Seizures and epilepsy in early life

Question 1

Neonatal (<28 days) seizure syndromes

Answer 1

Benign Familial Neonatal Seizures (BFNS)
Early Infantile Epileptic Encephalopathy: EIEE (Ohtahara Syndrome)
Early Myoclonic Encephalopathy: EME

Question 2

Infancy ( >= 28 days to =<1 year old) seizure syndromes

Answer 2

Migrating Partial Seizures of Infancy
Infantile Spasms
Myoclonic Epilepsy in Infancy
Benign Infantile Seizures
Myoclonic Encepaholathy in Nonprogressive Disorders

Question 3

Childhood (>1 year old) seizure syndromes

Answer 3

Febrile seizures
Genetic Epilepsy and Febrile Seizures Plus (GEFS+)
Dravet Syndrome (also called Severe Myoclonic Epilepsy of Infancy or SMEI)
Benign Epilepsy with Centrotemporal Spikes BECTS (“Rolandic Epilepsy”)
Panayiotopoulos Syndrome (Early Childhood Onset “Occipital” Epilepsy)
Gastaut Syndrome (Late Childhood Onset “Occipital” Epilepsy)
Rasmussen Syndrome

Question 4

Benign Familial Neonatal Seizures (BFNS)

Answer 4

Neonatal

Also known as “3rd day fits,” this disorder has mapped to chromosomes 20 and 8 (KCNQ2 and 3, K+ channels).

Seizures consist of tonic posturing, apnea/cyanosis, autonomic signs, face and limb clonus, and last 1–3 min.

If treatment required, medications can be continued until 3–6 mos of age. Patients may develop other types of seizures later in life.

Question 5

Early Infantile Epileptic Encephalopathy: EIEE (Ohtahara Syndrome)

Answer 5

Neonatal

The onset is in first 3 months of life.

Structural brain lesions are the most common etiology but the following genes also have been associated with EIEE: STXBP1, CDKL5, ARX, KCNQ2.

EEG reveals suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases.

The primary semiology consists of frequent tonic spasms in isolation or clusters (other seizure types can occur, as well).

Neonates can have hundreds of seizures per day. There is a high mortality rate in infancy. Prognosis is characterized by profound neurodevelopmental deficits in survivors.

Seizures are typically resistant to treat- ment but controlled by school age in half of children. Many neonates later progress to West syndrome (see below) at 3-6 months of age and then Lennox-Gastaut syndrome at 1-3 years of age.

Question 6

Early Myoclonic Encephalopathy: EME

Answer 6

Neonatal

The onset of EME is very early, typically in first month of life (some cases are familial).

In terms of etiology, concurrent metabolic disorders are common (the classic one is glycine encephalopathy but others have been noted, as well—a B6 trial is reasonable but it typically is unsuccessful).

The EEG (while awake) shows multifocal spikes on slow background ± periodic activity. Unlike EIEE, suppression-burst is observed primarily during sleep

The seizure semiology typically is myoclonus in the limbs and face. Focal seizures and tonic spasms are common.

Conventional treatments are typically used with very limited success. Corticosteroids have only a minimal effect on seizures. Myoclonus usually resolves by weeks to months but focal seizures persist. Mortality is high in the early ages. The prognosis is poor for resolution of seizures and neurodevelopment.

Question 7

Migrating Partial Seizures
of Infancy

Answer 7

Infancy

In this syndrome, development is initially normal, and then seizure starts between 1 week and 7 mos (mean = 3 mos).

The list of genetic mutations associated with this syndrome is expanding rapidly.

The interictal EEG ini- tially shows multifocal slowing, which pro- gresses and later includes a disruption of sleep architecture. The ictal EEG shows multifocal origins of seizures with migration to different regions (morphologically, including rhythmical delta or sharp waves/spikes).

Initially, there are sporadic focal motor seizures but eventually they become prolonged or occur in clusters and may secondarily generalize There are associ- ated extrapyramidal signs and tone worsens over time. There is early intractability but seizure control may improve with age in survivors. Early deaths may be associated with respiratory difficulties.

Neurodevelopmental prognosis in survivors generally is poor.

