Generalised Epilepsy

1. Overview

Generalised epilepsy encompasses a group of epilepsy syndromes characterised by seizures that arise from, and rapidly engage, bilaterally distributed neuronal networks at onset. [1] These networks can include cortical and subcortical structures but do not necessarily include the entire cortex. The International League Against Epilepsy (ILAE) 2017 classification distinguishes generalised epilepsies from focal epilepsies based on seizure semiology, EEG findings, and neuroimaging. [2]

Generalised epilepsies account for approximately 30-40% of all epilepsy cases, with a strong genetic component in many subtypes, leading to the term "genetic generalised epilepsies" (GGE) replacing the older terminology of "idiopathic generalised epilepsy." [3] The most common syndromes include juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE), and juvenile absence epilepsy (JAE).

The clinical importance of correctly identifying generalised epilepsy lies in treatment selection—certain antisepileptic drugs (AEDs) effective in focal epilepsy (such as carbamazepine, oxcarbazepine, and phenytoin) can paradoxically worsen generalised seizures, particularly absence and myoclonic seizures. [4] Conversely, broad-spectrum AEDs like valproate, lamotrigine, and levetiracetam are first-line choices. Management is further complicated by teratogenicity concerns, particularly with valproate, requiring careful counselling in women of childbearing potential. [5]

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2. Epidemiology

Prevalence and Incidence

Epilepsy affects approximately 50 million people worldwide, with generalised epilepsies representing 30-40% of all cases. [3,6] The prevalence of active epilepsy in developed countries ranges from 4 to 10 per 1,000 population. [6]

Demographics

Age: Most genetic generalised epilepsies have onset in childhood or adolescence, though generalised tonic-clonic seizures can occur at any age. [3]

Sex: CAE shows slight female predominance (female:male ratio ~2:1), while JME affects females more commonly (female:male ratio ~1.5-2:1). [7,8]

Genetic factors: First-degree relatives of individuals with GGE have a 2-4 fold increased risk of epilepsy compared to the general population. [9] Twin studies demonstrate concordance rates of 70-85% in monozygotic twins versus 20-30% in dizygotic twins for genetic generalised epilepsies. [9]

Risk Factors

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3. Aetiology & Pathophysiology

Aetiology

Genetic Generalised Epilepsies (GGE): The majority of generalised epilepsies have a genetic basis, typically with complex polygenic inheritance. [10] Over 20 genes have been implicated, predominantly involving:

• Ion channel genes: SCN1A, SCN1B, KCNQ2, KCNQ3 (sodium and potassium channels)
• GABAergic genes: GABRA1, GABRB3, GABRG2 (GABA receptor subunits)
• Synaptic transmission genes: SYN1, STXBP1

Specific monogenic epilepsies (e.g., Dravet syndrome with SCN1A mutations) represent a minority but have important prognostic and therapeutic implications. [10]

Acquired/Structural Generalised Epilepsies: Less common but include:

• Metabolic disorders (glucose transporter deficiency, mitochondrial disease)
• Diffuse brain injury (hypoxic-ischaemic encephalopathy)
• Progressive myoclonic epilepsies (Unverricht-Lundborg disease, Lafora disease)

Pathophysiology

Exam Detail: Neuronal Network Hypothesis: Generalised seizures arise from abnormal thalamocortical circuits. [13] The thalamus acts as a pacemaker, with recurrent excitatory connections between cortex and thalamus generating oscillatory activity. In generalised epilepsies, dysregulation of this network leads to hypersynchronous discharge.

