Epilepsy and Its Differential Diagnosis

9.1   Fundamentals

9.2   Generalized Seizures

9.3   Focal (Partial) Seizures

9.4   Status Epilepticus

9.5   Episodic Neurologic Disturbances of Nonepileptic Origin


The patient was 76 years old when his wife, returning home from a brief shopping trip, found him confused and disoriented. His trousers were wet, and a broken coffee cup lay on the floor. She phoned the family doctor. The patient returned to normal consciousness within half an hour; by the time the doctor arrived, he was fully alert and oriented, but he had no recollection of what had happened and spoke of a complete “blackout.” The doctor examined him thoroughly and told him and his wife to call him at once if anything similar happened again. A few weeks later, while out walking with his wife, he suddenly fell. His eyes looked to one side, and, a few seconds later, the right corner of his mouth began to twitch, followed by his right arm and, finally, his entire body. Bloody froth came out of his mouth. A minute or two later, he was still lying motionless and unconscious on the ground. His wife called an ambulance. On arrival in the hospital he was awake again, but confused; half an hour later, he was fully alert and oriented.

The emergency medical team took a thorough history from the patient’s wife, as he once again had no recollection of the event. He had always been healthy in the past, except for high blood pressure. About 6 months previously, however, he had had a transient “speech problem,” and, at the same time, the right corner of his mouth had hung down, and his right arm had been weak. These problems had all resolved within a few days.

Clearly, the patient had had two epileptic seizures a few weeks apart. The initial disturbance, with disorientation, was a seizure of the “dyscognitive” type. The course of the second seizure, as observed by his wife, with twitching that successively spread from the right corner of the mouth to the right arm to the whole body, implied a focal onset of epileptic activity with secondary generalization. The epileptic focus was most likely to be in the left cerebral hemisphere. The focal onset and the patient’s advanced age implied that the seizures, in this case, were probably symptomatic. Accordingly, his electroencephalogram (EEG) showed a focus with slow waves and periodic steep potentials in the left frontal lobe. A magnetic resonance imaging scan revealed scarring in the area of an old stroke, presumably reflecting the event of 6 months before, in which he had been transiently aphasic with a mainly brachiofacial hemiparesis.

Lamotrigine was given to prevent further seizures, and he remained seizure-free for 2 years thereafter. Lamotrigine was then slowly tapered to off. He is now 81 and has had no further seizures.

Stroke is the most common cause of symptomatic epilepsy in the elderly. This type of epilepsy generally takes a benign course; anticonvulsive treatment is usually needed only for a limited time.

9.1 Fundamentals

Key Point

An epileptic seizure is produced by a temporally limited, synchronous electric discharge of neurons in the brain. It involves a combination of suddenly arising motor, somatosensory, special sensory, autonomic, and/or behavioral disturbances that reproduces itself in characteristic fashion each time the patient has a seizure, but varies from patient to patient. On rare occasions, seizure activity persists for more than 20 minutes and may go on for hours, or even longer, without interruption (status epilepticus). The epileptic event may affect a circumscribed area of the brain (partial or focal seizures) or both cerebral hemispheres at the same time (generalized seizures). Some, but not all, seizures involve an impairment of consciousness.

In their differential diagnosis, epileptic seizures must be carefully distinguished from other episodic events involving neurologic deficits and disturbances of consciousness.

Epidemiology One percent of all persons have epileptic seizures. The child of a parent with genetic epilepsy has a 4% likelihood of suffering from it.

Pathophysiology Epileptic seizures are due to the uncoordinated activity of neurons in the brain, which expresses itself electrophysiologically as an abnormality of the fluctuations of electrical potential that are seen in an EEG (see section ▶ 4.3.2). (If the surface EEG is normal, such abnormalities can be revealed by recording with depth electrodes.) The underlying cause is an imbalance of excitatory and inhibitory currents, with predominance of excitatory neurotransmitters such as glutamate and aspartate, or diminished activity of inhibitory neurotransmitters such as gamma-aminobutyric acid. Altered network structures are responsible: these promote the generation and intermittent spread of uncoordinated neural activity. The uncoordinated discharge of neurons in a particular area of the brain is accompanied by a local increase in blood flow.

Etiology In structural epilepsy, epileptic seizures are produced by structural lesions in the brain (so-called epileptogenic structural changes: scar, tumor, congenital malformation). Metabolic epilepsy is due to metabolic disturbances (e.g., hypoglycemia) or toxic influences (e.g., alcohol). These are both types of symptomatic epilepsy. In contrast, the genetic epilepsies involve a genetic predisposition to epileptic seizures, in the absence of a structural lesion. The epilepsies of unknown cause are presumed to be of symptomatic origin, although their cause cannot (yet) be demonstrated. Molecular genetic techniques have made it possible to trace certain forms of focal epilepsy back to specific mutations in the genome.