Question 8

Infantile Spasms

Answer 8

Infancy

The peak onset is 5 mos (typically 4–8 mos).

The etiologies may be symptomatic (i.e., with an identifiable underlying cause, representing 75–85% of patients) or asymptomatic. Underlying conditions may be genetic (ARX, STXBP1), metabolic, congenital infection, neonatal infection, among many oth- ers. Intellectual disability is seen in 75–90% of patients.

Clinically, this epilepsy syndrome is characterized by flexor or extensor spasms in clusters.

The eponym West syndrome is defined by the triad of spasms, the EEG appearance of hypsarrhythmia, and developmental delay.

The differential diagnosis includes benign myoclonus, benign myoclonic epilepsy, and gastroesophageal reflux (EEG easily distinguishes these from one another).

Treatment includes steroids (ACTH, prednisolone), viga- batrin, the ketogenic diet, zonisamide, and vitamin B6, noted in different published case series. Animal models are generated by inducing early injury and genetic manipulations.

Question 9

Myoclonic Epilepsy of Infancy

Answer 9

Infancy

With an onset of 4 mos–3 yo, this syndrome is eventually outgrown in most patients.

The EEG shows generalized spike/polyspikes lasting 1–3 s.

Clinically, there are axial or upper extremity myoclonic jerks with head drops; trunk flexion or extension has been noted, and the lower extremities are only involved rarely.

This syndrome is associated rarely with antecedent febrile seizures.

Reflex myoclonic seizures are a sub- group (induced by auditory, tactile stimuli); some patients are photosensitive.

The differential diagnosis includes infantile spasms and benign myoclonus. The EEG and normal development differentiate MEI from infantile spasms (hypsar- rhythmia) and benign myoclonus (normal EEG).

Neurodevelopment generally is normal but patients may develop other seizures later in life. Treatment typically is with VPA, LEV, or CZP.

Question 10

Benign Infantile Seizures

Answer 10

Infancy

The terminology used for this family of disorders is in development as of this writing but both familial and non-familial forms have been noted.

The onset is between 3 and 20 mos in a devel- opmentally normal infant.

In the familial form, mutations in PRRT2 (same gene as paroxysmal kinesigenic dyskinesia), ASC-1 (amino acid transporter), and SCN2A have been noted (there likely are others). Structural and metabolic workup is negative.

The EEG shows a focal ictal onset (posterior or temporal); interictal EEG typically is normal.

The non-familial form onset can be in the 2nd year of life, with equal sex predominance. In the familial form, onset typically is 4–7 mos, with a female predomi- nance.

Seizures are characterized by focal onset (head, face, limbs) clonic seizures, may secon- darily generalize, and can occur in clusters with varying lateralization.

Medicines usually are prescribed but seizures generally are easy to treat.

The prognosis is good for both seizures and development.

Question 11

Myoclonic Encephalopathy in Nonprogressive Disorders

Answer 11

Infancy

Three forms of this epilepsy syndrome have been described:
1. Absence + myoclonic seizures
2. Alternating bilateral positive and negative myoclonus
3. Mild onset with focal facial (then limbs) sei- zures.

Question 12

Absence + myoclonic seizures

Answer 12

Infancy

1 of 3 types of myoclonic encephalopathy in nonprogressive disorders

The EEG shows theta–delta or delta with spikes. Typically, this is diagnosed in the 1st year of like. There usually is a genetic etiology (Angel- man, Prader–Willi, Rett, others). Treatment in combination with ESM-VPA may work in some patients.

Question 13

Alternating bilateral positive and negative myoclonus

Answer 13

Infancy

1 of 3 types of myoclonic encephalopathy in nonprogressive disorders

The EEG shows diffuse rhythmic slow spike-waves or multifocal spike-waves or theta–delta. There may be dyskinetic movements. The onset usually is ~ 6 yo. Seizures are medically intractable seizures, and infants show poor neurodevelopment. Structural brain malformations have been noted in some patients.

Question 14

Mild onset with focal facial (then limbs) sei- zures.