Absence Seizures (3 Hz Spike-Wave): Mediated by abnormal oscillations in thalamocortical circuits involving:

1. T-type calcium channels (Cav3.1) in thalamic reticular nucleus neurons generate burst firing
2. GABA-B receptors in thalamocortical relay neurons facilitate rhythmic inhibition
3. Cortical glutamatergic neurons provide excitatory feedback
4. Result: 3 Hz spike-wave discharges with sudden onset/offset [14]

Tonic-Clonic Seizures: Result from runaway excitation in cortical networks:

1. Tonic phase: Sustained depolarisation, high-frequency discharges (NMDA-mediated)
2. Clonic phase: Alternating depolarisation/hyperpolarisation (GABAergic modulation)
3. Termination: Neuronal exhaustion, ionic disturbances, endogenous anticonvulsant mechanisms [1]

Myoclonic Seizures: Brief burst of synchronous neuronal firing, likely originating from motor cortex but rapidly generalising through thalamocortical networks. [8]

Molecular Mechanisms:

• Excitation/Inhibition imbalance: Reduced GABAergic inhibition or enhanced glutamatergic excitation
• Ion channel dysfunction: Altered sodium channel inactivation (SCN1A mutations) reduces inhibitory neuron function preferentially
• Synaptic plasticity: Abnormal long-term potentiation/depression in epileptic networks [10]

Key Concept: Unlike focal epilepsies with identifiable structural lesions, generalised epilepsies typically show normal neuroimaging but abnormal neuronal network function driven by genetic factors affecting ion channels and neurotransmitter systems. [2]

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4. Clinical Presentation

Classification of Generalised Seizure Types (ILAE 2017)

Generalised seizures are classified into six main types: [2]

Generalised Tonic-Clonic Seizures (GTCS)

Sequence of Events:

Key Examination Findings:

• Lateral tongue bite: Highly specific (90% specificity) for generalised tonic-clonic seizures vs syncope (where tip-of-tongue bite may occur) [16]
• Eyes open during seizure: Typical of epileptic seizures (vs eyes closed in psychogenic non-epileptic seizures) [16]
• Urinary incontinence: Present in ~30-50% of GTCS, less specific [16]
• Post-ictal confusion: Prolonged in GTCS (> 5 minutes), brief/absent in syncope (less than 1 minute) [16]

Absence Seizures

Typical Absence (Childhood Absence Epilepsy):

• Onset: 4-8 years of age [7]
• Semiology: Sudden behavioural arrest, staring, unresponsive to stimuli, lasting 5-20 seconds
• Motor features: Eyelid fluttering (common), oral/manual automatisms (less common)
• EEG: 3 Hz generalised spike-and-wave discharges [14]
• Provocation: Hyperventilation provokes absences in > 90% of cases [7]
• Frequency: Can be very high (tens to hundreds per day)
• Awareness: Complete amnesia for the event
• Prognosis: 70-80% remit by late adolescence [7]

Atypical Absence (seen in Lennox-Gastaut syndrome):

• More gradual onset/offset
• less than 3 Hz spike-wave on EEG
• Associated with intellectual disability and other seizure types [15]

Myoclonic Seizures (Juvenile Myoclonic Epilepsy)

Clinical Features (JME): [8]

• Age of onset: 12-18 years (peak ~15 years)
• Morning predominance: Myoclonic jerks occur shortly after waking (80-90% of patients)
• Semiology: Brief, bilateral, synchronous muscle jerks (often upper limbs > lower limbs)
• Consciousness: Preserved during isolated myoclonic jerks
• Associated seizures:
  • "GTCS: Present in 95% of JME patients (often precipitated by sleep deprivation)"
  • "Absence seizures: 10-30% of patients"
• Triggers: Sleep deprivation (most common), alcohol, stress, photic stimulation (in photosensitive individuals, 30-40%)
• Prognosis: Lifelong condition requiring treatment in most cases; relapse rate > 90% if AEDs discontinued [8]

Common Precipitants and Triggers

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5. Differential Diagnosis

Key Differentials

Critical Differentiating Feature: Presence of epileptiform discharges on EEG during or between events strongly supports epilepsy diagnosis. [2]

Clinical Pearl: Lateral tongue bite: The single most specific clinical feature for generalised tonic-clonic seizures (specificity ~90%), as opposed to tip-of-tongue bite which can occur with syncope. [16]

Eyes open vs closed: Eyes are typically open during true epileptic seizures but closed in psychogenic non-epileptic seizures (> 90% of PNES). [16]

