Two or more different IGE phenotypes may be found in the same pedigree. Clinical and EEG overlap may be observed (Fig. 1)(22,23). Additionally, one IGE syndrome [i.e., juvenile myoclonic epilepsy (JME)] may evolve out of another typical IGE syndrome [i.e., childhood absence epilepsy (CAE)] after several years, when the patient reaches the manifestation age for the myoclonus (21,24). Based on such evidence, the concept of a biologic continuum has been proposed, with changes in the classification system (25). A similar IGE genotype may be present, but differing clinical symptoms (IGE syndrome) may depend on modifying genes or other factors (26). Supportive of this is recent documentation of a novel de novo mutation in one subject with CAE that evolved into JME (27). Animal studies demonstrate a dosage-sensitive gene function (haploinsufficiency) specific to brain, which may explain the mechanism of the IGE (28).
Juvenile myoclonic epilepsy
JME is a common form of IGE, having an overall prevalence of 5–10%(29). Individuals present between the ages of 8 and 26 years, but in >75%, initial manifestations occur between ages 12 and 18 years. Early morning myoclonus, primarily involving both upper extremities, precipitated by sleep deprivation, fatigue, or alcohol, is characteristic at onset (30–33). Generalized tonic–clonic (GTC) seizures occur in >90%, and 30% have absence seizures. The GTC seizures are often preceded by a series of myoclonic jerks (31). When absence seizures occur, they are often infrequent. Studies from independent groups have provided evidence for the existence of a JME locus on chromosome 6p (designated EJM1) (21,34–36). This expresses the phenotype of classic JME. A separate susceptibility locus for JME maps to chromosome 15q14 (37). CAE that evolves to JME has a locus on chromosome 1p (21).
The EEG background is typically normal. The characteristic interictal EEG findings are generalized 4- to 6-Hz polyspike and slow-wave complexes; however, many patients have 3- to 4-Hz spike and slow-wave complexes. Photosensitivity is seen in about one third of patients; however, the yield may be increased by extending intermittent photic stimulation for ≤5 min (38). Documentation of photosensitivity has important management implications. Fewer than 10% of patients persistently have normal EEG findings (29). Asymmetric EEG findings, including lateralized sharp waves, unilateral spike, or polyspike and slow-wave complexes, or voltage asymmetries have been reported in 38% of patients (29). In most cases, they shifted between the hemispheres on consecutive EEG recordings. Occurrence of lateralized or persistently focal EEG abnormalities can occur (29,39,40). This may result in misdiagnosis or a delay in JME diagnosis. Sleep EEGs had the highest diagnostic yield, with some authors reporting abnormalities in 100% of cases (30). Epileptiform discharge rates on sleep EEGs typically increased significantly during the transition phase (i.e., the asleep-to-awakening state). More than half of patients may show normalization of the EEG after drug therapy (41).
The characteristic ictal EEG for a myoclonic jerk in JME is a bilaterally symmetrical, frontocentrally accentuated, generalized polyspike-and-wave complex. The spikes usually have a frequency of 10–16 Hz, and the slow waves have a frequency of 2–5 Hz (32).
Rarely, structural brain lesions may be found, but these do not appear to influence the therapeutic response or prognosis in JME (42). A single case of JME has been reported in a man with mental retardation and structural brain changes presumed secondary to acquired perinatal damage (43). Voxel-based analysis of magnetic resonance imaging (MRI) has revealed an increase in cortical gray matter (especially mesial frontal lobes) in 40% of patients with JME (39).
JME may be mimicked by nonepileptic seizures, but this is a rare semiology for nonepileptic seizures (44).
Juvenile absence epilepsy
Juvenile absence epilepsy (JAE) is an infrequent IGE with onset in adolescence (47). There probably exists an overlap between this and JME (22). This occurs in predominantly neurologically normal patients, with no sex preference. The absence seizure frequency is less than in CAE, with absences occurring sporadically. The majority of patients also have GTC seizures. When GTC seizures accompany, they mostly occur on awakening. The similarities between JAE and GMA support the concept of a neurobiologic continuum for IGE (48). JAE appears to be an intermediate syndrome between CAE and JME.
The EEG background is usually normal. The characteristic feature of the interictal and ictal EEG is a generalized, regular, spike-and-wave complex at 3.5–4 Hz, maximally over the frontal head regions. This can be precipitated by hyperventilation, sleep deprivation, and infrequently by photic stimulation.
