• Benign familial neonatal seizures
• Benign neonatal convulsions
• Benign rolandic
• CEOP
• Childhood absence (pyknolepsy)
• Early myoclonic encephalopathy
• Grand mal seizures on awakening
• Infant benign myoclonic
• Infant severe myoclonic
• Infantile spasms
• Juvenile absence
• Juvenile myoclonic
• Landau-Kleffner syndrome
• Lennox-Gastaut syndrome
• Myoclonic absences
• Myoclonic-astatic seizures
• References
• Slow sleep spikes and waves
• Unverricht-Lundborg Disease
• Ring Chromosome 20 Syndrome
• Ring Chromosome 20 Symptom List

• normal neurologic examination
• negative evaluation for another etiology of the seizures
• normal developmental and intellectual outcome
• positive family history of newborn or infantile seizures with benign outcome
• onset of seizures during the neonatal or early infantile period) 25

Early reports indicated that the seizures began during the first week of life, usually on the third day. More recently, the onset in some patients has been noted to be after the first week. Whether these infants should be considered to have a distinct syndrome is not yet settled.

The seizures usually occur frequently for a few days and then stop. The infant is usually alert and vigorous during the interictal period.

Clonic seizures, which may appear to be focal or multifocal, are the most frequent type, although generalized seizures have also been reported. The seizures are generally brief, lasting for approximately 1 to 2 minutes, but may occur as many as 20 to 30 times a day.

Linkage analysis in large families of patients with benign neonatal convulsions have demonstrated two loci for the disorder, located on chromosomes 20q13.3 and 8q24. The genes encode voltage-gated K+ channels expressed in the brain (KCNQ2 and KCNQ3).25

Electroencephalography

The EEG is of little assistance in making the diagnosis of benign familial neonatal seizures. It may or may not be abnormal interictally, and no diagnostic features have been described. Abnormalities reported have included spikes, sharp waves, "epileptiform" patterns, "generalized periodicity," and slowing. Abnormal findings are frequently transient, however.

In many published case reports, electroencephalography was not performed or the results were not described in sufficient detail.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

A set of clinical features may be stereotyped enough to warrant classification as a syndrome even though cases are not common. One pattern of seizures in very young infants is known as benign neonatal convulsions or benign neonatal idiopathic seizures. These seizures occur in otherwise healthy, full-term infants.26,27,29,30

Criteria used to make the diagnosis include:27-29,31

1. birth after 39 weeks of gestation
2. an APGAR score of 9 or above 5 minutes after birth
3. the presence of a seizure-free interval between birth and the onset of seizures
4. clonic or apneic seizures, or both
5. negative evaluations for etiology
6. a favorable outcome in regard to neurologic development
7. lack of seizures outside the neonatal period

Typically the seizures begin on the fifth day of life. Some authors have used the term "fifth-day fits."27 Benign idiopathic neonatal seizures and fifth-day fits appear to be identical syndromes. In a review of six different series of patients with benign idiopathic neonatal seizures, Plouin27 noted that in all 182 patients described, the onset of seizures occurred between the first and seventh day of life. In 80% of these infants, the initial seizure occurred on the fourth, fifth, or sixth day of life. The first seizure occurred on day 5 in half of the cases for which the exact day was reported.

The seizures are usually partial clonic and may be confined to one body part or migrate from one region to another. Apnea may occur with the clonic activity or be the sole manifestation of the seizure. Tonic seizures are rare.

The seizures often occur in a crescendo of activity. Initially the infant is normal between seizures. The seizures then increase in frequency until the child goes into status epilepticus. The flurry of seizures usually lasts less than 24 hours but may continue for a few days.27,29

Electroencephalography

EEG findings in benign idiopathic neonatal seizures vary. In a survey of 101 EEGs from infants with the disorder,27 the interictal EEG:

• was normal in 10 infants
• was excessively discontinuous in 6
• showed "focal or multifocal" abnormalities in 25
• showed the theta pointu alternant pattern in 60

The theta pointu alternant pattern consists of dominant theta activity that is discontinuous, unreactive, often asynchronous, and has intermixed sharp waves. It is present throughout sleep and the awake state and may persist up to the 12th day of life, even after the seizures have ceased.

The theta pointu alternant pattern is not specific for benign seizures and can be seen after a variety of neonatal encephalopathies. However, Plouin27 claims that this EEG pattern is associated with a favorable prognosis regardless of etiology.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

Originally described by Marinus Rulandus in 1597,2 benign rolandic epilepsy (BRE) is classified as an idiopathic, localization-related epileptic syndrome. It is characterized by:

• nocturnal generalized seizures of probable focal onset
• diurnal partial seizures arising from the lower rolandic area
• an EEG pattern consisting of a midtemporal-central spike focus3-16

Both daytime and nighttime seizures may occur, although in most children the seizures usually occur during sleep. More than half of the children with BRE have nocturnal seizures only.14 Approximately 15% have seizures during sleep and while awake, and 10% to 20% have them in the waking state alone.17 The increase in seizure incidence during sleep parallels the increase in spikes seen during drowsiness and sleep on the EEG.