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6. Investigations

First-Line Investigations

EEG Findings in Generalised Epilepsies

Exam Detail: | Syndrome | Characteristic EEG Pattern | Activation Techniques | Reference | |----------|---------------------------|----------------------|-----------| | Childhood Absence Epilepsy | 3 Hz generalised spike-and-wave discharges | Hyperventilation (provokes absence in > 90%) | [7,14] | | Juvenile Myoclonic Epilepsy | 4-6 Hz generalised polyspike-and-wave | Photic stimulation (in photosensitive patients, 30-40%), sleep deprivation | [8,14] | | Juvenile Absence Epilepsy | 3-4 Hz generalised spike-and-wave | Hyperventilation | [7,14] | | GTCS alone | Often normal interictal; may show generalised polyspike-wave or brief bursts | Sleep, sleep deprivation | [14] |

Key Points:

• Background rhythm: Normal in genetic generalised epilepsies [14]
• Posterior predominance: Some GGE show posterior-predominant discharges (e.g., CAE, JAE)
• Fragment patterns: Brief bursts (less than 3 seconds) of generalised spike-wave may not correlate with clinical absences
• Photosensitivity: Photoparoxysmal response seen in 10-15% of all GGE patients, up to 40% in JME [8]

Neuroimaging

MRI Brain:

• Indication: All patients with new-onset epilepsy to exclude structural causes [2]
• Expected finding in GGE: Normal structural imaging
• Protocol: Epilepsy-specific protocol (thin-slice T1, T2, FLAIR, coronal views through hippocampi)
• Abnormal findings: Suggest focal epilepsy or underlying pathology (tumour, cortical dysplasia, hippocampal sclerosis, vascular malformation)

Genetic Testing

Indications:

• Epileptic encephalopathies (e.g., Dravet syndrome, Lennox-Gastaut syndrome)
• Family history suggesting monogenic epilepsy
• Associated developmental delay or dysmorphic features
• Specific syndromes with known genetic associations (e.g., SCN1A testing in suspected Dravet syndrome) [10]

Yield: Low in typical GGE (mostly polygenic); higher in specific syndromes

Additional Investigations

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7. Classification: Generalised Epilepsy Syndromes (ILAE 2017)

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8. Management

General Principles

1. Confirm diagnosis: Epilepsy diagnosis requires ≥2 unprovoked seizures > 24 hours apart, OR 1 seizure with high risk of recurrence (> 60% at 10 years) based on EEG/imaging. [2]
2. Identify syndrome: Syndrome diagnosis guides AED choice and prognostication.
3. Broad-spectrum AEDs: Generalised epilepsies require broad-spectrum agents; sodium channel blockers (carbamazepine, oxcarbazepine, phenytoin) can worsen absences and myoclonic seizures. [4]
4. Risk stratification: Assess SUDEP risk, driving eligibility, lifestyle modifications.

Lifestyle and Trigger Avoidance

Pharmacotherapy

First-Line Antiepileptic Drugs

Exam Detail: | Patient Population | First-Line AED | Dosing | Mechanism | Efficacy | Key Adverse Effects | Reference | |-------------------|----------------|--------|-----------|----------|---------------------|-----------| | Males / women not of childbearing potential | Sodium valproate | Start 500-600 mg/day divided BD; titrate to 1000-2000 mg/day | Enhances GABAergic inhibition; blocks sodium/calcium channels | 70-80% seizure freedom in GGE | Tremor, weight gain, hair loss, hepatotoxicity, thrombocytopenia | [5,18] | | Women of childbearing potential (WOCBP) | Lamotrigine OR Levetiracetam | Lamotrigine: Start 25 mg/day, titrate slowly (risk of SJS); target 100-400 mg/day
Levetiracetam: Start 500 mg BD, titrate to 1000-1500 mg BD | Lamotrigine: Blocks sodium channels, modulates glutamate
Levetiracetam: Binds SV2A (synaptic vesicle protein) | Lamotrigine: 50-60% seizure freedom
Levetiracetam: 40-60% seizure freedom | Lamotrigine: Rash (10%, SJS less than 0.1%), headache
Levetiracetam: Irritability, mood changes, fatigue | [5,18] |

Valproate Pregnancy Prevention Programme: [5]

