Seizures that occur in association with particular epilepsy syndromes are
particularly refractory to available therapies. They will be briefly reviewed
here.

Infantile spasms

Infantile spasms constitute a unique and very serious epilepsy syndrome
confined to infants. The usual characteristic features of this syndrome are:

  • tonic or myoclonic seizures
  • hypsarrhythmic EEGs
  • mental retardation

This triad is referred to as West's syndrome. (Not all cases of infantile
spasms conform strictly to this definition, however.) Other names used in the
literature include:

  • massive spasms
  • salaam seizures
  • flexion spasms
  • jackknife seizures
  • massive myoclonic jerks
  • infantile myoclonic seizures
  • Blitz-Nick-Saalam Krampfe (in the German literature)

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. 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:

  • 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 rate

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.

Infantile spasms are frequently associated with developmental delay. In a
review of the literature, Lacy and Penry 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.

Abnormal neurologic findings on physical examination are also commonly
reported. Lacy and Penry 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.

Electroencephalography

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

  • 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. Some patients with infantile spasms do
not show a hypsarrhythmic pattern. 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.

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

Adapted from http://professionals.epilepsy.com/page/syndromes_spasms.html and
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)

Lennox-Gastaut syndrome

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 experts.

The child with LGS typically has a mixture of seizure types. The most
frequently occurring 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. 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. 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, 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.

Generalized tonic-clonic (GTC) seizures and atypical absence seizures are
seen in over half of the patients with LGS. 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.

Patients with LGS typically have very frequent seizures. Markand found that
60% of his patients had seizures daily, whereas Papini and colleagues, 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.
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. Only few patients escape mental
retardation. 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.

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 include:

  • 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 http://professionals.epilepsy.com/page/syndromes_lennox.html and
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)

Ring Chromosome 20 syndrome

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. Why the formation of
the ring causes epilepsy and other symptoms of the syndrome is not well
understood.

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.

The age of the onset of the syndrome has been reported between one day of
postnatal life to 17 years. 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. 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. 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. 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.

Diagnosis

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. 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.

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. 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).

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.

Adapted from
http://professionals.epilepsy.com/page/Ring_Chromosome_20_Syndrome.html, by Dr.
Syed Hosain.

Landau-Kleffner syndrome

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

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. Unlike typical acquired childhood aphasia, receptive dysfunction usually is the dominant feature early in the course of the disorder.
  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, 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 fluctuates 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. 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 http://professionals.epilepsy.com/page/syndromes_lanau.html and
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)

Progressive myoclonic epilepsies: Unverricht-Lundborg disease

Unverricht-Lundborg disease is the most common of the rare genetically
heterogeneous progressive myoclonic epilepsies. 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.

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. Unverricht-Lundborg is characterized by severe stimulus-sensitive
myoclonus, generalized tonic-clonic seizures, and EEG findings with marked
sensitivity to photic stimulation. 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. 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. 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.
Long term studies suggest that many patients are incapacitated by ataxia and
myoclonus at the end of the disease. Today, patients may live into their sixties
or seventies with proper medication and therapies.

Diagnosis/testing

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.

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. Disease-causing repeats are greater
than 30 repeats with over 100 repeated dodecamers found in some patients. 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. No correlation between the repeat size and the age at onset
or the severity of the disease has been reported.

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. 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.
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. 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. 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. Mental deterioration, dementia, intention tremor, and
dysarthria may develop, together with ataxia, late in the disease, usually over
a 10 – 20 year span. 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.

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.

Seizure medicines 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. 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.

Authored by: Steven C. Schachter MD on 5/2008
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