The disorder always begins during childhood. The age range is from 3 to 13 years, with the peak incidence occurring between the 7th and 8th year of life.14 It is somewhat more common in boys than in girls.4,5,17,18 Most affected children have normal intelligence and normal findings on the neurologic examination.18

The disorder is usually familial. Fifty percent of close relatives (siblings, children, and parents of the probands) demonstrate the EEG abnormality between the ages of 5 and 15 years. Before 5 and after 15 years of age, penetrance is low, and few patients demonstrate the abnormality. Only 12% of patients who inherit the EEG abnormality have clinical seizures. The EEG trait of midtemporal central spikes has been linked to chromosome 15q15, but the epilepsy appears to have a multifactorial inheritance.19

Diagnosis of the syndrome, which depends on the patient's history and EEG features, allows the clinician to offer the patient and parents a rational plan for treatment, genetic counseling, and prognosis.

The syndrome is called rolandic epilepsy because of the characteristic feature of partial seizures involving the region around the lower portion of the Rolandic fissure. The same syndrome is sometimes called benign childhood epilepsy with centrotemporal spikes (BCECTS).

Features of seizures

Lombroso20 described the characteristic features of seizures in BRE:

• somatosensory stimulation of the oral-buccal cavity
• speech arrest
• preservation of consciousness
• excessive pooling of saliva
• tonic or tonic-clonic activity of the face

Less often, the somatosensory sensation will spread to the face or arm. Rarely, a typical jacksonian march of tonic or tonic-clonic activity will occur.

Although the somatosensory aura is quite common, a history of this symptom is frequently not elicited, especially in young patients.20

Motor phenomena during daytime attacks are usually restricted to one side of the body and include tonic, clonic, or tonic-clonic events. These attacks most frequently involve the face, although the arm and leg may be involved. Although seizures rarely generalize when the patient is awake, the sensory or motor phenomena may change sides during the course of the attack.16 Arrest of speech may occur at the beginning of the seizure or during its course. Consciousness is rarely impaired during daytime attacks.

After the seizure the child may feel numbness, pins and needles, or "electricity" in the tongue, gums, and cheek on one side. Postictal confusion and amnesia are unusual in benign rolandic epilepsy.

In nocturnal seizures the initial event is typically clonic movements of the mouth, along with salivation and gurgling sounds from the throat. Secondary generalization of the nocturnal seizure is common. The initial focal component of the seizure may be quite brief, so parents may not see this portion of the seizure. Some nocturnal seizures remain partial and do not generalize. It is likely that the frequency of seizures during sleep is underreported.

Seizure frequency in benign rolandic epilepsy is typically low. 4,17,18 Lerman17 states that 10% to 13% of children will have only one seizure, regardless of drug therapy. In a study of 100 patients with benign rolandic epilepsy, Lerman and Kivity18 found that 13 of the patients had only one seizure and 66 had infrequent seizures. However, 21% of the patients had frequent seizures. Status epilepticus is extremely rare in this disorder.

Patients with clearly typical clinical and EEG features do not need a CT or MRI.

Electroencephalography

BRE is characterized by a very distinctive EEG pattern. The characteristic interictal EEG abnormality is a high-amplitude, usually diphasic spike with a prominent following slow wave (See EEG). The spikes (<70 milliseconds) or sharp waves (<200 milliseconds) appear singly or in groups at the midtemporal (T3, T4) and central (rolandic) region (C3, C4). When bipolar recording montages are used, the spikes may appear most prominent in the central or midtemporal region and usually occur synchronously in both regions. Although typically present in both regions, at times they may shift from one to the other or be seen only in the midtemporal or central region.

The rolandic discharges typically occur only during childhood, peaking at about age 10.

The spikes may be confined to one hemisphere or occur bilaterally. The spike focus is unilateral in about 60% of patients. In 40% there are bilateral spike foci either on the initial EEG or on subsequent recordings.17 Unilateral spikes do not have a predominance for either hemisphere in patients with this syndrome. When bilateral, the spikes can be synchronous or asynchronous, symmetric or asymmetric.

Rolandic spikes usually occur on a normal background. However, when the spikes occur frequently, focal slowing may appear to occur in the region of the spikes. This "pseudoslowing" is secondary to the slow waves accompanying the spikes.

The spikes are often activated by sleep.21,22 In approximately 30% of children with BRE, spikes appear only in sleep.21 Sleep states are usually normal in BRE. Some records show generalized spike-wave discharges without any concomitant clinical signs of absence seizures.22 These diffuse spike-and-wave discharges, which can occasionally occur during the awake state, are strongly activated by sleep.22 Most children with BRE who have spike-wave discharges during sleep do not have typical absence seizures.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

There are two distinct forms of CEOP:23,24

• The early-onset type (Panayiotopoulos syndrome) occurs in young children, with a peak age of onset of 5 years.
• The late-onset type (Gastaut type) has an age of onset of around 8-9 years.
• Both syndromes are associated with occipital spikes.

The early-onset type is characterized by ictal vomiting and deviation of the eyes, often with impairment of consciousness and progression to generalized tonic-clonic seizures. The seizures are infrequent and often solitary, but in about one-third of the children the episodes evolve into partial status epilepticus. Two-thirds of the seizures occur during sleep.

The late-onset type consists of brief seizures with mainly visual symptoms such as elementary visual hallucinations, illusions, or amaurosis, followed by hemiclonic convulsions. Postictal migraine headaches occur in half of the patients.

Electroencephalography

The interictal EEG in both conditions is characterized by normal background activity and well-defined occipital discharges. The occipital spikes are typically high in voltage (200 to 300 mV) and diphasic, with a main negative peak followed by a relatively small positive peak and a negative slow wave. The discharges may be unilateral or bilateral and are increased during non-rapid eye movement (REM) sleep. An important feature in this syndrome is the prompt disappearance of the occipital discharges with eye opening and their reappearance 1 to 20 seconds after eye closure.

