DR. SACHIN ADUKIA

Idiopathic Generalized epilepsy in Adults

Renamed: Genetic generalised epilepsy

15 - 20% of all epilepsies including adults and children

c/b absence, myoclonic seizures, and tonic–clonic seizures with EEG pattern of bilateral, synchronous, and symmetrical spike and wave or polyspike and wave discharges.

These share a continuum of clinical phenotypes, normal cognition, similar EEG findings and fair Sz control on Rx

Photosensitivity is common

Classification

Classified as per predominant seizure type and age of onset

International classification benign myoclonic epilepsy in infancy

epilepsy with febrile seizures plus (EFS+)

epilepsy with myoclonic–astatic seizures

epilepsy with myoclonic absences (MAE)

childhood absence epilepsy (CAE)

IGEs with variable phenotypes juvenile absence epilepsy (JAE) juvenile myoclonic epilepsy IGE with tonic–clonic seizures alone (GTCA)

Age of onset for IGEs

Onset in adult life considered rare

Adult patients with an electro-clinical picture compatible with IGE often represent relapse of childhood epilepsy

No cut off limit for age defined by international classification

De novo IGE in adult life reported: C Marini et al (2003)- 28 % of IGE began at or > 20 yrs Gastaut’s report (1981)- 35% of IGE cases began > age

18

Inhertitance and genetic considerations

genetic aetiology with complex inheritance.Family and twin studies suggest shared genetic

origin

Juvenile absence epilepsy

JAE may be linked to chromosome 8, 21,18, probably 5

Heterogeneity may be common.

Autopsy and MRI studies may show microdysgenesis Other cerebral microstructural changes

JAE is an IGE syndrome mainly manifesting with severe Typical absence seizures [TAS].

80% also suffer from GTCSs

1/5 have sporadic myoclonic jerks

Demography

Peak age at onset – 9 to 13 years (70% of patients)

Range: 5 to 20 years

Myoclonic jerks and GTCSs usually begin 1–10 years after the onset of absences. GTCSs may precede

Both sexes are equally affected.

In pts > 20 years, prevalence of JAE :- around 2-3%

Clinical features

Frequent and severe typical absences are the characteristic and defining seizures of JAE

hallmark of the absence is abrupt, brief and severe impairment of consciousness with total or partial unresponsiveness.

ongoing voluntary activity usually stops at onset but may be partly restored during the ictus.

Automatisms are frequent, usually occurring 6–10 s after onset of EEG discharge

Duration of absences : 4 to 30 s but it is usually long (about 16 s).

GTCSs occur in 80% of patients, mainly after awakening, may be nocturnal or diurnal

Myoclonic jerks : s/i 15–25% , are infrequent, mild and of random distribution.

Seizure-precipitating factors

Mental and psychological arousalsleep deprivationfatiguealcohol excitementlights

alone or usually in combination

However, clinical photosensitivity, which is a consistent provocation of seizures (absences, GTCSs or jerks), may be incompatible with JAE.

Diagnosis= EEG findings

The ictal EEG shows 3–4 Hz GPSWD.

frequency at initial phase of the discharge is usually fast (3–5 Hz).

There is a gradual, smooth decline in freq. from initial to terminal phase.

The discharge is regular, with well-formed spikes and polyspikes, which retain a constant relation with the slow waves

Prognosis

Life-long disorder

Seizures can be controlled in 70–80%

With age, after 4th decade, absences become less severe in terms of impairment of cognition, duration and frequency

GTCSs are usually infrequent, often brought on by precipitating factors

Treatment

Valproate- controls all seizure types in 70–80%Lamotrigine- controls absence and GTCSs in 50–60%

good monotherapy option in women, where valproate is unsuitable.

If monotherapy with valproate is partially effective, small doses of lamotrigine (particularly if GTCS is the

problem) Ethosuximide (particularly if absences persist)

Levetiracetam: All Sz types

Rx is lifelong, as withdrawl attempts may precipitate Sz despite years of Sz free interval

Juvenile Myoclonic Epilepsy Term “juvenile myoclonic epilepsy” was proposed in 1975 and

adopted by ILAE in 1989. ILAE 2010: JME would be included in the group of

electroclinical syndromes of unknown cause with a high likelihood of complex genetic defects.

AKA: Janz syndrome; previously ‘impulsive petit mal” Is genetically determined. Incidence: 1 per 1000-2000 people internationally. represents approximately 5-10% of all epilepsies; 20 to 30% of all

IGEs Both sexes are equally affected mean age of onset is 15 years, range of 5 to 34 years majority diagnosed between 12 and 18 years.