• Contraindication: Valproate is contraindicated in pregnancy unless no suitable alternative (MHRA 2018)
• Teratogenicity: 10% major congenital malformations (neural tube defects, cardiac, craniofacial); 30-40% neurodevelopmental delay
• Requirements for WOCBP:
  • Annual risk acknowledgement form
  • Effective contraception (highly effective methods)
  • Pregnancy testing before initiation and regularly during treatment

Second-Line and Adjunctive Options

Avoid in Generalised Epilepsy: Carbamazepine, oxcarbazepine, phenytoin, gabapentin, pregabalin, vigabatrin (may worsen absences and myoclonic seizures). [4]

Treatment by Syndrome

Acute Management: Status Epilepticus

Definition: Generalised convulsive status epilepticus = continuous seizure ≥5 minutes OR recurrent seizures without recovery of consciousness. [19]

Emergency Protocol: [19]

Non-Convulsive Status (Absence Status): [19]

• Prolonged confusional state with continuous or near-continuous absence seizures
• EEG: Continuous generalised spike-wave
• Treatment: IV benzodiazepine (lorazepam 4 mg), then IV valproate or levetiracetam

Special Populations

Pregnancy and Epilepsy

Pre-conception Counselling: [5]

• Switch from valproate to lamotrigine or levetiracetam if possible
• Optimise seizure control before conception
• Start high-dose folic acid 5 mg daily (reduces neural tube defect risk)
• Discuss risks: 90-95% chance of healthy baby, but 2-3x baseline malformation risk with AEDs

During Pregnancy:

• Monitor AED levels (lamotrigine levels drop significantly due to increased clearance)
• Arrange fetal anomaly scans (cardiac, neural tube)
• Plan delivery with multidisciplinary team
• Avoid valproate; if essential, use lowest effective dose with folic acid

Breastfeeding: Most AEDs compatible (lamotrigine, levetiracetam, valproate excreted in low amounts); infant should be monitored for sedation. [5]

Elderly Patients

• Lower starting doses, slower titration
• Increased risk of drug interactions (polypharmacy common)
• Hyponatraemia risk with carbamazepine/oxcarbazepine (though these should be avoided in GGE anyway)
• Falls risk with sedating AEDs

Non-Pharmacological Therapies

When to Withdraw AEDs

Criteria for considering AED withdrawal: [2]

• Seizure-free for ≥2 years
• Single seizure type
• Normal neurological examination and IQ
• Normalisation of EEG (if initially abnormal)

Relapse risk: 40-50% overall; higher in JME (> 90%), lower in CAE with remission (20-30%). [8]

Recommendation: Lifelong treatment generally advised for JME; consider withdrawal in CAE/JAE if remission achieved and EEG normalised. [8]

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9. Complications

SUDEP Risk Counselling: All patients should be informed about SUDEP risk and measures to reduce it (optimising seizure control, avoiding alcohol/sleep deprivation, considering nocturnal supervision devices). [21]

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10. Prognosis & Outcomes

Overall Outcomes

Syndrome-Specific Prognosis

Predictors of Good Outcome

• Early age of onset with typical syndrome (CAE, JAE)
• Good response to first AED
• Normal intelligence
• No structural brain abnormality
• Good medication adherence

Predictors of Poor Outcome

• Late diagnosis and treatment initiation
• Presence of multiple seizure types
• Developmental delay or intellectual disability
• Structural brain abnormality (suggests not true GGE)
• Poor adherence to AEDs

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11. Prevention & Counselling

Primary Prevention

• Genetic counselling: For families with known monogenic epilepsy syndromes (e.g., Dravet syndrome with SCN1A mutation)
• Pre-conception planning: Women with epilepsy should optimise AED choice before pregnancy [5]

Secondary Prevention (Preventing Recurrent Seizures)

• AED adherence: Critical to preventing breakthrough seizures
• Trigger avoidance: Sleep hygiene, moderate alcohol, photosensitivity precautions
• Regular follow-up: Monitor AED levels, side effects, seizure frequency

Patient Education and Safety

Driving: [6]