Prognosis

The prognosis in the early-onset type is excellent. The symptoms typically resolve with several years of onset.

The prognosis in the late-onset form varies. Although most patients have a benign course, seizure control may be difficult in some. Seizures may continue into adulthood, but many children outgrow them.

For another perspective on this disorder, see Benign occipital epilepsy of childhood with occipital paroxysms.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

Pyknolepsy refers to a syndrome of typical absence seizures (both simple and complex) in otherwise normal, prepubertal children older than about 3 to 5 years. There is a strong genetic predisposition, and girls are more frequently affected. The absences are very frequent (occurring at least several times daily), and tend to cluster.

The absences may remit during adolescence, but generalized tonic-clonic seizures may develop.

The EEG reveals a bilateral, synchronous, symmetric 3-Hz spike-and-wave discharge with normal interictal background activity.

No distinct clinical or EEG features completely differentiate childhood absence epilepsy from juvenile absence epilepsy.

Early myoclonic encephalopathy, or neonatal myoclonic encephalopathy, is a seizure disorder that begins in the neonatal period.67 Seizures consist of:

• partial or fragmentary erratic myoclonic seizures
• massive myoclonia
• partial motor seizures (jerking movements of one side)
• tonic seizures.

The EEG demonstrates bursts of spikes, sharp waves, and slow waves separated by suppression of the background activity.

Early myoclonic encephalopathy is associated with a variety of different etiologies, including nonketotic hyperglycinemia.

The seizures are very difficult to treat and affected infants are usually severely impaired neurologically. More than half of them die before 1 year of age.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

Epilepsy with grand mal seizures on awakening is an uncommon syndrome in which generalized tonic-clonic seizures occur exclusively or predominantly shortly after awakening.38 The onset is usually in the second decade. If patients have other seizure types, they are usually absence or myoclonic seizures. Photosensitivity is a common feature.

The EEG typically shows generalized spike-wave activity.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

Benign myoclonic epilepsy in infancy is a rare syndrome in which brief bouts of generalized myoclonus occur during the first or second year of life.32,33 The infants do not have other seizure types.

The EEG typically shows generalized spike-waves occurring in brief bursts during the early stages of sleep.

Usually, these seizures are easily controlled with antiepileptic drugs and are limited to the first few years of life. Generalized tonic-clonic seizures may occur during adolescence, however. While many children do well from a development standpoint, some children with the disorder are impaired cognitively.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

De novo truncating mutations of the SCN1A gene on 2p24 encoding for the neuronal voltage-gated sodium channel alpha1 subunit have been found in this syndrome.73 Interestingly, inherited missense mutations of the same gene will result in generalized epilepsy, febrile seizures plus (GEFS+).

At the time of the first febrile seizure, the EEG is usually normal and without any paroxysmal abnormalities. Between ages 1 and 2 years, generalized spike-and-wave or polyspike-and-wave activity is seen during the seizures. When absence seizures occur, they are also associated with generalized spike-and-wave activity. Focal and multifocal spikes and sharp waves are also seen.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

Infantile spasms are an age-specific disorder beginning during the first 2 years of life. The peak age of onset is between 4 and 6 months. Approximately 90% of infantile spasms begin before 12 months of age.39 It is rare for infantile spasms to begin during the first 2 weeks of life or after 18 months.

Infantile spasms may vary considerably in their clinical manifestations. Some seizures are characterized by brief head nods, whereas other seizures consist of violent flexion of the trunk, arms, and legs. Most patients have more than one seizure type. Infantile spasms can be classified into three major groups:40

• Flexor: flexion of the neck, trunk, arms, and legs. Spasms of the muscles of the upper limbs result in either adduction of the arms or a self-hugging motion, or adduction of the arms to either side of the head with the arms flexed at the elbow.
• Extensor: a predominance of extensor muscle contractions, which produce abrupt extension of the neck and trunk, along with extensor abduction or adduction of the arms, legs, or both.
• Mixed flexor-extensor: flexion of the neck, trunk, and arms and extension of the legs, or flexion of the legs and extension of the arms with varying degrees of flexion of the neck and trunk.

Asymmetric spasms occasionally occur, in which the infant maintains a "fencing" posture.

Infantile spasms may also be associated with autonomic dysfunction characterized by:

• pallor
• flushing
• sweating
• pupillary dilatation
• lacrimation
• changes in respiratory and heart rate41,42

Infantile spasms frequently occur in clusters, and the intensity and frequency of the spasms in each cluster may increase to a peak before progressively decreasing. The seizures are very brief, and the casual observer may miss single seizures. The number of seizures per cluster varies considerably. Some clusters have as many as 150 seizures. The number of clusters per day also varies. Some patients have as many as 60 clusters per day. Clusters can occur during sleep or shortly after awakening. Crying or irritability during or after a flurry of spasms is commonly observed. The number of infantile spasms that occurs at night is similar to the number that occurs during the day.41

Infantile spasms are frequently associated with developmental delay. In a review of the literature, Lacy and Penry41 reported that only 10% of patients were developmentally normal at the time their infantile spasms were diagnosed. Patients whose symptomatic infantile spasms have identifiable causes have a higher incidence of retardation than patients whose spasms have idiopathic causes.42

Abnormal neurologic findings on physical examination are also commonly reported. Lacy and Penry42 reported that 70% of patients with infantile spasms have abnormal findings on neurologic examination. Children with identifiable etiologies for the spasms are much more likely to have neurologic impairment than those in the idiopathic group.42,43

Electroencephalography

Infantile spasms are usually associated with markedly abnormal EEGs. The most common interictal abnormality is hypsarrhythmia (See EEG).41,44-46 There are several variations:47

• hypsarrhythmia with interhemispheric synchrony
• hypsarrhythmia with a consistent focus of abnormal discharge
• hypsarrhythmia with episodes of attenuation
• hypsarrhythmia consisting primarily of high-voltage slow activity with few sharp waves or spikes

Example of hypsarrhythmia in an infant with infantile spasms. There are multifocal spikes and sharp waves. In addition, brief periods of suppression are noted. (Calibration 50 microvolts and 1 sec.)