Progressive myoclonic epilepsies
Progressive myoclonic epilepsies are rare, accounting for only 1% of all epilepsy cases in childhood and adolescence (49,50). A PME syndrome is characterized by the association of (a) a myoclonus syndrome involving massive myoclonus and asymmetric myoclonus, (b) generalized tonic–clonic seizures, (c) mental deterioration resulting in dementia, and (d) a neurologic syndrome with cerebellar manifestations (51). A large number of causes for the PME have been identified, many with specific genetic etiologies that can now be identified. Some PME disorders, with special emphasis on the recent molecular genetics discoveries and EEG aspects, are reviewed. Overall, the EEG typically shows a slowing of the background rhythm, generalized epileptiform discharges (Fig. 2), and photosensitivity (51). Giant cortical responses are often observed with somatosensory evoked potentials (SSEPs; Fig. 3) (51).
Figure 2. Progressive myoclonic epilepsy with generalized, irregular polyspike or spike and slow-wave complexes seen in sleep.
Download figure to PowerPoint
Figure 3. Somatosensory evoked potentials of the left median nerve in an adolescent with Lafora body disease. Note the giant cortical response (N20-P22 amplitude = 14.89 μV).
Download figure to PowerPoint
Unverricht–Lundborg disease (Baltic myoclonus, locus symbol EPM1) is an autosomal recessive disorder, which occurs in the Finnish population with an incidence of one in 20,000. Stimulus-sensitive myoclonus begins between ages 6 and 15 years, and then mild mental retardation, ataxia, and dysarthria slowly develop. Unverricht–Lundborg disease was mapped to chromosome 21q 22.3, and the EPM1 gene was shown to encode cystatin B (34). Cystatin B, a member of a superfamily of cysteine protease inhibitors, is thought to inactivate proteases that leak out of the lysosome. Clinical and EEG photosensitivity are observed in ∼90% of patients. The EEG background is initially normal and slows over time. Irregular, generalized spike or polyspike and slow-wave complexes, maximal over the anterior head regions, are seen. In sleep, these epileptiform discharges may diminish in number.
Progressive myoclonus epilepsy with polyglucosan intracellular inclusion bodies (Lafora disease) is an autosomal recessive disorder localized to chromosome 6q-24 (34,52). The gene mutated in Lafora disease, EPM2A, encodes an intracellular protein tyrosine phosphatase, laforin. Periodic acid–Schiff-positive cytoplasmic inclusion bodies are present in neurons, heart, liver, and muscle. An axillary skin biopsy, which includes sweat gland ducts, reveals the characteristic inclusions. The onset occurs between 6 and 19 years. The initial seizures are often generalized tonic–clonic and associated with partial visual seizures involving scotomas or simple visual hallucinations. Soon after disease presentation, asymmetric myoclonic jerks occur, followed by dementia, ataxia, and visual loss. At presentation, the EEG may resemble an IGE, showing a normal background with isolated generalized spike and slow-wave discharges (Fig. 4). The EEG abnormalities often precede clinical symptoms. Photosensitivity is usually present (Fig. 5). The EEG quickly progresses to show background slowing, fast irregular generalized spike or polyspike and slow-wave discharges, and occipital spikes. The epileptiform discharges decrease during sleep. Initially, high-voltage somatosensory and visual-evoked potentials (VEPs) are recorded.
Figure 4. EEG performed in an 11-year-old girl with Lafora body disease after her first seizure. The semiology was consistent with an absence event. Note the brief generalized spike and slow wave burst seen interictally, resembling an idiopathic generalized epilepsy.
Download figure to PowerPoint
Figure 5. Adolescent with Lafora body disease. EEG during photic stimulation at 6 Hz shows marked photosensitivity and subsequent myoclonic jerks.
Download figure to PowerPoint
Mitochondrial genes are maternally inherited, and diseases due to mutations of mitochondrial DNA (mtDNA) include encephalopathies, myopathies, and multisystem disorders. Myoclonic epilepsy with ragged-red fibers (MERRF) is characterized by epilepsy, intention myoclonus, muscle weakness, progressive ataxia, and deafness. An A-to-G transition mutation at nucleotide pair 8344 in the pseudouridyl loop of the tRNAlys gene has been described in most families (34). The clinical phenotype varies depending on the amount and tissue distribution of mutant mtDNA in an individual. The age at onset varies greatly between childhood and the elderly. The EEG findings are an abnormally slow background, generalized irregular spike-and-wave, or polyspike-and-wave discharges, and occasional focal epileptiform discharges (53). Photosensitivity is uncommon, and when it occurs, the discharges show a posterior predominance. The normal elements of sleep are poorly differentiated, and in some patients, the generalized discharges are markedly attenuated.