Pathology

Pathologic analyses of brain specimens in JME are typically normal.

Occasionally increased no. of partially dystropic neurons in stratum moleculare, white matter, hippocampus, and cerebellar cortex

An indistinct boundary between cortex and subcortical white matter and between lamina 1 and 2 can also be found. This is known as microdysgenesis

Some families have specific mutations beta-4 subunit of calcium channels chloride channel 2 protein.

A Canadian family with JME hads increased GABA-A receptor subunit degradation from a mutation of the alpha1-subunit GABRA (A322D) resulting in hyper excitability

Genetics

Around 50–60% of families of probands with JME report seizures in first- or second-degree relatives.

2 proposed models of inheritance polygenic with a lower manifestation threshold for females Autosomal dominant with variable penetrance.

two-locus model: dominant gene on chromosome 6p, and yet-unknown recessive gene.

Fifteen chromosomal loci are suspected of central role, only 3 are considered as putative JME causing genes: EFHC1, GABRA1, and CLCN2

Possible susceptibility locus in chromosome 6p11–12 (EJM1) or 15q14 (EJM2)

A gene, C6orf33, in the EJM1 region has been identified.

Clinical manifestations

JME is characterised by:1. Myoclonic jerks on awakening2. GTCSs in nearly all3. Typical absences > 1/3

Characteristic age-related onset.

Absences - between the ages of 5 and 16 years. Myoclonic jerks follow 1–9 years later- age of 14 or 15

years. GTCS appear few months later than myoclonic jerks,

occasionally appear earlier

Myoclonic jerks

occur after awakening

most prominent and characteristic seizure type.

shock-like, irregular and arrhythmic clonic movements of proximal and distal muscles UL

May be restricted to fingers: Pt. drops things or looks clumsy

may be violent enough to cause falls.

1/5 describe jerks as unilateral, but VEEG shows b/l jerks

Typical absence seizures

1/3 have typical absences: brief with subtle impairment of consciousness

Absences appearing < age 10 years may be more severe. They become less frequent and severe with age.

1/10 do not perceive absences, despite Generalised Polyspike Wave Discharges > 3 s.

On video-EEG with breath counting during hyperventilation, these discharges manifest as mildly impaired cognition, eyelid flickering or both.

GTCSs:- clonic–tonic–clonic

usually follow the onset of myoclonic jerks.

Myoclonic jerks, usually in clusters and often with an accelerating frequency and severity may precede a GTCS so-called clonic–tonic–clonic generalised seizure.

Status epilepticus

Myoclonic status epilepticus: almost invariably starts on awakening, precipitated by sleep deprivation / missed medication.

Consciousness may not be impaired, although absences are often interspersed with myoclonic jerks.

Pure absence status epilepticus is very rare.

Generalised tonic–clonic status epilepticus is infrequent.

Circadian distribution

Myoclonic jerks within 30-60 min of awakening. rarely occur at other times unless the patient is tired.

GTCSs - mainly on awakening, may also be purely nocturnal or random

Absence seizures rarely show a circadian predilection.

Cognition and behavior

Majority have normal global cognitive capacities.

However, formal neuropsychological testing demonstrates variable degrees of frontal lobe dysfunction

likely influenced by - antiseizure drugs, seizure frequency, genetic variability, psychosocial conditions, and educational level

Advanced neuroimaging studies suggeste underlying structural cause: involvement of frontal thalamocortical circuits Dysfunction in dopaminergic and serotoninergic

neurotransmission systems abnormal attenuation of normal age related decline in cortical

volume compared with healthy controls over 2 years

Psychiatric comorbidity

increased risk for comorbid psychiatric illness and personality disorder. Up to 50 % meet formal criteria for a psychiatric disorder (mostly

anxiety or mood disorder), 20 to 35 percent have cluster B personality traits such as

impulsivity, humor reactivity, emotional instability, difficulty accepting social rules

Poorly controlled seizures and antiseizure drugs themselves may also put patients at risk for psychiatric side effects and mood disorder

Functional MRI suggest frontalinsular network dysfunction may contribute to emotional disturbances

Seizure-precipitating factors

Sleep deprivation, fatigue, excessive alcohol intake Photosensitivity is confirmed with EEG > 30%. < 1/10 have seizures induced by photic stimulation in daily

life Others:

mental stress Emotions: excitement Concentration mental and psychological arousal failed expectations or frustration.

Diagnosis = EEG

MRI may show abnormalities in mesio-frontal cortical structures in some

EEG in untreated patients is usually abnormal 3–6 Hz GPSWD intradischarge fragmentations unstable intradischarge frequency :- 2 to 10 Hz, with a mean of 3–5

Hz.