During sleep (especially REM sleep) the hypsarrhythmic pattern may be markedly reduced or totally disappear.47 Some patients with infantile spasms do not show a hypsarrhythmic pattern.44 Some do not have hypsarrhythmia early in the course of the disorder but go on to develop the pattern.

Although hypsarrhythmia is associated primarily with infantile spasms, it occurs in other disorders as well.48

The ictal EEG changes during infantile spasms vary.40,50 Kellaway and colleagues40 found 11 different types of ictal EEG patterns, but 72% of seizures have shown a marked generalized attenuation of electrical activity.45,49 Ictal EEG abnormalities and clinical seizure type are not closely correlated.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

Juvenile absence epilepsy begins around puberty and differs from childhood absence epilepsy in that the seizures are more sporadic. Sex distribution is equal.

This syndrome blurs with juvenile myoclonic epilepsy because generalized tonic-clonic seizures and myoclonic seizures are often seen on awakening.

On EEG, the spike-waves are often slightly faster than 3 Hz.

No distinct features completely differentiate juvenile absence epilepsy from childhood absence epilepsy.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

Juvenile myoclonic epilepsy (JME), also known as Janz syndrome, is a familial disorder that typically begins in the second decade of life and is characterized by mild myoclonic seizures, generalized tonic-clonic (GTC) or clonic-tonic-clonic seizures (a variation of GTC seizures in which there is an initial clonic phase), and occasionally absence seizures.

Janz described a familial disorder of myoclonic epilepsy associated with an excellent prognosis in patients who were otherwise mentally and neurologically normal. Janz initially called the syndrome "impulsive petit mal" to indicate that the myoclonic jerks are a type of minor seizure.34

The myoclonic seizures are usually mild to moderate in intensity and involve the neck, shoulders, and arms. The movements involve an entire extremity or body part rather than an isolated muscle contraction. They can occur either singularly or repetitively and may cause the patient to drop objects. They are generally bilateral, although sometimes asymmetric with changing left-right accentuation. Rarely the jerks may involve the legs and cause the patient to fall to the ground. More commonly, they are quite mild and the patient may attribute them to nervousness or clumsiness.35

Occasionally, the jerks become more severe and violent jerks occur in rapid succession, in a chorea-like episode. Myoclonic status can occur, in which the patient has myoclonic jerks every few seconds or salvos of three to five jerks. Despite preserved consciousness, the patient is often incapacitated by the continuous myoclonic jerks.

Usually the myoclonic seizures occur only during the first several hours after awakening from a night's sleep or a nap. In some patients they may continue all day, but this pattern is less frequent. In these patients the seizures may be less frequent in the middle of the day and increase again when the patient becomes fatigued. The seizures of JME typically are aggravated by sleep deprivation.

Nearly all patients with JME have tonic-clonic or clonic-tonic-clonic seizures. In one study of 43 patients, only 2 were free from these seizure types.36 In another study,37 10 of 12 patients had GTC seizures. In a large majority of cases, the myoclonic jerks precede the onset of the GTC seizures, but occasionally the GTC seizures occur before the onset of the myoclonic seizures, or the two types begin simultaneously. Like the myoclonic seizures, the tonic-clonic seizures often occur shortly after awakening or during early-morning sleep. At times patients will have a series of myoclonic seizures culminating in a generalized seizure. In addition, some patients will have several days of an increasing number of myoclonic seizures, followed by GTC seizures.

Absence seizures also occur in a substantial number of patients. In one report,36 40% of patients also had absences, usually in association with tonic-clonic or clonic-tonic-clonic seizures. As with other seizure types, these often occur shortly after awakening.

JME begins in childhood, usually in the second decade. In a study of 43 patients, the average age of seizure onset was 13.6 years, the range being 8 to 24 years.36 Findings from physical and neurologic examinations of these patients are usually normal and normal intelligence is the rule.

A positive family history of epilepsy is common. The mode of inheritance appears to be polygenic, with females having a lower threshold than males.36

Electroencephalography

The interictal EEG in this disorder is distinctive and easily distinguished from those of other forms of generalized epilepsy.36 Characteristic features of the EEG are the fast (3.5- to 6-Hz) spike-and-wave and multiple spike-and-wave complexes (See EEG). This pattern contrasts with the 3-Hz spike-and-wave complexes seen in classic absence and the slow (1.5- to 2.5-Hz) spike-and-wave complexes of the Lennox-Gastaut syndrome (LGS).

Example of a rapid spike-and-wave discharge in a patient with JME.

During myoclonic seizures, the ictal EEG consists of 10- to 16-Hz rapid spikes, followed by irregular slow waves. Photosensitivity may activate the epileptiform discharges.

If the diagnosis is suspected and the awake EEG is normal, a sleep-deprived EEG must be obtained, because this may be the only time the abnormality is present.