• UK: Must be seizure-free for 12 months to hold Group 1 licence (car/motorcycle); 10 years seizure-free and off AEDs for Group 2 (HGV/bus)
• Patients must inform DVLA and stop driving until criteria met
• Failure to do so may invalidate insurance

Safety in Daily Life:

• Avoid swimming alone
• Shower rather than bath (or shallow bath with supervision)
• Avoid heights without safety measures
• Epilepsy alarm devices for nocturnal seizures

Occupational Restrictions:

• Cannot work at heights, with heavy machinery, as pilot/train driver
• Individual risk assessment for each occupation

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12. Key Guidelines

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Exam-Focused Sections

Common MRCP/Neurology Exam Questions

1. "Describe the ILAE classification of generalised seizure types."

   • Absence, myoclonic, tonic-clonic, tonic, atonic, clonic [2]

2. "What are the key differences between childhood absence epilepsy and juvenile myoclonic epilepsy?"

   • Age of onset (CAE: 4-8 years; JME: 12-18 years)
   • Seizure types (CAE: absences ± rare GTCS; JME: myoclonic jerks, GTCS, ± absences)
   • EEG (CAE: 3 Hz spike-wave; JME: 4-6 Hz polyspike-wave)
   • Prognosis (CAE: 70-80% remit; JME: lifelong, > 90% relapse off meds) [7,8]

3. "Which antiepileptic drugs should be avoided in generalised epilepsy and why?"

   • Carbamazepine, oxcarbazepine, phenytoin (sodium channel blockers that can worsen absences and myoclonic seizures) [4]

4. "Outline the management of a woman of childbearing potential with newly diagnosed juvenile myoclonic epilepsy."

   • Avoid valproate (teratogenic)
   • First-line: levetiracetam or lamotrigine
   • Pre-conception counselling, high-dose folic acid 5 mg
   • Discuss contraception, pregnancy planning, risks to fetus [5]

5. "What is the immediate management of generalised convulsive status epilepticus?"

   • IV lorazepam 4 mg (repeat once after 5 minutes)
   • If ongoing: IV phenytoin/levetiracetam/valproate
   • Refractory: intubation + general anaesthesia [19]

Viva Points

Viva Point: Opening statement for "Tell me about generalised epilepsy":

"Generalised epilepsy encompasses a group of epilepsy syndromes characterised by seizures arising from bilaterally distributed neuronal networks at onset, as per the ILAE 2017 classification. These account for approximately 30-40% of all epilepsies, with a strong genetic basis in many cases, hence the term 'genetic generalised epilepsies.' The most common syndromes include juvenile myoclonic epilepsy, childhood absence epilepsy, and generalised tonic-clonic seizures alone."

Key facts to mention:

• ILAE 2017 classification: generalised vs focal onset [2]
• Six generalised seizure types: absence, myoclonic, tonic-clonic, tonic, atonic, clonic [2]
• Broad-spectrum AEDs required; avoid sodium channel blockers [4]
• Valproate most effective but teratogenic—avoid in women of childbearing potential [5]
• SUDEP risk: 1-2 per 1,000 person-years, higher with uncontrolled GTCS [21]

Common OSCE/PACES Scenarios

Scenario 1: Explaining diagnosis of JME to 16-year-old

• Use age-appropriate language
• Explain myoclonic jerks, GTCS, triggers (sleep deprivation, alcohol)
• Discuss treatment (likely levetiracetam or lamotrigine)
• Address concerns: driving (cannot drive until seizure-free 12 months), lifestyle changes
• Lifelong condition but excellent seizure control expected with medication

Scenario 2: Pre-conception counselling for woman with epilepsy on valproate

• Explain teratogenicity risk (10% major malformations, 30-40% neurodevelopmental delay) [5]
• Plan switch to lamotrigine or levetiracetam before conception
• High-dose folic acid 5 mg daily
• Emphasise importance of seizure control during pregnancy
• Arrange preconception epilepsy review with specialist

Common Mistakes

❌ Prescribing carbamazepine for generalised epilepsy (worsens absences and myoclonic seizures) [4]

❌ Failing to counsel women of childbearing potential about valproate teratogenicity (MHRA serious safety concern) [5]

❌ Missing the diagnosis of JME because patient only reports GTCS and doesn't mention early morning jerks (always ask specifically about myoclonic jerks) [8]

❌ Not checking EEG in suspected epilepsy (essential for syndrome classification and confirming generalised epileptiform activity) [2]

❌ Stopping AEDs in JME after 2 years seizure-free (> 90% relapse rate; lifelong treatment generally required) [8]

Model Viva Answer

Q: A 15-year-old presents with episodes of brief jerking of the arms on waking, and had one generalised tonic-clonic seizure last week. What is your approach?