Answer 14

Infancy

1 of 3 types of myoclonic encephalopathy in nonprogressive disorders

Onset in this form typically is 7 mos–5 yo. The EEG shows generalized spike-waves or bilateral continuous slow activity and then EEG and clinical deterioration (with both pyramidal and extrapyramidal signs, as well as myoclonus). This form may be associated with neonatal anoxia. Seizures are medically intractable.
Because the prognosis is somewhat different,
this syndrome should be distinguished from the progressive myoclonus epilepsies.

Question 15

Febrile seizures

Answer 15

Childhood

By definition, febrile seizures have an onset between 1 mo and 5 years.

Any seizure semiol- ogy can be seen but generalized tonic–clonic eizures are the most commonly noted one.

By definition, there is no evidence of intracranial infection or defined cause for the seizure.

The incidence is 3–5% of the US population. The median age of presentation is 18 mos and half of patients present between 12 and 30 mos. In terms of genetics, 10–20% of siblings also have these seizures.
Recurrence of febrile seizure is:
*33% will have a second FS (range in studies is 23–42%);
*1⁄2 of those will have a 3rd FS (range in studies is 7–30%);
*50% recur in 1st 6 months; 75–90% recur in 1st year.

Recurrence risk is influenced by: age (<1 year doubles the risk), FS in 1st degree relative (up to double the risk), low-grade fever at seizure onset, and illness frequency.

Risk factors for develop-ing epilepsy after a FS include a positive family history of epilepsy, abnormal neurodevelopment, occurrence of a complex febrile seizure, a pos- tictal Todd’s paralysis, number of febrile seizures (more seizure = greater risk), and duration of febrile seizure (longer seizure = greater risk)

Question 16

Genetic Epilepsy and Febrile Seizures Plus (GEFS+)

Answer 16

FS+ is defined as a FS after 6 yo or occurrence of other seizure types. Almost any type of seizure has been documented for FS+. FS+ is associated with mutations in SCN1A, SCN1B, or GABRG2 but importantly, mutations only are seen in 10– 20% of those with GEFS+ (so genetic testing generally is not advised).

Question 17

Dravet Syndrome (also called Severe Myoclonic Epilepsy of Infancy or SMEI)

Answer 17

Childhood

Characterized by a prolonged FS in 1st year of life, there is a seizure-free period followed by the appearance of myoclonic seizures at 1–4 years (8% of patients have an onset <3 yo).

Approximately 70–80% of patients have mutations in SCN1A, so genetic testing generally is indicated for prognosis and to obviate the need for further diagnostic workup. The so-called SMEI “borderland” (SMEB) lacks certain core features of SMEI but has been documented in various pedigrees but is no longer believed to be a separate entity.

The EEG shows spike and wave or polyspike and waves.

Develop- ment is normal early and then deteriorates clini- cally (including pyramidal signs and ataxia). Treatment with Na-channel medications (e.g., carbamazepine, lamotrigine) may worsen seizures in these patients. Some patients have clear seizure exacerbations when exposed to extrinsic (or even generating intrinsic) heat—thus, these environmental stimuli should be avoided when possible and practical.

Question 18

Benign Epilepsy with Centrotemporal Spikes BECTS (“Rolandic Epilepsy”)

Answer 18

Childhood

This is the most common focal epilepsy in childhood, with an onset between 2 and 14 years (peak 7–10 years).

The interictal EEG shows spikes that are diphasic with a phase reversal over temporal, central, or parietal regions (longitudinal bipolar montage). They typically are bilateral but one side may have more spikes than the other. Salvos of central and temporal spikes are seen, with an increase in persistence during drowsiness and sleep. Slowing after spikes suggests seizures will be more challenging to control. When seen by those unfamiliar with this syndrome, spikes may be mistaken for multifocal epilepsy.

Sensory symptoms may be seen in the tongue, lips, gums, or cheek; drooling also may be noted. Motor symptoms typically are in the tongue, larynx, or pharynx. Seizures usually occur during sleep (1st part of the night) but 10–20% of patients have seizures only while awake.

The differential diagnosis includes malformations of cor- tical development, vascular anomalies, and other lesions. These conditions should be considered if there are unilateral spikes, very frequent seizures, or lack of improvement.

