Epileptic Encephopathies

Epileptic encephalopathies (EE) are a group of severe epilepsy disorders in which the epileptic electrical discharges themselves contribute to progressive psychomotor dysfunction and cognitive decline. The International League Against Epilepsy (ILAE) defines these as conditions where the epileptic activity leads to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone.

A related concept is Developmental and Epileptic Encephalopathy (DEE), where the underlying genetic or structural etiology contributes to developmental delay independent of the seizure burden, while the seizures simultaneously worsen the condition.

Classification by Age of Onset

These syndromes typically present at specific ages due to the maturation levels of the brain.

A. Neonatal and Early Infantile Period

1. Early Myoclonic Encephalopathy (EME)

• Onset: First 2 months of life (often neonatal).
• Seizure Type: Fragmentary, severe myoclonic seizures, and erratic focal seizures.
• Etiology: Predominantly metabolic (e.g., Non-ketotic hyperglycinemia, organic acidemias),.
• EEG: Burst-suppression pattern (periods of flat background interrupted by high-voltage spikes). This pattern is often enhanced by sleep.
• Prognosis: Ominous; high mortality and severe impairment.

2. Ohtahara Syndrome (Early Infantile Epileptic Encephalopathy - EIEE)

• Onset: Neonatal to early infancy (first 3 months).
• Seizure Type: Primarily tonic spasms (singly or in clusters).
• Etiology: Structural brain malformations (e.g., hemimegalencephaly) or genetic variants (e.g., STXBP1, KCNQ2),.
• EEG: Burst-suppression pattern (consistent during both sleep and wakefulness).
• Evolution: Often progresses to West syndrome and later Lennox-Gastaut syndrome.

3. Epilepsy of Infancy with Migrating Focal Seizures (EIMFS)

• Clinical Features: Multifocal seizures with autonomic symptoms (apnea, flushing). Seizures are nearly continuous.
• Genetics: Strongly associated with KCNT1 (gain-of-function) mutations,.
• EEG: Ictal rhythms migrating from one brain region to another contiguous or contralateral region.

B. Infancy

1. West Syndrome (Infantile Spasms)

• Triad:
  1. Epileptic Spasms: Sudden flexion, extension, or mixed movements of proximal muscles, often occurring in clusters upon awakening,.
  2. Psychomotor Regression: Arrest or loss of developmental milestones.
  3. Hypsarrhythmia: Chaotic, high-voltage background with multifocal spikes and sharp waves on EEG,.
• Etiology: Diverse. Includes structural (Tuberous Sclerosis Complex - TSC), genetic (ARX, CDKL5), or metabolic causes,.
• Management:
  • First-line: ACTH (Adrenocorticotropic hormone) or high-dose oral corticosteroids,.
  • TSC-associated: Vigabatrin is the drug of choice,.
  • Prognosis: Variable; better in cryptogenic cases. Often evolves into Lennox-Gastaut syndrome.

2. Dravet Syndrome (Severe Myoclonic Epilepsy of Infancy)

• Genetics: Loss-of-function mutation in SCN1A (sodium channel gene) in ~80% of cases.
• Clinical Course:
  • Onset: ~6 months with prolonged febrile or afebrile clonic seizures (often hemiclonic).
  • Evolution: Development of myoclonic, atypical absence, and focal seizures between 1–4 years. Developmental regression/stagnation occurs after onset.
  • Triggers: Hyperthermia (fever, hot bath), photic stimulation.
• Management:
  • Contraindicated: Sodium channel blockers (Carbamazepine, Phenytoin, Lamotrigine) as they exacerbate seizures.
  • Effective Agents: Valproate, Clobazam, Stiripentol, Cannabidiol (CBD), and Fenfluramine,.

C. Childhood

1. Lennox-Gastaut Syndrome (LGS)

• Onset: 2–10 years (peak 3–5 years),.
• Triad:
  1. Multiple Seizure Types: Tonic (especially nocturnal), Atonic ("drop attacks"), and Atypical Absence are characteristic,.
  2. Cognitive Impairment: Intellectual regression is invariable.
  3. EEG: Slow spike-and-wave discharges (<2.5 Hz) and Generalized Paroxysmal Fast Activity (GPFA) in sleep.
• Management: Highly refractory. Valproate, Lamotrigine, Topiramate, Clobazam, Rufinamide, and Epidiolex (CBD) are used,. Corpus callosotomy may be palliative for drop attacks.

