Epilepsy & Seizures 2

Question 1

Definition of epilepsy syndrome

Answer 1

a cluster of features incorporating seizure types, EEG, and imaging features that tend to occur together

Question 2

Electroclinical Syndromes Arranged by Age at Onset

Answer 2

Question 3

West Syndrome: characteristics, treatment and prognosis

Answer 3

• infantile spasms
• neurologic or psychomotor deterioration
• interictal!! EEG pattern known as hypsarrhythmia (chaotic, high-amplitude recording with multifocal spike-and-slow wave discharges)

Choosing initial therapy
For most children with infantile epileptic spasms syndrome, we suggest initial treatment with hormonal therapy using corticotropin injection gel (ACTH) or oral glucocorticoids rather than vigabatrin.
This recommendation is based upon advantages of hormonal therapy in effectiveness, risk profile, and longer experience compared with vigabatrin

For infants with IESS and tuberous sclerosis complex, vigabatrin is first-line therapy

Duration of initial therapy –
Hormonal therapy is generally given at the maximum dose for 14 days, followed by a gradual taper starting on day 15.
Vigabatrin is generally continued for six months in patients who respond to therapy, with continued evaluation for toxicity

Refractory infantile spasms – Lack of a successful response to initial therapy within two weeks should prompt a change in treatment strategy. Alternatives for children who do not respond to hormonal therapy or vigabatrin include:

• Sequential therapy – Our general approach after failure of the first standard treatment (hormonal or vigabatrin) is to switch to the alternative standard treatment
• Combination therapy – Treatment with both hormonal therapy and vigabatrin may be more effective than hormonal therapy alone, and many centers and protocols utilize combination therapy as first-line management
• Ketogenic diet – A ketogenic diet may control spasms in cases refractory to first-line treatment.
• Surgery – Patients with refractory infantile spasms who have focal brain lesions and no evidence of diffuse brain damage or degenerative or metabolic disease should be evaluated for early epilepsy surgical intervention.

● Outcomes –
Mortality ranges from 3 to 33 percent, and most patients will have impaired neurodevelopmental outcome and/or epilepsy.
There is insufficient evidence to conclude that successful treatment of infantile spasms improves the long-term prognosis, although that is suggested by some observational data.

Question 4

West syndrome treatment adverse effects

Answer 4

-Hormonal therapy – Adverse effects are common and include hypertension, irritability, infection, reversible cerebral atrophy, and rarely death due to sepsis.
Monitoring should include measurement of blood pressure (baseline and once weekly) and serum glucose, potassium, and sodium levels (baseline and every other week).
Infectious contacts should be avoided, and infections should be treated promptly

-Vigabatrin – Permanent visual field constriction due to retinal toxicity is a potentially severe adverse effect of vigabatrin.
Ophthalmologic evaluation and monitoring is recommended

Question 5

Dravet syndrome: characteristics

Answer 5

Birth to one year –
The most common presenting symptom is a hemiclonic or generalized seizure, often precipitated by fever, in an otherwise healthy infant between five and eight months of age.
Early seizures tend to be prolonged and recurrent and may evolve into status epilepticus.
Neurodevelopmental decline typically begins shortly after seizure onset.

One to five years –
refractory epilepsy characterized by multiple types of seizures, both febrile and afebrile, including convulsive seizures, myoclonic seizures, atypical absence seizures, and focal seizures.
Neurologic signs include hypotonia, ataxia, pyramidal signs, myoclonus, and behavioral disturbances.

Five years to adult –
improved seizure control but persistent, moderate to severe intellectual disability and motor system abnormalities, including crouch gait, antecollis, and other parkinsonian features.

There is an increased risk of premature mortality, due primarily to sudden unexpected death in epilepsy (SUDEP) and status epilepticus.

** Notable feature: extreme sensitivity to body temperature variation (warm trigger seizures)!!

Question 6

Dravet syndrome management

Answer 6

Seizure triggers, including increased body temperature, flashing lights, and visual patterns, should be avoided as best as possible.

For patients with DS, we suggest valproate as initial antiseizure therapy.
Most patients with DS require two or more drugs to achieve reasonable seizure control.

● Failure of initial therapy – Clobazam is our preferred add-on therapy in patients with DS if seizures remain poorly controlled despite adequate valproate dosing and serum levels.

The approach to patients with poor seizure control or intolerance to first-line therapy is individualized but generally includes trials of second- through fourth-line therapies such as clobazam, fenfluramine, stiripentol, cannabidiol (pharmaceutical), topiramate, and/or ketogenic diet.

