Electro-clinical syndromes by age of onset—childhood, adolescence, and adult Flashcards
Childhood absence epilepsy (summary)
Childhood absence epilepsy occurs in children 4–8 years of age with peaks around 6 years. It is more frequent in girls. CAE is characterized by very frequent absence seizures (pyknolepsy). Hyperventilation induces the absence seizures. Based on clinical and electrographic features, absence seizures are classified as typical and atypical absence seizures.
Typical absence seizures are associated with transient impaired consciousness (behavioral arrest, staring) with or without eye fluttering and automatisms. Onset and cessation are abrupt. Ictal EEG shows >2.5 Hz generalized spike and wave lasting >3 s (average <10 s).
Atypical absence seizures tend to have less abrupt onset and cessation, greater change in tone, longer duration, and variable impairment of consciousness. Interictally, the EEG shows gen- eralized irregular and asymmetric slow spike and waves (1.5–2.5 Hz). The ictal EEG is similar to the interictal discharges but may be associated with diffuse fast activity.
CAE pathophysiology
Pathophysiology:
10
According to the cortical focus theory, spikes are generated at a cortical focus and propagate rapidly via cortico-cortical networks to both hemispheres resulting in rapid synchronization. Paroxysmal oscillation in the cortico-thalamic loops amplifies and sustains the spike-wave discharges.
CAE genetics
Genetics:
Genetic mutations currently account for a small proportion of patients with absence epi- lepsy. Mutations in GABA receptor (GABRG2, GABRA1), calcium channels, and non-ion channel proteins have been identified in CAE. Glut-1 transporter deficiency is described in about 10% of children with early-onset (under the age of 4 years) absence epilepsy.
Animal models (generalized epilepsy/ absence epilepsy):
Several animal models are available for gen- eralized epilepsy and absence epilepsy, which include acute pharmacologic models [pentylenetetrazole (PTZ), penicillin, THIP, GBL], chronic models [genetic absence epilepsy rats from Strasbourg (GAERS), Wistar Albino Glaxo/Rijswijk (WAG/Rij)] and other models [AY-9944, MAM-AY].
CAE treatment options
Treatment options:
These include ethosuximide, lamotrigine, and valproate [1]. A double-blinded, randomized, comparative clinical trial compared the three medications in CAE and found that ethosuximide provided the best combination of seizure control and fewest attentional side effects, making it the optimal initial monotherapy in CAE.
Ethosuximide provided better seizure control compared to lamotrigine and fewer attentional effects compared to valproic acid. Although CAE is often perceived as “benign”, many children with CAE have cognitive deficits and long-term psychosocial problems.
Epilepsy with myoclonic absences
The majority (70%) of children with epilepsy with myoclonic absences are boys. The average age of onset is 7 years. In about one-third of patients a specific cause is identified. Family history of epilepsy is reported in 20%. Neu- roimaging abnormalities, mainly some degree of diffuse atrophy, are seen in 17% of patients.
Patients have variable impairment of con- sciousness. Myoclonic jerks involving shoulders, arms, and legs are seen. Tonic contractions, particularly elevation of the arms, are often noted. At times, the tonic activity may be asymmetric. Arrest of respiration and urinary incontinence may occur. Seizures last 10–60 s and frequent seizures may occur on awakening. Other seizure types such as GTC, absence, and drop seizures may also occur. Some children may evolve to Lennox-Gastaut syndrome (LGS), and cognitive impairment may occur.
The ictal EEG shows 3 Hz rhythmic, bilateral, synchronous, and symmetric spike-wave dis- charges. Intermixed polyspikes may be seen. Bilateral myoclonias occur at same frequency as spike waves, i.e., 3/second. Treatment options include valproate and ethosuximide [2].