The neuronal ceroid lipofuscinoses (NCLs) are characterized by the accumulation of abnormal amounts of lipopigments in lysosomes. Eight forms of NCL have now been identified on the basis of clinicopathologic, biochemical, and genetic testing (54–61). Two have onset during or near adolescence. All forms are autosomal recessive, except Kuf disease (CLN4), which also could be autosomal dominant. The juvenile form (JNCL or Batten–Spielmeyer–Vogt disease) begins between ages 4 and 10 years. This is the most common form in the United States. Most patients have visual failure and have the gradual development of dementia and extrapyramidal features, with seizures as a minor manifestation (54). The EEG background is initially normal, but then generalized slow activity appears. Generalized epileptiform discharges are often slow spike-and-wave complexes, typically activated by sleep. The electroretinogram (ERG) is flat, and VEPs are low amplitude or absent.
Adult NCL or Kuf disease typically begins between ages 11 and 55 years. Kuf differs from early-onset forms, in that visual symptoms are absent. Kuf disease occurs as a progressive myoclonic epilepsy or as a dementia with motor disturbances. The VEP is typically normal, in contrast to the abnormal VEP seen in childhood NCL. Giant cortical responses may be seen on SSEPs. The EEG findings are nonspecific, with initial generalized slowing of background activity and generalized epileptiform discharges (62). Photosensitivity may occur, but again it is rare, in contrast to the childhood forms in which it is common. Only tonic seizures may be observed.
Previously, diagnosis of NCL was based on age at onset and clinicopathologic findings. Recent phenotype/genotype analysis has been performed in large numbers of individuals with NCL (61,63). This has changed the diagnostic approach to NCL. Mutations in the CLN1 gene on chromosome 1p32 were associated with three different phenotypes: juvenile, infantile, and late infantile. Two common mutations account for 64% of the patients. Whereas a missense point mutation, 223AC, was the most common among juvenile-onset forms, a nonsense point mutation, 451CT, was the most common in infantile onset. All of the CLN1 probands were palmitoyl protein thioesterase (PPT) deficient and showed granular osmiophilic deposits (GRODs) at the electron microscopic (EM) level. Rarely the juvenile-onset form may be seen with mutation in the CLN2 gene on chromosome 11p15, and curvilinear bodies (CV) are seen on EM. All CLN2 probands had a deficiency of tripeptidyl-peptidase I (TTP I) activity. Typical juvenile NCL is due to a mutation of the CLN3 gene on chromosome 16p12.1. Fingerprint profiles (F) may be the only abnormality, or this may be seen with CV or GROD on EM. Adult NCL is due to a mutation of CLN4, and the chromosome location is unknown. The EM typically shows a mixture of F, CV, and GROD. The diagnosis of NCL is now based on clinicopathologic findings, ultrastructural studies, enzymatic assay, and molecular genetic testing. The recognition of variable onset from infancy to middle age supersedes the previous, traditional emphasis on age-related NCL forms.
Mesial temporal lobe epilepsy
Temporal lobe epilepsy associated with hippocampal sclerosis is the most common form of human epilepsy and represents a discrete syndrome that can be recognized in adolescence. Diagnosis of medically refractory MTLE before or during adolescence is important, because the seizures and their consequences can be eliminated by surgical therapy (anteromesial temporal lobectomy) in 80–90% of patients, and early surgical intervention provides the greatest opportunity for complete psychosocial rehabilitation. Recent volumetric MRI studies have suggested that hippocampal sclerosis is a progressive disorder with a risk for cognitive dysfunction (64). The characteristic clinical features and an ability to identify hippocampal disturbances noninvasively with modern MRI have allowed MTLE to be established as a discrete epileptic syndrome (65–69).