Model Answer:

"This presentation is highly suggestive of juvenile myoclonic epilepsy, the most common genetic generalised epilepsy syndrome with onset in adolescence. The key features are myoclonic jerks shortly after waking, and GTCS which are present in 95% of JME patients.

My approach would be systematic:

Immediate assessment: Confirm the semiology—brief, bilateral jerks without loss of consciousness for the myoclonic events, and the sequence of the GTCS (tonic-clonic phases, post-ictal confusion). Ask specifically about triggers: sleep deprivation is the most common precipitant in JME.

Investigations: I would arrange an EEG, which in JME typically shows 4-6 Hz generalised polyspike-and-wave discharges, and may demonstrate photosensitivity in 30-40% of cases. An MRI brain would be performed to exclude structural pathology, though this is usually normal in GGE. Basic bloods to exclude metabolic causes.

Management: Given the single GTCS and myoclonic jerks, treatment is indicated. As the patient is adolescent and sex is not specified, if male I would consider sodium valproate first-line given its superior efficacy in JME, achieving 70-80% seizure freedom. However, if female of childbearing potential, valproate is contraindicated due to teratogenicity, and I would use levetiracetam or lamotrigine instead, as per NICE NG217 guidelines.

Education: Crucial to counsel about trigger avoidance—regular sleep, avoiding alcohol and binge drinking, photosensitivity precautions if relevant. The patient cannot drive until seizure-free for 12 months. I would explain that JME is a lifelong condition with excellent seizure control expected on medication, but relapse rate exceeds 90% if AEDs are discontinued, so long-term treatment is required."

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References

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2. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512-521. doi:10.1111/epi.13709

3. Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry. 1996;61(5):433-443. doi:10.1136/jnnp.61.5.433

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5. National Institute for Health and Care Excellence. Epilepsies in children, young people and adults: NICE guideline [NG217]. Published April 2022. https://www.nice.org.uk/guidance/ng217

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7. Glauser TA, Cnaan A, Shinnar S, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med. 2010;362(9):790-799. doi:10.1056/NEJMoa0902014

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12. Herzog AG, Harden CL, Liporace J, et al. Frequency of catamenial seizure exacerbation in women with localization-related epilepsy. Ann Neurol. 2004;56(3):431-434. doi:10.1002/ana.20214

13. Blumenfeld H. Cellular and network mechanisms of spike-wave seizures. Epilepsia. 2005;46 Suppl 9:21-33. doi:10.1111/j.1528-1167.2005.00311.x

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16. Avbersek A, Sisodiya S. Does the primary literature provide support for clinical signs used to distinguish psychogenic nonepileptic seizures from epileptic seizures? J Neurol Neurosurg Psychiatry. 2010;81(7):719-725. doi:10.1136/jnnp.2009.197996

17. Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010;51(4):671-675. doi:10.1111/j.1528-1167.2009.02285.x

18. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369(9566):1000-1015. doi:10.1016/S0140-6736(07)60460-7

19. Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus—Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515-1523. doi:10.1111/epi.13121

20. Ryvlin P, Rheims S, Hirsch LJ, Sokolov A, Jehi L. Neuromodulation in epilepsy: state-of-the-art approved therapies. Lancet Neurol. 2021;20(12):1038-1047. doi:10.1016/S1474-4422(21)00300-8

21. Devinsky O, Hesdorffer DC, Thurman DJ, Lhatoo S, Richerson G. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016;15(10):1075-1088. doi:10.1016/S1474-4422(16)30158-2