Epilepsy with myoclonic astatic epilepsy
[Also known as Doose syndrome, or Epilepsy with myoclonic astatic epilepsy]
Age of onset is 1–5 years, and the child is normal at onset. There is strong family history of idiopathic epilepsy in 15–32%. Myoclonic and atonic seizures with falls suggest the diagnosis
mix of generalized seizures occurs including myoclonic, atonic, absence, GTC, and tonic (less common). Non-convulsive status epilepticus may occur on awakening from sleep or nap. GTC is usually the first seizure and is seen in 75–95% of patients. Prognosis for seizure and cognitive outcome is variable.
EEG shows bursts of 2–3 Hz generalized spike wave and polyspike waves, which increase with sleep. 4–7 Hz rhythmic theta activity over the central regions and vertex is a specific find- ing. Myoclonic-atonic seizures are electrograph- ically associated with a single generalized spike/polyspike wave (unlike LGS which shows secondary bilateral synchrony) or 3–4 Hz activ- ity lasting 2–6 s.
Neuroimaging is normal. Glut-1 deficiency syndrome is identified in about 5 % of children with Doose syndrome. SCN1A mutation is reported as a cause. Treatment options include valproate, lamotrigine, ethosuximide, topiramate, levetiracetam, and the ketogenic diet.
Lennox-Gestaut Syndrome (LGS)
LGS is characterized by the triad of 1. multiple seizure types: tonic (nocturnal tonic seizures are characteristic), atonic, atypical absence, GTC, and partial seizures; 2. EEG features of slow background with generalized slow spike-wave discharges at 1.5–2 Hz, multifocal discharges, and generalized fast activity at 10–25 Hz in sleep; and 3. cognitive dysfunction and intellec- tual disability.
The peak age of onset is 3–5 years. Infantile spasms precede LGS in 10–25%. LGS results from structural/metabolic causes in 70–78%, including meningo-encephalitis, cortical dys- plasia, hypoxia, and traumatic brain injury, among others. In 22–30% of children the cause is unknown. Family history of epilepsy is reported in 3–30%.
Several medications are used in the treatment of LGS, but seizure control is usually inadequate [3].
Epileptic Encephalopathy
with Continuous Spike and Wave During Sleep (CSWS)
Electrical status epilepticus in sleep (ESES) is defined commonly as epileptiform activity occupying >85% of NREM sleep. Two syn- dromes, Landau–Kleffner Syndrome (LKS) and continuous spike and wave during sleep (CSWS), are associated with ESES.
1. Landau–Kleffner Syndrome (LKS):
LKS usually occurs in children 3–10 years of age and manifests as language regression with verbal auditory agnosia (word deafness with normal hearing test). Seizures occur in two-thirds. ADHD features are common. Brain MRI is normal; however, cases with structural causes have been reported. Func- tional studies, such as SPECT and PET, have demonstrated temporal lobe abnormalities.
2. Continuous spike and wave during sleep (CSWS)
CSWS manifests as global regression in cognition and behavior. The majority of patients have seizures. CSWS is sometimes associated with identifiable pathology; e.g., neuronal migrational disorders, polymicro- gyria, shunted hydrocephalus, porencephaly, and thalamic lesions. Family history of sei- zure is reported in 10–15%.
Treatment: Various medications, including valproate, ethosuximide, and benzodi- azepines; immune modulatory therapy (ster- oids, IVIG); and surgery have been used in the treatment of ESES.
Juvenile Absence Epilepsy (JAE)
JAE, unlike CAE, is associated with less frequent absence seizures (one to a few per day) and is more frequently associated with GTC seizure (in 80%). The impairment of consciousness is less severe in JAE. The age of onset ranges from 10– 17 years.
Juvenile Myoclonic Epilepsy (JME)
The age of onset for JME is 12-18 years (mean age 14.6). Seizures occur mostly upon awaken- ing in the morning but can occur after waking from a nap. Sleep deprivation, stress, fatigue, and alcohol are major seizure provoking factors.
Seizure types in JME include myoclonic sei- zures (may be repetitive), GTC seizures (occur in 80–95% of patients; typically preceded by clus- ters of myoclonic jerks; clonic–tonic–clonic sei- zures; frequency—one or two/year), and absence seizures (in 18–38% of patients).