This threefold classification, like all classifications, has its limits. There will always be cases whose classification is ambiguous or uncertain; for example, there are some genetically based structural changes of the brain that are epileptogenic. Moreover, there is often more than one etiologic factor at work. Thus, diseases of the brain are more likely to produce epileptic seizures in persons with an inherited predisposition to seizures than in other, normal individuals.

Clinical features General characteristics of epileptic seizures are as follows:

  • Epileptic seizures are events of sudden onset.

  • They occur with variable frequency (generally in the range of a few seizures per year to several per day).

  • Stereotypy: epileptic seizures generally take a similar course each time they occur, with an identical, “predetermined” sequence of manifestations, and are of similar duration each time as well.

  • They often present with motor phenomena (in particular, repetitive, clonic twitching or changes of muscle tone) and sometimes with somatosensory, special sensory, and/or autonomic manifestations.

  • Depending on their type, they may involve an impairment or loss of consciousness, or consciousness may be preserved during the seizure.

  • The seizure may be preceded by premonitory symptoms of various kinds (auras, e.g., nausea, a rising sensation of warmth, or a feeling of unreality).

  • In some patients, seizures occur in response to specific provocative and precipitating factors (sleep deprivation, alcohol withdrawal, medications, strobe lighting, hyperventilation, fever).

9.1.1 Classification of the Epilepsies

Epilepsy can be classified according to several criteria ( ▶ Table 9.1 and ▶ Table 9.2), including:

  • Etiology, for example:

    • “Genuine/idiopathic” = genetic.

    • Symptomatic = structural or metabolic.

    • Cryptogenic = of unknown cause.

  • Age of onset, for example:

    • Epilepsy of childhood or adolescence.

    • Epilepsy of adulthood.

    • Late epilepsy (age 30 and up; always consider a primary organic disease as the cause).

  • Setting in which seizures are most frequent, for example:

    • Sleep epilepsy.

    • Epilepsy on awakening.

  • EEG correlate and corresponding topographic localization, for example:

    • Generalized epilepsy.

    • Focal (= partial) epilepsy.

  • Finally, the clinical features of each seizure. The International League against Epilepsy has developed, and recently revised, a nomenclature for the different clinical types of epileptic seizure, which is reproduced in ▶ Table 9.2. For completeness, the table includes both the older and the newer nomenclature, because the older system is still in widespread use. ▶ Table 9.1 (classification of the epilepsies) also includes the terminology of both systems of classification.

    Table 9.1 Classification of the epilepsies

    Previous terminology

    New terminology

    • Idiopathic

    • Genetic

    According to current knowledge, the seizures are the direct result of one or more known or presumed genetic changes. The epileptic seizures are the main manifestation of the genetic disease

    • Symptomatic

    • Structural or metabolic

    The patient is suffering from an entirely different condition or disease that has been shown in conclusive scientific studies to be associated with a markedly elevated risk of developing epilepsy, or there are clearly recognizable structural changes in the brain of a type known to be epileptogenic

    • Cryptogenic

    • Of unknown cause

    “Of unknown cause” is a neutral designation of the fact that the nature of the underlying cause of the patient’s epilepsy could not be determined up to the present time

    Source: Adapted from Diener HC, Weimar C, Berlit P, et al. Leitlinien für Diagnostik und Therapie in der Neurologie. Stuttgart: Thieme; 2012.

    Table 9.2 Classification of epileptic seizure types as proposed by the International League against Epilepsy

    Previous terminology

    New terminology

    Localization-related (focal, partial) seizures

    Focal seizures

    • Simple focal (simple partial)

      • Focal motor

      • Aura

      • Automatisms

    • Complex focal (complex partial), psychomotor

    • Secondary generalized

    Characteristics of focal seizures relating to impairment during the seizure:

    • Without impairment of consciousness or attention:

      • With observable motor or autonomic components (cf. section ▶ 9.3.1 and ▶ Table 9.9)

      • With only subjective somatosensory, special sensory, or mental phenomena (cf. ▶ Table 9.9)

    • With impairment of consciousness or attention: dyscognitive type

    • With progression to a bilateral convulsive seizure (with tonic, clonic, or tonic–clonic elements)

    Generalized seizures

    Generalized seizures

    • Tonic–clonic (grand mal)

    • Absences

    • Myoclonic

    • Clonic

    • Tonic

    • Atonic (astatic)

    • Tonic–clonic (in any combination)

    • Absences

      • Eyelid myoclonus with absence

      • Typical

      • Atypical

      • With special features

      • Myoclonic absence

    • Myoclonic

      • Myoclonic

      • Myoclonic–atonic

      • Myoclonic–tonic

    • Clonic

    • Tonic

    • Atonic

    Unclassifiable seizures


    Epileptic spasms

    Source: Adapted from Diener HC, Weimar C, Berlit P, et al. Leitlinien für Diagnostik und Therapie in der Neurologie. Stuttgart: Thieme; 2012.