Question 7

Medication to avoid in Dravet syndrome

Answer 7

Carbamazepine and its analogs (oxcarbazepine and eslicarbazepine), lamotrigine, and phenytoin should not be used for seizure prevention in patients with DS due to their potential to worsen seizure control

Question 8

Pathogenic variant in Dravet syndrome

Answer 8

SCN1A gene (in 80% of patients)

Question 9

Most common childhood epilepsy

Answer 9

Benign epilepsy with centrotemporal spikes (Rolandic)

Question 10

Childhood absence epilepsy: 1) seizure types 2) age of onset 3) self-limiting 4) EEG findings

Answer 10

1) Absence
generalized tonic-clonic (rare)
2) 4 to 10 years
3) Yes
4) Normal background, occipital intermittent rhythmic delta activity,
3–3.5 Hz generalized spike-wave discharges easily provoked with hyperventilation!!

Question 11

Childhood absence epilepsy management

Answer 11

*For children with newly-diagnosed CAE, we recommend ethosuximide rather than valproic acid or lamotrigine.
Ethosuximide is well tolerated and associated with complete seizure freedom in over half of children after 16 weeks of therapy.

*For children who fail or do not tolerate first-line therapy with ethosuximide, we suggest switching to valproate monotherapy.

Lamotrigine is a reasonable alternative in females of childbearing age based on the fetal risks of valproate.

Question 12

Benign epilepsy with centrotemporal spikes: 1) age of onset 2) clinical features

(Rolandic)

Answer 12

1) Seizure onset typically occurs between 3 and 14 years of age, and most children outgrow it by 16 years of age

2) The most common seizure type is a focal seizure with motor symptoms involving the face and no impairment of consciousness.
The characteristic ictal symptoms correspond to the origin of seizures in the rolandic or perisylvian sensorimotor cortex, which represents the face and oropharynx, and include
* facial numbness or twitching
* guttural (βραχνός) vocalizations
* hypersalivation
* drooling
* dysphasia
* speech arrest.
* Motor activity in the upper, but not lower, extremity is also common.

Three-quarters of seizures occur at night or on awakening

Question 13

Benign epilepsy with centrotemporal spikes: EEG findings

(Rolandic)

Answer 13

EEG findings of BECTS are characteristic, with centrotemporal sharp waves (70 to 100 milliseconds) that have several distinctive features

● The morphology is biphasic, with a negative sharp peak followed by a positive rounded component (amplitude 50 percent of the negativity).
● The sharp waves often have a “horizontal dipole,” which typically reveals a maximum negativity in the centrotemporal region and a maximum positivity at the vertex or in the frontal region.
● The sharp waves often occur in repetitive bursts and can be bilateral and independent.
● Epileptiform activity is markedly activated by non-rapid eye movement sleep, and occasionally occurs only in sleep
● The background EEG activity is normal.

Question 14

Benign epilepsy with centrotemporal spikes: management

(Rolandic)

Answer 14

For patients with BECTS who have focal seizures without impairment of consciousness, we suggest against using antiseizure medication!!

Antiseizure medications with efficacy in focal seizures can reduce the frequency of secondary generalized seizures in BECTS and can be considered in those patients with a high frequency or severity of seizures.

Options include:
levetiracetam (the most common first choice due to its good safety profile, tolerability, and lack of drug-drug interactions)
and other antiseizure medications (eg, oxcarbazepine, sulthiame, gabapentin) with demonstrated effectiveness in focal epilepsies

Question 15

Is there family history of epilepsy in benign epilepsy with centrotemporal spikes?

Answer 15

There is a well-described familial tendency for seizures; up to 40% of cases have a positive family history of febrile seizures, epilepsy, or epileptiform EEG findings.

Question 16

Lennox Gastaut Syndrome diagnostic criteria

Answer 16

Mandatory criteria:

1) Tonic seizures and

At least one additional seizure type from among the following:
- Atypical absences
- Atonic
- Myoclonic
- Focal impaired awareness
- Generalized tonic-clonic
- Nonconvulsive status epilepticus
- Epileptic spasms

2) EEG with generalized slow spike-and-wave complexes of <2.5 Hz (or history on prior EEG)
3) EEG with generalized paroxysmal fast activity in sleep (or history on prior EEG)
4) Age <18 years at onset
5) Long-term outcome of drug-resistant epilepsy and mild to profound intellectual disability

Exclusionary criterion:
* EEG with persistent focal abnormalities but without generalized spike-and-wave pattern

Question 17

Juvenile myoclonic epilepsy: 1) seizure types 2) age of onset 3) self-limiting 4) EEG findings

Answer 17

1)
* Myoclonic usually involving the arms and shoulders (preferentially occuring in the morning)
* generalized tonic-clonic and absence (more rare)

2) 10 years to mid-twenties
3) No!! Usually require treatment throught their lives
4)
* The classic interictal EEG pattern in JME is 4 to 6 Hz bilateral polyspike and slow wave discharges with frontal predominance over a normal background activity
* high-amplitude polyspike-wave discharges with myoclonic seizures
* photoparoxysmal response in up to 40% of patients!!