The Landau-Kleffner syndrome is a childhood disorder consisting of acquired aphasia and epileptiform discharges involving the temporal or parietal regions of the brain.74-89

The typical sequence is as follows:

1. A seizure disorder develops in the child, but it is usually well controlled with antiepileptic drugs.
2. Aphasia develops; its onset may be abrupt or insidious.87 Unlike typical acquired childhood aphasia, receptive dysfunction usually is the dominant feature early in the course of the disorder.74,90
3. Spontaneous verbal expression slowly becomes reduced, and the child may use stereotypies, perseverations, and paraphasias.
4. In some cases the disorder progresses to the point where the child cannot even recognize sounds, so that total auditory agnosia develops. The child becomes indifferent to auditory stimulation and may not even recognize the sound of a telephone or barking dog, thus often appearing to be deaf or autistic. Reading, writing, and signing may be relatively spared.
5. Often an expressive aphasia develops later in the course of the disorder.

In the original description of the syndrome, verbal auditory agnosia was the language disturbance,81 but some patients may have expressive aphasia early in the course.

Only about 70% of patients have seizures. In one-third of cases, a single seizure or status epilepticus occurs, usually early in the course of the syndrome. The seizures usually begin in children who are between 5 and 10 years of age. After age 10, only 20% of patients still have seizures. The patients usually have generalized tonic-clonic and atypical absence seizures. Complex partial seizures with automatisms are uncommon.

In addition to aphasia, most patients have behavioral and psychomotor disturbances that may suggest autism. The neurologic examination, except for the mental status examination, is usually normal.

The clinical course of the disorder fluctuates85,88 and spontaneous remissions can occur.

Electroencephalography

The EEG is nonspecific in this syndrome. Typical EEG findings are frequent and repetitive spikes, sharp waves, and spike-and-wave activity. Usually, the discharges are bilateral and located in the temporal region or parietal-occipital region.

Sleep usually activates the record, and at times the abnormality is seen only in sleep recordings.79,88 Often patients will have continuous spike-and-wave activity during sleep. There appears to be an overlap between Landau-Kleffner syndrome and the syndrome known as continuous spike-wave discharges during sleep (CSWDS).

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

Lennox-Gastaut syndrome (LGS) is characterized by a mixed seizure disorder. Tonic seizures and a slow spike-and-wave EEG pattern are major components. The syndrome always begins in childhood. Mental retardation is considered a component by some authors.51

The child with LGS typically has a mixture of seizure types. The most frequently occurring52,53-59 are:

• tonic
• tonic-clonic
• myoclonic
• atypical absences
• "drop attacks"-a form of atonic, tonic, or myoclonic seizures

Tonic seizures are a key component of LGS.55,58 They are usually brief, lasting from a few seconds to 1 minute, with an average duration of about 10 seconds. The seizures may cause falls and injury. Eyelid retraction, staring, mydriasis, and apnea are commonly associated and may be the most prominent features.55 During tonic seizures the patient is unconscious, although arousal from light sleep may occur. Because they are often very brief, the seizures frequently go undetected. Tonic seizures in LGS typically are activated by sleep and may occur repetitively throughout the night. They are much more frequent during non-REM sleep than during the awake state and usually do not occur during REM sleep.

Atonic seizures are common in LGS but they occur less often than tonic and myoclonic seizures. Most atonic seizures last only 1 to 4 seconds. In the shortest attacks, patients may show only head nodding or sagging at the knees. The seizures are so brief that it is difficult to determine whether consciousness is lost. If a fall occurs, the patient usually gets up immediately and resumes what he or she was doing. Many children with drop attacks have myoclonic or tonic seizures. In a study of 48 drop attacks in 15 children with LGS,60 only 4% of the seizures were of the atonic type.

Myoclonic seizures, occurring either in isolation or as a component of absence seizures, may occur in LGS but usually are not the most common seizure type. However, occasionally the myoclonus is so prominent that some investigators have described a myoclonic variant of LGS.55

Generalized tonic-clonic (GTC) seizures and atypical absence seizures are seen in over half of the patients with LGS.56,57 GTC seizures usually cause the most concern to parents and may precipitate hospitalization. Atypical absences are generally longer than typical absences and are more likely to include changes in postural tone and myoclonic jerks.51

Patients with LGS typically have very frequent seizures. Markand56 found that 60% of his patients had seizures daily, whereas Papini and colleagues,61 in a longitudinal study of 16 patients with LGS, found the mean daily frequency of seizures to range from 9 to 70. Some children with this syndrome have hundreds of seizures daily.

Mental retardation is present before seizure onset in 20% to 60% of patients.55 Some patients whose seizures have idiopathic or cryptogenic etiologies have normal IQ scores or developmental histories before the onset of their seizures, but deterioration often occurs in LGS.55 Only few patients escape mental retardation.55 Marked fluctuations in cognitive abilities occur in LGS patients. To some degree, these are correlated with the intensity of EEG abnormalities.

In addition to cognitive difficulties, behavioral problems are very common in LGS, from hyperactivity with aggressive behavior to frank psychotic and autistic behavior.

Other neurologic abnormalities have been reported in 30% to 88% of patients with LGS.56,57,62

Electroencephalography

The identifying EEG finding in LGS is a slow spike-and-wave discharge superimposed on an abnormal, slow background. The slow spike-and-wave or sharp-and-slow-wave complexes consist of generalized discharges occurring at a frequency of 1.5 to 2.5 Hz. The morphology, amplitude, and repetition rate may vary both between bursts and during paroxysmal bursts of spike-and-wave activity. Transient and shifting asymmetries of the discharge frequently occur.