EEG findings suggesting other diagnoses include decreased frequency of spikes in sleep, fast spikes or polyspikes, or a suggestion of burst suppression following spikes.

In terms of prognosis, BECTS typically is out- grown by age 16. Nearly 80% of patients have <6 seizures so treatment is not recommended for most patients. There are concerns about language development, which should be specifically screened even if school performance is average (high-functioning students may not need this). Occasionally, BECTS resolves only to have other types of seizures develop after 18 years of age. Treatment, if needed, has included CBZ, OXC, LEV, VPA, GPN, and sulthiame.

Question 19

Panayiotopoulos Syndrome
(Early Childhood Onset “Occipital” Epilepsy) [8]

Answer 19

Peak onset between 3 and 6 years

The interictal EEG classically shows occipital spikes in salvos (increased in sleep) but spikes can be seen over any region.

Seizures start with behavioral agitation and then headache, autonomic symptoms, and motor (hemiclonic or generalized tonic clonic) seizures. Seizures tend to be prolonged. Autonomic symptoms (including status epilepticus) include vomiting, pallor, cyanosis, among other symptoms. Approximately 2/3 of patients have seizures out of sleep.

This condition is treated only rarely because 85% of patients have =< 5 seizures over their lifetime.

Question 20

Gastaut Syndrome (Late Childhood Onset “Occipital” Epilepsy)

Answer 20

Peak onset of 8–11 years

The interictal EEG classically shows occipital spikes in salvos but spikes can be seen anywhere. There is an increased frequency of epileptiform activity during sleep and with eye closure.

Seizures start with elementary visual auras and may progress to partial vision loss or classical focal-onset sei- zures (only rarely will they generalize). In contrast to Panayiotopoulos syndrome, autonomic symptoms are not prominent but headache is seen commonly. Seizures are fairly frequent but of short duration. Also in contrast to Panayiotopoulos syndrome, a daytime occurrence of sei- zures is common.

Because seizures are fairly frequent, this epilepsy syndrome usually requires treatment but seizures tend to remit 2–7 years after onset.

Question 21

Rasmussen Syndrome

Answer 21

Childhood

Onset typically occurs between 3 and 14 years

There likely is an immune-mediated etiology but a specific organism or trigger has not been identi- fied to date, despite exhaustive research (the association with mGluR3 antibodies has since been disproven because it is neither sensitive nor specific, although depending on his/her perspec- tive, examiners may ask this question on a test).

Patients are almost always neurodevelopmentally normal prior to the onset of seizures. On occasion, there will be an antecedent nonspecific febrile illness days to weeks before the first seizure. Rarely, this syndrome will develop in patients with other autoimmune diseases.

Diagnostic criteria include the following [9]:
Need either all three criteria in Part A or two of three in Part B (start with Part A).
Part A:
1. Clinical: Focal seizures (±epilepsia partialis continua) and unilateral cortical deficit(s).
2. EEG: Unihemispheric slowing ± epilepti- form activity and unilateral seizure onset.
3. MRI: Unihemispheric focal cortical atrophy
and at least one of the following:
– Gray or white matter T2/FLAIR hyperin-
tense signal
– Hyperintense signal/atrophy of ipsilateral
caudate head

Part B:
4. Clinical: Epilepsia partialis continua or pro- gressive unilateral cortical deficit(s).
5. MRI: Progressive unihemispheric focal cor- tical atrophy.
6. Histopathology: T-cell-dominated encephalitis w/activated microglial cells (typically, but not necessarily forming nodules) and reactive astrogliosis.

Treatment initially is with antiseizure medicines, although seizures become refractory to treatment.

Immunomodulators such as corticos- teroids, intravenous immunoglobulin, and certain chemotherapeutic agents (e.g., cyclophos- phamide) have been used to mitigate the impact of the progressive nature of this disease, with only limited success.

Unfortunately, most patients eventually need a hemispherectomy for seizure control (the unihemispheric nature of the disease, which remains unexplained, makes this surgery an option). Prognosis is largely determined by preoperative level of function. Postoperative rehabilitation is necessary to optimize outcomes.