Question 18

Juvenile myoclonic epilepsy treament

Answer 18

In patients with JME, treatment with a broad spectrum antiseizure medication (eg, valproate, levetiracetam, lamotrigine, topiramate) is recommended

Question 19

Is there family history in juvenile myoclonic epilepsy?

Answer 19

About one third of patients diagnosed with JME have a family history of epilepsy.

Question 20

Which epilepsy syndrome is characterized by myoclonic-tonic-clonic seizures

Answer 20

Juvenile myoclonic epilepsy

Question 21

Juvenile absence epilepsy: 1) seizure types 2) age of onset 3) self-limiting 4) EEG findings

Answer 21

1) Absence
generalized tonic-clonic
myoclonic (rare)

2) Adolescence to early adulthood

3) No
4) Normal background, polyspikes may be present, 3–3.5 Hz generalized spike-wave discharges

Question 22

What is mesial temporal sclerosis

Answer 22

a term that pathologically describes loss of hippocampal neurons and gliosis in the CA1 and hilar regions

Question 23

Mesial temporal lobe epilepsy seizure type

Answer 23

● An “aura” (a focal seizure with sensory or psychic symptoms) occurs in most patients.
Common features include a rising epigastric sensation (often likened to a “roller coaster” sensation), and psychic or experiential phenomena, such as déjà vu, jamais vu, or fear.
Auras of taste (gustatory hallucinations) and smell (olfactory hallucinations) are less common!!
Auras can occur in isolation or can precede a focal seizure with impairment of consciousness or awareness.
In either case, patients with mesial TLE usually recall the seizure aura.

● Focal seizures with impairment of consciousness or awareness (also called focal dyscognitive or complex partial seizures) usually manifest with a behavioral arrest and staring and last between 30 and 120 seconds.
The patients are generally unaware and unresponsive during this period.
Occasionally, such patients present with amnestic attacks, but more detailed questioning or observation of the seizures reveal the presence of olfactory hallucinations, other seizure auras, or ictal automatisms.

● Automatisms are common, occurring in approximately 60 percent of focal seizures with impairment of consciousness in patients with mesial TLE.
These are repetitive, stereotyped, purposeless movements.
In TLE, they are typically mild, involving the hands (picking, fidgeting, fumbling) and mouth (chewing, lip smacking).

● Gelastic seizures are defined as focal seizures with uncontrollable stereotyped laughter

● Postictal confusion usually resolves within minutes.
If postictal psychosis occurs, it typically lasts for days to weeks and often does not begin immediately after the seizure.
Postictal hemiparesis can occur contralateral to the seizure focus, and postictal aphasia can occur with a seizure emanating from the dominant hemisphere
Postictal wandering is not specific to TLE, but is seen more often with temporal compared with extratemporal seizures

● Heart rate changes

Question 24

Mesial temporal lobe epilepsy lateralizing features

Answer 24

Lateralizing features can occur during or after a focal seizure.

• Unilateral automatisms are usually ipsilateral to the seizure focus, while dystonic posturing almost invariably occurs on the contralateral side.
• Head deviation at seizure onset is usually ipsilateral to the seizure; when it occurs later, it is contralateral. This later head turning also has a more forceful, involuntary appearance and is so-characterized as “versive.”
• Contralateral clonic activity is relatively unusual.
• Nose-wiping, performed by the hand ipsilateral to the focus of seizure onset, is a common postictal event in mesial TLE.

** Lateralizing findings in the setting of mesial temporal sclerosis should be interpreted with some caution, as many of these patients have bilateral, independent seizure foci.

Question 25

What is common in history of patients with mesial temporal lobe epilepsy

Answer 25

Febrile seizures

Question 26

What can be found in patients with unilateral temporal seizures

Answer 26

Patients with unilateral temporal seizures may show bilateral temporal interictal epileptiform discharges, presumably because of connectivity between the temporal lobes

Question 27

How can the yield of a positive antibody test be predicted In patients with longer-standing epilepsy who may not have initially presented as an emergency

Answer 27

through an Antibody Prevalence in Epilepsy (APE) score of greater than 4

Question 28

Reflex epilepsy syndromes: 1) which are the most common and 2) common seizure types

Answer 28

Reflex epilepsy syndromes are epilepsies in which seizures are provoked by a specific stimulus.