The area of maximum voltage, although variable, is usually frontal or temporal. Hyperventilation and photic stimulation rarely activate them.

Sleep increases the frequency of the discharges. During non-REM sleep, slow spike-and-wave discharges may be replaced by multiple spike-and-wave discharges. In REM sleep, the paroxysmal activity decreases markedly.

The typical EEG manifestation of tonic seizures is the occurrence of fast-rhythm discharges of 10 to 20 Hz and of progressively increasing amplitude, at times followed by a few slow waves or spike-waves. This pattern was previously called the grand mal discharges of Gibbs. Patients may also have bursts of multiple spike-and-wave discharges during tonic seizures.

EEG patterns characteristic of other seizure types in LGS include63:

• atonic seizures-usually a fast-rhythm discharge, but sometimes bursts of slow spike-wave complexes or high-amplitude 10-Hz discharges
• myoclonic seizures-bursts of arrhythmic, multiple spike-wave or irregular spike-wave activity
• atypical absence seizures-slow (<2.5 Hz) and often asymmetric and irregular spike-and-wave activity

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

Myoclonic absences typically occur multiple times daily and often are very difficult to treat.65 The EEG typically shows generalized, rhythmic 3 Hz spike-wave or polyspike-wave.

The myoclonic jerks in this syndrome are quite prominent. More subtle myoclonus often occurs as a component of absence seizures. In a study of 426 typical and 500 atypical absence seizures in 54 children in which simultaneous EEG frequency modulation radiotelemetry and videotape monitoring were deployed, Holmes and colleagues66 found myoclonic jerks in 13% of typical absences and 12% of atypical absences.

In this study, absence seizures were classified by EEG criteria. Seizures with generalized, regular, symmetric spike-and-wave discharges were classified as typical absences. Absences with slow (<2.5 Hz), irregular, or asymmetric spike-and-wave discharges were classified as atypical absences.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

Doose64 described a group of children with myoclonic and astatic seizures, often in combination with absence, generalized tonic-clonic, and tonic seizures. In this syndrome, astatic seizures (defined as seizures during which the patient is unable to stand) occurred suddenly, without warning, and the children collapsed onto the floor as if their legs had been pulled from under them. No loss of consciousness was apparent. At times the astatic seizures are so short that only a brief nodding of the head and slight flexion of the knees are seen. From the clinical description of these seizures, it appears that they are atonic.

In these children, the loss of postural tone often is immediately preceded by myoclonic jerks-hence the term myoclonic-astatic seizures. The myoclonic seizures in this disorder involve symmetric jerking of the arms and shoulders with simultaneous nodding of the head. Some myoclonic jerks are violent, causing the arms to fling upward, and some are so mild that they are easier to feel than see.

This disorder is more common in boys than in girls. The age of onset is between 1 and 5 years. With few exceptions, mental and motor development is normal before the onset of the illness. The prognosis is generally unfavorable, however, and dementia develops in most patients. Absence status is reported to play a role in the pathogenesis of the dementia.

Electroencephalography

The EEG pattern consists of bilaterally synchronous, regular or irregular 2- to 3-Hz spike-and-wave discharges. The background activity exhibits an excess of monomorphic theta activity.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

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A condition characterized by continuous spikes and waves occurring during sleep was described in 1971 under the name of subclinical electrical status epilepticus induced by sleep in children and later under the name of electrical status epilepticus during sleep.68 The original description stressed the importance of defining the syndrome by the amount of spike-wave activity during sleep. To meet the requirements of the syndrome, spike-wave activity should occupy no less than 85% of the time of slow sleep. Consequently, this syndrome also is known as continuous spike-wave discharges during sleep (CSWDS).

In one series of 18 patients,68,69 epilepsy appeared at a mean age of 4 years, 6 months. The types of clinical seizures varied:

• unilateral seizures (5 patients)
• generalized motor seizures (8 patients)
• motor seizures involving the facial muscles, with mandibular contraction and loss of consciousness (4 patients)
• myoclonic absences (1 patient)

In half these patients, the first seizure occurred during sleep.

In another series of 5 children, 3 atypical absence seizures and partial seizures were observed.

The syndrome can be differentiated from Lennox-Gastaut syndrome (LGS) by the total amount of sleep occupied by spike-wave discharges. In children with CSWDS, generalized spike-wave activity occurs during more than 85% of sleep time, versus less than 50% in LGS. Another difference is that tonic seizures, which are so common in LGS, are rare in children with CSWDS.68,70

Comparisons to Landau-Kleffner syndrome

There appears to be an overlap between CSWDS and the Landau-Kleffner syndrome. Of 18 children in one series, 11 who were normal before the development of CSWDS experienced a decrease in IQ ranging from 45 to 78 points.69 A very marked reduction in language function occurred in 6 children. In 10 cases, disturbances in behavior were found, including decreased attention, hyperactivity, and aggressiveness. In 7 children who had abnormal psychomotor development before the onset of CSWDS, their mental deficiency worsened. Deterioration in behavior and speech after the onset of CSWDS was also observed in the 5 children in the other series.70

Hirsch et al71 reported on five children in whom the Landau-Kleffner syndrome developed when they were between the ages of 3 and 7. The EEG in the wake state demonstrated focal and generalized spike-wave activity on a normal background. During sleep the discharges always increased. At some point during the development of the syndrome, the patients had bilateral spike-wave activity lasting for more than 75% of their sleep time. The authors suggested that the Landau-Kleffner syndrome and this syndrome represent different points on a single spectrum.