2. Landau-Kleffner Syndrome (LKS)

• Definition: Acquired epileptic aphasia. A previously normal child loses language skills (verbal auditory agnosia).
• EEG: Electrical Status Epilepticus in Sleep (ESES)—continuous spike-waves occupying >85% of slow-wave sleep, typically bitemporal or generalized.
• Seizures: Occur in ~70% of patients but are often infrequent and nocturnal; the linguistic regression is the hallmark.
• Treatment: Steroids (high dose/pulsed), Benzodiazepines, Valproate. If refractory, Multiple Subpial Transection (MST).

3. Epilepsy with Continuous Spike-Waves in Slow-Wave Sleep (CSWS)

• Clinical Features: Global regression (cognitive, behavioral, motor) associated with ESES on EEG. Unlike LKS (which is language-specific), CSWS affects global domains.
• Treatment: Similar to LKS (Steroids, Benzodiazepines) to suppress the electrical status in sleep.

4. Myoclonic-Astatic Epilepsy (Doose Syndrome)

• Clinical Features: Onset 3–5 years with myoclonic jerks followed immediately by atonic loss of tone (drop attacks). Generalized tonic-clonic seizures may occur.
• Prognosis: Variable; better than LGS.
• Management: Valproate, Ethosuximide, Levetiracetam. The Ketogenic Diet is particularly effective,.

Etiology and Pathophysiology

The etiology of EE is categorized into:

1. Genetic: Single gene mutations affecting ion channels (SCN1A, KCNQ2), synaptic transmission (STXBP1), or cell signaling (mTOR pathway),.
2. Structural: Malformations of cortical development (e.g., Lissencephaly, Focal Cortical Dysplasia), Tuberous Sclerosis,.
3. Metabolic: Pyridoxine dependency, Biotinidase deficiency, GLUT-1 deficiency, Mitochondrial disorders (e.g., Alpers-Huttenlocher due to POLG),,.
4. Infectious/Inflammatory: Congenital infections (TORCH), Autoimmune encephalitis (e.g., Anti-NMDA receptor).
5. Unknown: Previously termed cryptogenic.

Diagnostic Evaluation

1. Video-EEG: Essential for classifying seizure types (e.g., spasms vs. myoclonus) and identifying syndromic patterns (e.g., hypsarrhythmia, burst-suppression).
2. Neuroimaging (MRI): High-resolution MRI (epilepsy protocol) to identify structural lesions like focal cortical dysplasia or tuberous sclerosis,.
3. Genetic Testing: Gene panels or Whole Exome Sequencing are crucial, especially for early-onset encephalopathies (e.g., SCN1A for Dravet, KCNT1 for EIMFS).
4. Metabolic Screening: Indicated in infants with refractory seizures. Tests include CSF/plasma amino acids, urine organic acids, and trial of Pyridoxine (Vitamin B6),.

Management Principles

Management is challenging as these conditions are often drug-resistant.

1. Pharmacotherapy

• Broad Spectrum: Valproate, Clobazam, Topiramate, and Levetiracetam are broad-spectrum agents often used in LGS and Dravet,.
• Syndrome Specific:
  • West Syndrome: ACTH or Vigabatrin.
  • Dravet Syndrome: Fenfluramine, Stiripentol, CBD.
  • Absence/Myoclonic: Ethosuximide, Valproate.
• Precision Therapy: Targeting the specific genetic defect.
  • KCNQ2 (loss of function): Retigabine.
  • KCNT1 (gain of function): Quinidine.
  • TSC: mTOR inhibitors (Everolimus).

2. Dietary Therapy

The Ketogenic Diet is highly effective for metabolic epilepsies like GLUT-1 deficiency and Pyruvate Dehydrogenase deficiency. It is also an effective adjunctive treatment for refractory syndromes like LGS, Dravet, and Doose syndrome.

3. Surgical and Palliative Options

• Resective Surgery: If a focal structural lesion (e.g., cortical dysplasia) is identified.
• Palliative Procedures: Corpus callosotomy for drop attacks in LGS.
• Vagus Nerve Stimulation (VNS): For refractory LGS or multifocal epilepsy not amenable to resection.

4. Immunotherapy

Steroids (Prednisone/Methylprednisolone) and IVIG are used for LKS, CSWS, West Syndrome, and autoimmune-mediated epilepsies (e.g., FIRES),.

Prognosis

The prognosis is generally guarded. While some syndromes like Benign familial neonatal seizures have favorable outcomes, the epileptic encephalopathies (West, LGS, Dravet) typically carry a high risk of:

• Intractable Epilepsy: Failure of multiple AEDs.
• Cognitive Decline: Ranging from learning disabilities to profound intellectual disability,.
• Mortality: Increased risk of Sudden Unexpected Death in Epilepsy (SUDEP) and aspiration pneumonia.