Interictal EEG demonstrates high amplitude generalized symmetric and synchronous 4–6 Hz polyspike-wave discharges. Photosensitivity is noted in about 30% of patients.
Family history of epilepsy is reported in 40– 50%. Inheritance is unclear, likely polygenic, but both autosomal dominant and recessive inheri- tance have been reported. Gene mutations iden- tified in some families include GABRA1 (GABA-A receptor gene on chromosome 5q34), CLCN2 (chloride channel 2 gene on chromo- some 3q26), and myoclonin1/EFHC1 (EH-hand motif protein on chromosome 6p12; found in 9% of JME).
Treatment: Valproate, lamotrigine (may wor- sen myoclonus), topiramate, and levetiracetam are used in the treatment of JME.
Epilepsy with GTC Seizures Only
Seizures may predominate in the morning (the earlier classification of epilepsy with grand mal on awakening included). Sleep deprivation is a trigger. Family history of generalized epilepsy and photosensitivity may be present.
Progressive Myoclonic Epilepsy (PME)
PME is a group of disorders presenting with severe myoclonic seizures (and tonic–clonic seizures) with progressive neurologic deterioration (ataxia, dementia). EEG shows progressive slowing, generalized and multifocal discharges, and photosensitivity typically at lower flash frequency.
PME includes Lafora disease, Myoclonus Epilepsy with Ragged Red Fibers (MERRF).
Neuronal Ceroid Lipofuscinoses, Sialidosis, and Unverrricht-Lundborg Disease. Dentatorubral- pallidoluysian atrophy (DRPLA) may also cause PME [4].
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE)
ADNFLE is caused by mutation of genes coding for neuronal nicotinic acetylcholine receptor subunits (CHRNA4, CHRNB2, CHRNA2). Sei- zure onset is in childhood with mean age of 11.7 years, and seizures persist into adulthood. The typical seizure manifests with sudden arou- sal from NREM sleep (stage II) with hyperkinetic or tonic movements. Seizures may cluster. Awareness is usually retained. Auras, which may be specific with sensory and psychic symptoms or non-specific, are frequently reported. Neu- roimaging is normal. Interictal EEG is usually normal. Ictal EEG may show bifrontal discharges.
Familial Temporal Lobe Epilepsy (Autosomal Dominant
with Incomplete Penetrance)
- Familial mesial temporal lobe epilepsy (FMTLE): FMTLE may occur with or with- out hippocampal sclerosis.
A. Benign FMTLE without hippocampal sclerosis or febrile seizures has its onset in adolescence or adulthood with aura of mesial temporal origin (psychic and auto- nomic features). Prognosis is excellent.
B. FMTLE associated with hippocampal sclerosis presents with complex partialseizure with automatisms. The mean age of onset is 10 years. Asymptomatic family members may have hippocampal sclerosis. The course is benign in the majority.
C. FMTLE associated with febrile seizures starts in the first to second decade of life and has a benign course. - Familial lateral temporal lobe epi- lepsy (Autosomal Dominant Partial Epilepsy with Auditory Features (ADPEAF)):
ADPEAF is associated with focal sei- zures. Elemental or complex auditory aura is prominent in 64% of patients. The epilepsy has a benign course. Leucine-rich glioma-inactivated 1 (LGI1) gene mutation is identified in 50% of families.
Familial Focal Epilepsy with Variable Foci
Different focal epilepsies are seen in different family members. Seizures and EEG abnormali- ties are consistent in each affected family mem- ber. Frontal lobe seizures predominate. Features that help to differentiate from ADNFLE include less frequent seizures, daytime seizures, more frequent secondary generalization, and rare clusters and auras. Seizure foci may also be temporal or occipital. Inheritance pattern is autosomal dominant with 70% penetrance; mapped to chromosome 22q12 [5].
Reflex Epilepsies
In reflex epilepsies, a specific stimulus or event repeatedly elicits seizure. Trigger stimuli include visual stimuli (light, patterns), startle, reading, tactile, music, drawing/praxis, bathing, thinking, arithmetics, decision making, and gaming.