In 6 children with subclinical "electrical status epilepticus" during sleep, the electrical status subsided during REM sleep in 5.71 All of the children were mentally retarded, and 2 failed to acquire speech.

As with the Landau-Kleffner syndrome, variable improvement may occur in affected children as CSWDS resolves.68,70 In one series,68 7 of the 11 children who were normal before the onset of CSWDS improved in performance, behavior, or both after it resolved. Two totally recovered and the others showed a slight degree of recovery.

Adapted from: Holmes GL. Classification of seizures and the epilepsies. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 1-36.
With permission from Elsevier (www.elsevier.com)

Reviewed and revised January 2004 by Gregory L. Holmes, MD, Dartmouth Medical School

Unverricht-Lundborg disease (EPM1; OMIM 254800) is the most common of the rare genetically heterogeneous progressive myoclonic epilepsies. Initially described by Unverricht in 1891,111 and Lundborg in 1903,106, it has also been known as Baltic myoclonus and Mediterranean myoclonus. Although it is found worldwide, higher incidence occurs in Finland (1 in 20,000) as well as in western Mediterranean (southern France, North Africa), eastern Mediterranean, United States, and Canada.91,108

As with all of the genetic progressive myoclonic epilepsies, clinically it is characterized by the triad of stimulus-sensitive myoclonus, epilepsy and progressive neurologic deterioration, and neurological signs depending on the cause.94 Unverricht-Lundborg is characterized by severe stimulus-sensitive myoclonus, generalized tonic-clonic seizures, and EEG findings with marked sensitivity to photic stimulation.103 The age of onset is between 6 and 18 years, with most patients presenting around 11 years of age. In a little over 50% of patients, the initial symptom is involuntary myoclonic jerks.100,108 Before disease onset, patients are usually healthy. The myoclonus events are action activated and stimulus sensitive, and may be provoked by light, physical exertion, and stress. They may be multifocal or focal. They may also progress to generalized shaking and unconsciousness. In the other half of patients, the presenting symptom is generalized tonic-clonic seizures.108 Generalized tonic-clonic seizures (clonic-tonic-clonic) typically are more pronounced upon awakening. Seizures can also be absence or focal motor.

The progression of the disease is slow and patients usually maintain normal cognitive functioning for a long time with slow intellectual decline spanning 10 – 20 years. Usually, some years after onset, ataxia, incoordination, intentional tremor, and dysarthria develop. The disease is inevitably progressive. Although mentally alert for many years, patients show emotional lability and depression.103 Long term studies suggest that many patients are incapacitated by ataxia and myoclonus at the end of the disease.94 Today, patients may live into their sixties or seventies with proper medication and therapies.

Diagnosis/Testing

Diagnosis

Diagnosis is based on clinical presentation of severe stimulus-sensitive myoclonus, age of seizure onset, and particular EEG findings. The EEG usually shows photosensitivity, abnormal slow background, generalized high-amplitude multispikes, 3- to 5-Hertz spike waves or polyspike and wave complexes. An armpit skin biopsy will reveal membrane-bound vacuoles in eccrine sweat glands. MRI scanning of the brain is usually normal. However, due to clinical variability between patients, even within the same family, genetic testing is often required to confirm the diagnosis.100,101,108

Gene testing

The most common genetic defect associated with Unverricht-Lundborg disease is homozygosity for a 12-base pair (dodecamer 5” CCC-CGC-CCC-GCG-3”) repeat in the cystatin B gene located on chromosome 21.105 Disease-causing repeats are greater than 30 repeats with over 100 repeated dodecamers found in some patients.94 This mutation accounts for approximately 90% of Unverricht-Lundborg disease alleles throughout the world and 99% of affected Finnish individuals. The expanded dodecamer is located 175 bp upstream from the translation initiation codon in the promoter region.102 No correlation between the repeat size and the age at onset or the severity of the disease has been reported.94

At least six mutations occur in the transcripton unit of the cystatin B gene. Three mutations at position 1925G > C, 20207G > A, and 2353A > G affect splice sites and predict splicing errors. Mutation at position 426G > C results in a missense mutation.104 The three mutations at position 1925G > C, 2388C > T, and 2400del/TC have been found in more than 1 patient, while mutations at position 426G > C, 2027G > A, and 2353A > G have only been reported in single patients. 92,109 Currently, testing for the three mutations, 1925G > C, 2388C > T, and 2400del/TC are available.

Treatment and Prognosis

Valproic acid is usually considered the first drug of choice as it diminishes myoclonus and the frequency of generalized seizures. 100,108 Furthermore, valproic acid, if started soon after the onset of symptoms, may delay or limit the progression of the disease. Clonazepam or piracetam are effective supplementary therapy with valproic acid. 93,96,97 Unfortunately, piracetam is not available in the United States. A closely related product, levetiracetam, has some theoretical benefit, but has not been fully tested in large populations of patients. Lamotrigine, topiramate, and zonisamide may also be beneficial for seizure control. However, the latter medications have not been rigorously tested.

The progression of the disease is slow, with intellectual preservation early in the disorder. 94 Mental deterioration, dementia, intention tremor, and dysarthria may develop, together with ataxia, late in the disease, usually over a 10 – 20 year span.99,100,108 Intelligence is typically only slightly affected with emotional lability a usual feature. Psychotic symptoms are usually not found. Myoclonus can be resistant to medical therapy, while seizure medications usually control generalized seizures. Some patients are incapacitated by ataxia and myoclonus.94

Surveillance: Clinical and Psychosocial Evaluation

Once the diagnosis has been confirmed, clinical evaluation of walking, coordination, handwriting, school performance, and emotional well-being are essential in monitoring the progression of the disease. Furthermore, the patient’s education is often interrupted due to emotional, social, and intellectual problems therefore, school performance may be affected. Also, psychological therapy may be needed for emotional issues, which are commonly associated with the disease, and is especially true during the teenage years. Some experts recommend clinical and psychosocial follow-up at 6-month intervals for teenage patients. Suicide is increased in patients with Unverricht-Lundborg disease and close watch of depression should be performed.