9.1.2 Practical Clinical Management of a Suspected Epileptic Seizure

History and physical examination A thorough history is of the essence for the diagnosis of epilepsy and its differentiation from other, nonepileptic disorders (see later). A description of the seizures should also be obtained from someone who saw the patient having a seizure, if possible, because patients usually suffer amnesia for the seizures. The questions to be asked are summarized in ▶ Table 9.3. A video clip of a seizure is also a helpful part of the history that can be very useful in differential diagnosis: nowadays, the patient’s family can generally make one of these easily with a smartphone. The position of the eyes during the seizure is particularly significant ( ▶ Fig. 9.1).

Table 9.3 History

Questions to be asked after a suspected epileptic seizure

About the current seizure

  • Premonitory signs?

  • Amnesia?

  • Loss of consciousness?

  • Eyes open or closed during the seizure?

  • Manner of waking up (rapidly or slowly)?

  • Postictal fatigue?

  • Injuries?

  • Tongue biting?

  • Urinary or fecal incontinence?

  • Possible provocative factors?

Past history

Family history of epilepsy?

Past events possibly causing brain damage?

  • Perinatal injury (left handedness, strabismus, psychomotor retardation)?

  • Meningitis, encephalitis?

  • Head trauma?

Prior episodes of impaired consciousness?

  • Febrile seizure(s) in childhood?

  • Unconsciousness?

  • Bedwetting (possibly due to nocturnal grand mal seizures)?

  • Twilight states? (Ask specifically about partial complex seizures and déjà vu)

If epileptic seizures have occurred in the past:

  • When was the first one?

  • When was the most recent previous one?

  • Frequency?

  • Characteristics of each seizure?

  • EEG obtained? If so, with what result?

  • Antiepileptic drugs taken, if any: which ones? In what dose? Taken regularly as directed? Adequate effect on seizures? Any side effects?

Abbreviation: EEG, electroencephalogram.


Fig. 9.1 Eye position in seizures and seizure-like disturbances. (a) Temporal lobe seizure, (b) extratemporal seizure, (c) psychogenic nonepileptic seizure, and (d) syncope. (Reproduced from Diener HC, Weimar C, Berlit P, et al. Leitlinien für Diagnostik und Therapie in der Neurologie. Stuttgart: Thieme; 2012.)

When performing the physical examination, the examiner should pay special attention to the following:

  • Any physical evidence that a seizure has occurred.

  • Any signs of a neurologic or general medical disease that may have caused the seizure ( ▶ Table 9.4).

    Table 9.4 Physical examination

    The physical examination of a patient after a suspected seizure

    Evidence that an epileptic seizure has occurred

    • Tongue bite

    • Incontinence of urine or stool

    • Conjunctival hemorrhage

    • External injury

    • Fractures

    • Shoulder dislocation

    Evidence implicating an underlying illness as the cause of the seizure

    • Neurologic deficits on physical examination, signs of intracranial hypertension (especially papilledema); these indicate an underlying organic disease of the brain

    • Abnormal mental status (indicating intoxication or the effect of licit or illicit drugs)

    • Evidence of general medical illness as the underlying condition (e.g., metabolic or endocrine disease, cardiovascular disease as a cause of a possible prior stroke)

General diagnostic aspects If the clinical findings suggest that an epileptic seizure has occurred, a series of laboratory studies and ancillary tests should be performed. These are indicated as part of the initial evaluation of every case of suspected epilepsy and mainly serve to detect, or rule out, any possible symptomatic cause of the seizure ( ▶ Table 9.5).

Table 9.5 Laboratory tests and ancillary testing

Laboratory tests and ancillary testing after a suspected epileptic seizure

Evidence that an epileptic seizure has occurred

Laboratory tests

Elevated CK

Elevated serum prolactin level (a few minutes after the seizure)

Evidence implicating an underlying illness as the cause of the seizure


If the routine EEG is normal, EEG with special provocative maneuvers may be indicated (e.g., sleep deprivation, hyperventilation); also long-term EEG, video-EEG, video telemetry

Brain imaging

(to detect or rule out a structural lesion)

  • MRI: special MRI protocols may be used depending on the type of seizure

  • CT: only to detect skull fractures, or if MRI is contraindicated

Lumbar puncture

If an inflammatory disease of the brain or meninges is suspected

Further laboratory tests

  • Routine and specialized tests, depending on clinical suspicion and the questions to be asked in the particular case

Abbreviations: CK, creatine kinase; CT, computed tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging.