1) The most common reflex epilepsy syndrome is photosensitive epilepsy.
Other reflex epilepsy syndromes include reading epilepsy and startle epilepsy.
2) Seizures are typically generalized tonic-clonic seizures, but other generalized seizure types may also occur.
Rarely, focal seizures may present as a reflex epilepsy.

Question 29

Which syndromes are characterized by generalized atonic seizures

Answer 29

Very brief atonic seizures are typical of the syndrome of epilepsy with myoclonic-atonic seizures (Doose syndrome).
More prolonged atonic seizures can be seen with Lennox-Gastaut syndrome or other symptomatic generalized epilepsies.

Question 30

In which epilepsy syndrome are myoclonic-atonic seizures common

Answer 30

Epilepsy with myoclonic-atonic seizures (Doose syndrome)

Question 31

Which epilepsy syndrome is characterized by eyelid myoclonia with absence seizures

Answer 31

Jeavons syndrome

Question 32

Examples of combined generalized and focal epilepsy

Answer 32

Dravet syndrome and Lennox-Gastaut syndrome.

Question 33

Epilepsy with generalized tonic-clonic seizures alone: 1) seizure types 2) age of onset 3) self-limiting 4) EEG findings

Answer 33

1) Generalized tonic-clonic
2) Childhood to mid-adulthood
3) No
4) Normal background, generalized spike/ polyspike-wave discharges

Question 34

Examples of well-described focal epilepsy syndromes

Answer 34

Well-described focal epilepsy syndromes include benign epilepsy with centrotemporal spikes and Panayiotopoulos syndrome.

Question 35

Panayiotopoulos syndrome: course, seizure types and EEG findings

Answer 35

Panayiotopoulos syndrome is a self-limited epilepsy characterized by having focal autonomic seizures, often prolonged, and focal occipital high-amplitude sleep-activated spikes seen on EEG.

Possible autonomic symptoms include vomiting, pallor, mydriasis, cardiorespiratory, gastrointestinal, and thermoregulatory symptoms, incontinence, and hypersalivation.

Question 36

Factors that contribute to epilepsy syndrome

Answer 36

• age of onset
• remission
• triggers
• diurnal variation
• intellectual and psychiatric dysfunction
• EEG findings
• imaging studies
• family history
• genetics

Question 37

Etiologies of epilepsy

Answer 37

Structural
Genetic
Infectious
Metabolic
Immune
Unknown

(A patient’s epilepsy may be classified into more than one etiologic category)

Question 38

When is an epilepsy considered of structural etiology

Answer 38

The concept behind a structural etiology is that a structural abnormality has a substantially increased risk of being associated with epilepsy based on appropriately designed studies.
A structural etiology refers to abnormalities visible on structural neuroimaging where the electroclinical assessment together with the imaging findings lead to a reasonable inference that the imaging abnormality is the likely cause of the patient’s seizures.

Structural etiologies may be acquired such as stroke, trauma, and infection, or genetic such as many malformations of cortical development.
Despite there being a genetic basis with such malformations, the structural correlate underpins the person’s epilepsy. Identification of a subtle structural lesion requires appropriate MRI studies using specific epilepsy protocols

** If the clinical and EEG data are discordant with localization of the visible structural abnormality, then the imaging abnormality is not relevant to the patient’s epilepsy

Question 39

Examples of structural etiology epilepsy

Answer 39

1) mesial temporal lobe seizures with hippocampal sclerosis
2) gelastic seizures with hypothalamic hamartoma
3) Rasmussen syndrome
chronic progressive inflammation (encephalitis) of one cerebral hemisphere
shrinkage of the affected side of the brain
4) hemiconvulsion-hemiplegia-epilepsy
5) tuberous sclerosis
Brain lesions characteristic of TSC include glioneuronal hamartomas, also called cortical tubers, white matter heterotopia, subependymal nodules, and subependymal giant cell tumors (SGCT), which are also known as subependymal giant cell astrocytomas (SEGAs)

and others

Question 40

When is an epilepsy considered of metabolic etiology

Answer 40

When epilepsy results directly from a known or presumed metabolic disorder in which seizures are a core symptom of the disorder.
Metabolic causes refer to a well-delineated metabolic defect with manifestations or biochemical changes throughout the body such as porphyria, uremia, aminoacidopathies, or pyridoxine-dependent seizures.
In many cases, metabolic disorders will have a genetic defect.
It is likely that most metabolic epilepsies will have a genetic basis, but some may be acquired such as cerebral folate deficiency.
The identification of specific metabolic causes of epilepsy is extremely important due to implications for specific therapies and potential prevention of intellectual impairment