Agents to Avoid

There is some suggestion that phenytoin exposure may exacerbate the disease in that it may enhance cerebellar symptoms, impair coordination, and impair cognition.95 For these reasons, it should be avoided. In addition, carbamazepine has no effect on any of the symptoms of Unverricht-Lundborg disease and should also be avoided.

Recent Research

Several recent papers have shown some efficacy for the use of levetiracetam for myoclonus. The use of the newer seizure medications is also under study.

Reviewed and revised March 2005 by Steven C. Schachter, M.D.

Ring Chromosome syndrome (RC20) is one of a number of chromosomal disorders associated with refractory epilepsy. A ring chromosome is formed by the fusion of two arms of a chromosome during pre-natal development.1 Why the formation of the ring causes epilepsy and other symptoms of the syndrome is not well understood.

The age of the onset of the syndrome has been reported between one day of postnatal life to 17 years.2 Development is usually normal before the onset of seizures. Clinically this syndrome is characterized by frequent nocturnal subtle seizures and EEG showing prolonged high voltage frontally dominant slowing intermixed with spikes or sharp waves.3,4 This syndrome is also characterized by behavioral problems, mild mental retardation, cognitive impairment and learning disabilities.

Epilepsy appears to be the first and major clinical symptom of this syndrome, is a constant feature, and is often drug resistant.5 Seizures associated with RC20 syndrome are often complex partial and reported as episodes of altered consciousness with staring, oral automatisms, unspecified automatic behavior, focal motor symptoms and/or head turning.6 Subtle nocturnal behavioral changes such as stretching, rubbing, turning-resemble arousal, subtle nocturnal seizures (SNS), and subtle nocturnal frontal lobe seizures (SNFL) have also been reported in studies of RC20 syndrome patients.5

How is this syndrome diagnosed?

Ring Chromosome 20 syndrome is diagnosed by recognition of the features outlined above and through looking at the pattern of chromosomes in the affected person’s cells. This is most easily done by looking at the chromosome pattern (karyotype) in blood cells but any other tissue including skin could be examined.7 Epilepsy is not present in all individuals with RC20 syndrome; however, it is the most consistent clinical feature. Unlike other chromosomal disorders with epilepsy, dysmorphism and other congenital malformations are rarely a part of this condition.8,9

Children can be misdiagnosed with Lennox-Gastaut syndrome or Landau-Kleffner syndrome. These two epilepsy syndromes have clinical similarities to RC20 syndrome and are characterized by frequent seizures, decline in learning ability and behavior and are often termed as cognitive epileptic encephalopathies. RC20 syndrome phenotype can also be mistaken for autosomal dominant nocturnal frontal lobe epilepsy (ADNFE). ADNFE is a familial partial epilepsy causing frequent, violent, brief seizures at night.10 Seizures usually begin in childhood and are easily controlled with carbamazepine unlike seizures in RC20 syndrome. The EEG features in RC20 syndrome may also have overlapping features of continuous slow spike and wave discharges in slow wave sleep (CSWS) and electrical status epilepticus in sleep (ESES).

How common is ring chromosome 20 syndrome?

RC20 syndrome is undoubtedly a rare condition. To date there are no published data on the incidence or prevalence of this syndrome. More than 50 cases have been reported in the medical literature. Since chromosomal analysis or karyotype testing is not a routine investigation when refractory epilepsy first presents, the diagnosis of RC20 syndrome may be delayed or go unrecognized. In other words, some people with difficult-to-control epilepsy may have a ring chromosome 20 but be unaware of it.

Management and Treatment

Since seizures with RC20 syndrome are typically difficult to treat, seizure control is very important. Every case is different and complex. Antiepileptic drugs are the mainstay and first line of treatment, however no one drug has been shown to be better than others. Patients are frequently exposed to multiple antiepileptic drugs. Epilepsy in RC20 syndrome is not amenable to resective surgery because of the lack of a focal epileptogenic region. Vagus nerve stimulation has been successful in a few cases reported in the literature.11

About the Ring Chromosome 20 Foundation

After years of testing, misdiagnosis, and a difficult journey to find medical treatment, the Ford family was told that the reason their young daughter Cara was having frequent and severe seizures was because of ring chromosome 20 syndrome. With so much uncertainty and little information about the syndrome available, Cara’s father, Stewart Ford decided to establish a Foundation to fund research and projects so that families and doctors can better understand this condition and its treatment.

The purpose of the Ring Chromosome 20 Foundation is to promote awareness of the syndrome and the importance of chromosomal testing in children with refractory epilepsy. The Foundation is based in New York City and in London. For more information about this syndrome and the Foundation, please visit www.ring-chromosome-20.org.

Reviewed and revised November 2006 by Steven C. Schachter, M.D.

If you know of patients with r(20) syndrome, we ask that you tell their families about our Foundation and let them know that they are not alone. Our organization promotes new research and we hope to provide as much information about this syndrome as possible.
Please visit our website, www.ring-chromosome-20.org and feel free to contact the Foundation at info@ring-chromosome-20.org.