General therapeutic aspects If the diagnosis of epilepsy can be made securely on the basis of the clinical findings and further testing, an appropriate course of therapy must be decided upon. Any underlying cause of symptomatic epilepsy should be treated (causally directed treatment); moreover, the predisposition to seizures can be treated symptomatically with one or a combination of drugs (antiepileptic drugs, AEDs). Not every epileptic seizure implies a need for treatment. In many patients with a first seizure, it may be best to wait and see whether the event will repeat itself, as long as this presents no special danger and the patient agrees. The decision whether to treat with drugs must always be taken on an individual basis, with due consideration of the patient’s personality, life situation, occupation, need to drive a car, and so forth.


The following situations are generally considered indications for treating epilepsy with drugs:

  • Two or more unprovoked epileptic seizures.

  • One or more unprovoked epileptic seizures in the setting of a known disease of the brain (epileptogenic structural lesion, encephalitis, cerebral hemorrhage, tumor, etc.).

  • Epilepsy-typical potentials on EEG.

  • Initial status epilepticus.

The general principles of the treatment of epilepsy are as follows:

  • Thorough patient education.

  • Avoidance of precipitating factors (regular sleep habits, no excessive alcohol consumption, no illicit drugs, caution with prescription drugs, avoidance of strobe lights).

  • Treatment of the underlying disease, if any (e.g., resection of a meningioma).

  • If pharmacotherapy is indicated: choice of a suitable drug for the particular seizure type ( ▶ Table 9.6).

  • Gradual increase of the dose till seizure control is achieved or intolerable side effects arise. Beware of treatment failure through underdosing: the side effect threshold varies greatly from patient to patient and must be crossed, or nearly so, before a drug can be declared ineffective.

  • Meticulous follow-up for possible side effects, with especially close observation in the initial phase of treatment.

  • Checking for compliance, for example, with serum levels, if the drug seems to be ineffective.

  • If treatment with the first drug tried is truly ineffective despite maximal dosing and adequate compliance, switch to another drug of first choice, in gradual and overlapping fashion.

  • Combination therapy only if monotherapy fails.

  • Determination of serum levels when:

    • Poor compliance is suspected.

    • Toxic drug effects are suspected.

    • Drug interactions are suspected, particularly those involving enzyme induction.

    • An already high dose is to be raised even further.

    • Medicolegal questions arise, particularly with respect to permission to drive.

  • Rules of thumb for the discontinuation of AEDs: the patient should be free of seizures for at least 2 years; the EEG should be free of potentials that are typical for epilepsy; traditionally, the drug is slowly tapered to off over several months (although the need for this has not been demonstrated); the patient and family must be explicitly told that seizures may recur during or after the tapering phase.

  • If a patient with focal seizures has not become seizure-free with two AEDs, the possibility of epilepsy surgery should be considered early.

  • In patients with treatment-resistant focal or generalized seizures, the seizure frequency can be reduced with vagus nerve stimulation.

▶ Table 9.6 contains an overview of the major AEDs that are currently available and the indications for each. A practical algorithm for the treatment of epilepsy is shown in ▶ Fig. 9.2.

Table 9.6 Antiepileptic drugs and their indications, by type of epilepsy. The drugs are listed in alphabetic order

Focal seizures

Generalized seizures

Special epilepsy syndromes of childhood

Focal seizures with or without secondary generalization

Primary generalized tonic–clonic seizures


Myoclonic seizures

West syndrome

(salaam spasms)

Lennox–Gastaut syndrome (myoclonic–astatic petit mal)

Rolandic epilepsy (benign epilepsy in childhood and adolescence with central spikes on EEG)

First choice



















Second choice



























Third choice: combinations

Lamotrigine + valproate

Valproate + clonazepam

Valproate + ethosuximide

Valproate + clonazepine

Lamotrigine + levetiracetam

Valproate + lamotrigine

Lamotrigine + levetiracetam

Valproate + topiramate

Lamotrigine + topiramate

Abbreviations: ACTH, adrenocorticotropic hormone; EEG, electroencephalogram.


Fig. 9.2 Pragmatic treatment algorithm for adult patients with epilepsy. *Choice of drug as in ▶ Table 9.6.

Only gold members can continue reading. Log In or Register to continue

Dec 28, 2017 | Posted by in NEUROLOGY | Comments Off on Epilepsy and Its Differential Diagnosis
Premium Wordpress Themes by UFO Themes