (continued)
EEG showed well-defined left temporal sharp waves (Figure 31-1A). Brain MRI showed a low-grade tumor involving the left temporal lobe (Figure 31-1B), which was stable on repeat MRI study. Seizures persisted despite titration of lamotrigine and introduction of oxcarbazepine. A partial seizure arising from the left temporal region was documented on video-EEG (Figure 31-1C).
Figure 31-1
The patient is a 24-year-old woman who presented with new-onset simple partial seizures misdiagnosed for 2 years as anxiety attacks. (A) Routine EEG shows left temporal spikes during NREM sleep. (B) Axial FLAIR brain MRI shows a low-grade tumor involving the anterior and medial aspects of the left temporal lobe. (C) Simple partial seizure recorded during video-EEG monitoring showing a left temporal onset of the epileptiform discharges.
How would you classify the seizure in this patient?
The patient suffers from a focal seizure without loss of consciousness. In 1981, the ILAE proposed a classification of seizures based on EEG and clinical information.6 Seizures were divided into partial seizures, when seizure onset was limited to one hemisphere, and generalized seizures when the entire brain was involved. Partial seizures were described as complex when consciousness was impaired, or as simple partial seizures, otherwise. Simple partial seizures may evolve into complex partial seizures. Both simple and complex partial seizures may evolve into secondarily generalized tonic-clonic seizures. These main categories were further divided in numerous subtypes according to ictal behavior (Table 31-4).
Classification of Seizures (ILAE 1981)
Partial Seizure Simple partial seizure With motor signs With sensory symptoms With psychic symptoms Complex partial seizure Consciousness impaired at onset Simple partial onset followed by impairment of consciousness Partial evolving to secondary generalized tonic, clonic, or tonic-clonic Generalized Seizure Tonic-clonic seizure Myoclonic seizure Absence seizure Typical Atypical Clonic seizure Tonic seizure Atonic (astatic) seizure Unclassified |
Newer nomenclature commonly used by neurologists is as follows:
Focal seizure = partial seizure
Focal dyscognitive seizure = partial complex seizure
Focal seizures evolving to a bilateral convulsive seizure = secondarily generalized tonic clonic seizure.
The second step after a formal diagnosis of epileptic seizures is to determine the specific type of epilepsy, or the epileptic syndrome. Despite recent classification proposals, the classic terminology introduced by the ILAE in 19897 remains widely used. The term idiopathic indicates a presumed genetic origin, the term symptomatic defines cases where structural lesions or pathological processes are identified, and the epilepsy is labeled cryptogenic when it is presumed to be symptomatic but without an identified lesion. As many as 40% of epilepsies can be classified as cryptogenic in the usual clinical practice. Table 31-5 describes the various etiologies of epilepsy identified in a large series of patients in Rochester, Minnesota.8 The relative risk of developing seizures associated with various risk factors for epilepsy is shown in Table 31-6.
Etiology of Epilepsy in Patients with Newly Diagnosed Seizures in Rochester, MN (1935–1984).8
| Genetic or Unknown | 65.5% |
| Symptomatic | |
| Vascular | 10.9% |
| Congenital | 8% |
| Trauma | 5.5% |
| Neoplastic | 4.1% |
| Degenerative | 3.5% |
| Infectious | 2.5% |
Relative Risks Associated with Various Risk Factors for Epilepsy or Seizures7
| Cerebral palsy | 17–34 |
| Complex febrile seizures | 2.8–7.7 |
| Severe military head trauma | 580 |
| Severe civilian head trauma | 25 |
| Stroke | 22 |
| Alzheimer disease | 10 |
| Viral encephalitis | 16.2 |
| Bacterial meningitis | 4.2 |
| Multiple sclerosis | 3.6 |
| Alcohol | 10.1 |
| Heroin | 2.6 |
| Marijuana | 0.36 |
| No adverse exposure | 1 |
In approximately 60% of patients, a precise electro-clinical syndrome can be identified providing useful clinical information regarding etiology, prognosis, and selection of the most effective AED. Age at seizure onset, clinical seizures, specific EEG findings, associated clinical findings, natural history, and treatment response are used to describe these entities. A list of the main syndromes according to age at seizure onset is shown in Table 31-7. This electro-clinical approach should be complemented by a specific etiology when, for example, a genetic disorder is identified.
Selected Epileptic Syndromes According to Age at Seizure Onset
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More details regarding epileptic syndromes can be found in the Blue Guide edited by the Marseille School9 and in the guide by Panayiotopoulos.10
What are the most common syndromes associated with partial seizures?
Temporal lobe epilepsy
Most frequent form of epilepsy in adults
Frequent mesial temporal (amygdala/hippocampus) origin
Frequent history of febrile seizures in childhood. Onset of afebrile seizures during childhood or after puberty
Seizure semiology: Aura (epigastric sensation, déjà vu), motionless stare, lip smacking, postictal confusion
EEG : anterior temporal sharp waves
Brain MRI: may show mesial temporal sclerosis (Figure 31-2A and B)
Seizures frequently refractory to medical treatment
Often good surgical candidates (temporal lobectomy)
Frontal lobe epilepsy
Variable seizure semiology according to different frontal lobe regions
Seizures often brief and frequent, with predilection during sleep
Brief tonic seizures, with bilateral asymmetric tonic posturing or “bizarre” behavior with high-amplitude movements of arms and legs, may be confused with PNES.
Scalp EEG frequently unrevealing, even during seizures.
Surgical treatment often difficult in the absence of brain lesions on MRI.
Benign rolandic epilepsy
Onset between 4 years of age and puberty
Child usually with normal psychomotor development and neurological examination
Nocturnal simple motor seizures (facial twitching, tongue, buccal involvement); may be secondary generalized.
EEG is characteristic with high-amplitude rolandic (centro-temporal) spikes activated during the sleep (Figure 31-3).
Seizures may be severe and frequent, but most (>90%) remit after puberty.
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