The clinical presentation of medically intractable MTLE consists of onset of habitual complex partial seizures during childhood, which may initially respond to antiepileptic drug (AED) therapy. The child does well for several years, but then complex partial seizures return in adolescence or early adulthood and are treatment resistant in at least one third (70). Usually there is a history of complex febrile seizures (71). There is an increased incidence of a family history of epilepsy and febrile seizures (72). The seizure characteristics include an aura in >90% of patients, with the most common being a rising epigastric sensation (51,73). The aura is followed by motor arrest and staring. Typical oroalimentary automatisms (i.e., lip smacking, chewing, swallowing) or fumbling, picking movements are characteristic. Unilateral dystonic posturing occurs contralateral to the side of onset. The duration of the seizure is usually between 30 and 90 s, with a postictal reorientation that may last several minutes. The seizure is followed by a postictal phase, which is longer if the event originated from the language-dominant side. The interictal EEG shows anterior temporal slowing and epileptiform discharges (Fig. 6A and B)(74,75). These are unilateral in most, but in ≤40% of patients, may occur bilaterally. When this occurs, they are preponderant over the side of seizure origin in half (74). Ictal EEG usually consists of unilateral, theta-frequency rhythmic sharp waves appearing within 30 s of the first ictal EEG abnormality (Figs. 7A–E and 8A and B)(74,76). High-resolution MRI demonstrates unilateral hippocampal atrophy with increased signal on T2-weighted and FLAIR images, seen best on oblique coronal views (Fig. 9). Other supportive studies are usually performed before epilepsy surgery (74,77,78). MTLE should be referred for surgical evaluation if two AEDs have failed to control the seizures. If surgery is performed, patients are relieved of disabling seizures before they interfere with critical social and vocational development during adolescence. This gives the best psychosocial outcome. If seizures continue through adolescence, even if they are abolished later in life by using surgical treatment, the patient may remain a psychosocial invalid. Early surgical intervention offers the greatest potential to restore an adolescent to a normal life. Most medically refractory epilepsy in childhood is extratemporal in origin. However, mesial temporal sclerosis and refractory temporal lobe epilepsy can present in childhood.
Figure 6. A, B: EEG in patient with right mesial temporal lobe epilepsy showing a characteristic unilateral interictal anterior temporal sharp wave.
Figure 8. A, B: Ictal EEG (consecutive tracings) in a patient with right mesial temporal lobe epilepsy shows right mesial temporal (SP2) rhythmic theta frequency sharp waves at seizure onset.
Figure 9. A 15-year-old girl with left-sided hippocampal sclerosis. Angled coronal T2-weighted magnetic resonance imaging shows an area of increased signal intensity and hippocampal atrophy on the left side. (The left hippocampus is on the right side of the figure.)
Download figure to PowerPoint
Davidson and Falconer (79) reported the first series of children younger than 16 years with intractable partial seizures who underwent temporal lobectomy. More than half of the children had their epilepsy on the basis of MTLE. Falconer thought that temporal lobectomy in childhood gave better results than that in people two to three decades older. Mizrahi et al. (80) noted more frequent psychosocial, behavioral, and educational problems occurring in patients whose temporal lobectomy was delayed until adult life. Independently, Meyer et al. (81) noted similar improvements and also concluded that children with medically intractable MTLE should be offered early consideration of surgical intervention.
It is now established that mesial temporal sclerosis and medically refractory temporal lobe epilepsy may present in childhood (72,79,82). The youngest reported case is younger than 1 year. The clinical semiology of the seizure, interictal, and ictal EEG are all similar to that of adults with MTLE (72,82,83). In younger children, the automatisms may be simpler, typically limited to lip smacking and fumbling hand gestures. Often these children will have a history of prior febrile seizures, which may be prolonged or with focal features (79). Modern neuroimaging reveals the characteristic findings of hippocampal sclerosis on MRI (82,84).
Recently Gaillard et al. (85) reviewed their experience in identifying mesial temporal sclerosis with MRI in children and adolescents (85). They identified six children younger than 5 years and nine children between 5 and 10 years, suggesting that MTLE may be more common in young children than previously assumed. This finding collaborates prior work that evaluated 63 children with new-onset TLE and identified 13 with MRI evidence of hippocampal sclerosis (86). All but one had a history of a significant antecedent (i.e., focal or prolonged febrile seizure, meningitis). Seizure onset had a bimodal distribution, showing peaks in early (aged 0–3 years) and late childhood (aged 7–10 years). Hippocampal sclerosis is probably the most common lesion in children with intractable TLE, and hippocampal sclerosis may be underdiagnosed in children.
The safety and efficacy of surgery for medically refractory MTLE in children and adolescents is excellent, paralleling that observed in young adults.