Question 41

Metabolic Epilepsies Presenting in Adolescence or Adulthood

Answer 41

Question 42

Clues of a metabolic etiology of epilepsy

Answer 42

The presence of other neurologic abnormalities, such as movement disorders and ataxia, systemic involvement, parental consanguinity (συγγένεια γονέων εξ αίματος), and a positive family history of a similar illness, can be clues

Question 43

Clues of an immune etiology of epilepsy

Answer 43

high seizure frequency
treatment resistance
progressive mental status change
neuropsychiatric symptoms
autonomic dysfunction
a viral prodrome
facial or faciobrachial dyskinesias

Question 44

When is an epilepsy considered of genetic etiology

Answer 44

The concept of a genetic epilepsy is that it results directly from a known or presumed genetic mutation in which seizures are a core symptom of the disorder. The epilepsies in which a genetic etiology has been implicated are quite diverse and, in most cases, the underlying genes are not yet known
1) the inference of a genetic etiology may be based solely on a family history of an autosomal dominant disorder (e.g, Benign Familial Neonatal Epilepsy)
2) a genetic etiology may be suggested by clinical research in populations with the same syndrome (e.g. Childhood Absence Epilepsy or Juvenile Myoclonic Epilepsy)
3) a molecular basis may have been identified and may implicate a single gene or copy number variant of major effect (e.g. Dravet syndrome - SCN1A gene)

A genetic etiology does not exclude an environmental contribution.
A genetic etiology refers to a pathogenic variant (mutation) of significant effect in causing the individual’s epilepsy

• In some cases, the genetic mutation is not identified, but the clinical presentation, EEG findings, and family history suggest a genetic etiology.

Question 45

Does genetic mean inherited

Answer 45

No, genetic does not equate with inherited. An increasing number of de novo mutations are being identified in both severe and mild epilepsies. This means that the patient has a new mutation that has arisen in him or her, and therefore is unlikely to have a family history of seizures and has not inherited the genetic mutation.
Nevertheless, this patient may now have a heritable form of epilepsy. For example if the individual has a de novo dominant mutation, their offspring will have a 50% risk of inheriting the mutation. This does not necessarily mean that their children will have epilepsy, as its expression will depend on the penetrance of the mutation

Question 46

When is an epilepsy considered of infectious etiology

Answer 46

It is the most common etiology.
Epilepsy directly results from a known infection in which seizures are a core symptom of the disorder.
An infectious etiology refers to a patient with epilepsy, rather than with seizures occurring in the setting of acute infection such as meningitis or encephalitis. Common examples in specific regions of the world include neurocysticercosis, tuberculosis, HIV, cerebral malaria, subacute sclerosing panencephalitis, cerebral toxoplasmosis, and congenital infections such as Zika virus and cytomegalovirus. These infections sometimes have a structural correlate. An infectious etiology carries specific treatment implications.
An infectious etiology may also refer to the postinfectious development of epilepsy, such as viral encephalitis leading to seizures in the aftermath of the acute infection

Question 47

When is an epilepsy considered of immune etiology

Answer 47

When epilepsy results directly from an immune disorder in which seizures are a core symptom of the disorder. An immune etiology can be conceptualized as where there is evidence of autoimmune- mediated central nervous system inflammation. Examples include anti-NMDA (N-methyl-D-aspartate) receptor encephalitis and anti-LGI1 encephalitis. Implications for treatment with targeted immunotherapies.

Question 48

Examples of epilepsy comorbidities

Answer 48

Nonepileptic seizures
Depression, anxiety, attention deficit hyperactivity disorder
Migraine
Cognitive impairment
Mortality, sudden unexpected death in epilepsy (SUDEP)

Learning, psychological, and behavioral problems. These range in type and severity, from subtle learning difficulties to intellectual disability, to psychiatric features such as autism spectrum disorders and depression, to psychosocial concerns. In the more severe epilepsies, a complex range of comorbidities may be seen, including motor deficits such as cerebral palsy or deterioration in gait, movement disorders, scoliosis, sleep, and gastrointestinal disorders

*It is important that the presence of comorbidities be considered for every patient with epilepsy at each stage of classification, enabling early identification, diagnosis, and appropriate management