Difficult to treat or progressive epilepsy syndromes
Seizures that occur in association with particular epilepsy syndromes are particularly refractory to available therapies. They will be briefly reviewed here.
Infantile spasms constitute a unique and very serious epilepsy syndrome confined to infants. The usual characteristic features of this syndrome are:
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:
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:
Asymmetric spasms occasionally occur, in which the infant maintains a "fencing" posture.
Infantile spasms may also be associated with autonomic dysfunction characterized by:
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.
Infantile spasms are usually associated with markedly abnormal EEGs. The most common interictal abnormality is hypsarrhythmia (See EEG). There are several variations:
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.
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 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.
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:
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.
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.
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.
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:
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.
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 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.
Topic Editor: Steven C. Schachter, MD. Last Reviewed: 5/10/08
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