1/3 – show photoparoxysmal responses.

1/3 - show focal EEG abnormalities of single spikes, spike–wave complexes or slow waves.

EEG discharge of myoclonic jerk is a gen. burst of polyspikes of 0.5–2 s

Ictal discharges of absences consist of spike/double/treble or polyspikes preceding or superimposed on slow waves

Polyspikes consist of 8-10 spikes with a characteristic ‘worm-like’ or compressed capital W appearance

Normal EEG in suspected JME should prompt an EEG during sleep and awakening

Diagnostic dilemma- misdiagnosis of JME is 90%

Reasons for misdiagnosis lack of familiarity with JME Improper h/o myoclonic jerks Misinterpreting absences as CPS misinterpretation of jerks as focal motor seizures high prevalence of focal EEG abnormalities.

Aids in diagmosis characteristic clustering of myoclonic / other generalised

seizures of IGEs circadian distribution precipitating factors and EEG manifestations.

Prognosis

All seizures are probably life-long, may improve after 4th decade of life

well controlled in upto 90% with approproate medication

Pts with all 3 types of seizure - more likely to be drug resistant

Pharmacological treatment

1. Valproate Is the most effective AED in the treatment of JME. Serious adverse reactions in women However may be considered as first line in men

2. Levetiracetam In non-control independent studies, 62–67% JME that failed

with valproate, became Sz free with levetiracetam monotherapy or polytherapy.

first anad only newer AED licensed for the Rx of myoclonic seizures in JME

favourable profile in women and pregnancy. good safety profile, and sparse meaningful interactions with

other drugs.

3. Lamotrigine It was promoted as the only alternative to valproate in women interactions with hormonal contraception and pregnancy ? teratogenic potential- have been reported.

4. Clonazepam small doses (0.5–2 mg HS) - most effective Rx for myoclonic

jerks. alone may not suppress GTCSs may suppress warning of impending GTCS manifested as

myoclonic jerks Mild JME with myoclonic jerks only: clonazepam alone may be

used

Treatment failure

If valproate is contraindicated or not tolerated, treatment with levetiracetam, lamotrigine or topiramate : broad spectrum agents

Combination therapy be considered after two single medication failures

Lamotrigine, levetiracetam, topiramate, zonisamide, and benzodiazepines are all options for adjunctive therapy

Lifestyle modification- Avoid Sz precipitants

Duration and withdrawal of medication

Life-long treatment usually considered necessary in JME

Withdrawal results in relapses, even if seizure free for many years with appropriate AED.

In mild forms of JME, reduce medication slowly over months or years, especially after 4th decade of life.

Persistence of myoclonic jerks consider continued medication.

Epilepsy with GTCS only GTCSs

occur on awakening (17–53%) diffusely whilst awake (23–36%) During sleep (27–44%) or randomly (13–26%)

GTCSs are most severe forms of epileptic seizures

while absences and myoclonic jerks may be mild and sometimes inconspicuous to the patient imperceptible to the observer.

A patient with a first GTCS has often suffered from minor seizures (absences, myoclonic jerks or both), sometimes many years prior to GTCS

Demographic data

high incidence in families ? EJM1 locus

Age at onset :- 6 to 47 years

peak at 16 or 17 years

Men (55%) > women, d/t alcohol exposure and sleep habits.

Prevalence - 13–15% among IGEs

Sz recipitzting factors: same

Photosensitivity- common

Diagnosis= EEG

GPSWD in half of patients with pure EGTCSA

Normal EEG should prompt a video-EEG on sleep and on awakening.

Myoclonic jerks / brief absences will often be revealed

Focal EEG abnormalities in the absence of generalised discharges are rare.

Photoparoxysmal responses are reported in 17% of females 9% of males

Prognosis

Life-long disease

High (83%) incidence of relapse on withdrawal of AED

Intervals between seizures become shorter with time, the precipitating factors less obvious, and GTCSs more random (diurnal and nocturnal),

Occurs due to evolution of disease or drug modifications.

References

Daroff RB, Jankovic J, Mazziotta JC, Pomeroy SL. Bradley's neurology in clinical practice. Elsevier Health Sciences; 2015 Oct 25.

Panayiotopoulos CP. A clinical guide to epileptic syndromes and their treatment: Based on the new ILAE diagnostic scheme. Bladon Medical Pub; 2010

Marini C, King MA, Archer JS, Newton MR, Berkovic SF. Idiopathic generalised epilepsy of adult onset: clinical syndromes and genetics. Journal of Neurology, Neurosurgery & Psychiatry. 2003 Feb 1;74(2):192-6.

Thank You