What are the differences between generalized and focal seizures, their clinical features, causes, and diagnostic approaches?

Seizure Classification and Clinical Approach

Seizures are fundamentally classified as focal onset (arising from one hemisphere), generalized onset (rapidly engaging both hemispheres bilaterally), or unknown onset, with this distinction being critical for treatment selection and prognosis. 1

Distinguishing Focal from Generalized Seizures

Focal Seizures

Focal seizures arise within networks of a single cerebral hemisphere and may remain localized or subsequently become more widely distributed. 1

• Awareness status: Can be classified as aware (consciousness intact) or with impaired awareness 1, 2
• Motor manifestations: Include automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, or tonic features 2
• Non-motor manifestations: Include autonomic, behavior arrest, cognitive, emotional, or sensory symptoms 2
• Evolution pattern: May progress to focal to bilateral tonic-clonic seizures 2

Generalized Seizures

Generalized seizures rapidly affect both hemispheres and both sides of the body from onset, even when caused by a focal lesion. 1

• Motor types: Tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, or epileptic spasms 2
• Non-motor types (absence): Typical, atypical, myoclonic, or eyelid myoclonia 2
• Key distinction: Loss of awareness occurs with most generalized seizure events 3

Clinical Features of Common Seizure Types

Focal Seizures with Impaired Awareness

• Prolonged behavioral arrest with mild automatisms is common 4
• May present with sensory symptoms that patients can describe if awareness is preserved 3
• Postictal confusion typically follows 4

Generalized Absence Seizures

• Brief episodes of behavioral arrest 4
• Characteristic generalized spike-and-wave discharges on EEG 4
• Part of primary generalized epilepsy syndromes like childhood absence epilepsy 5

Generalized Tonic-Clonic Seizures

• Bilateral motor involvement from onset 1
• May show focal features during the seizure, which can be misleading 6

Myoclonic Seizures

• Brief, shock-like jerks 4
• Part of syndromes like juvenile myoclonic epilepsy 5
• Can be misinterpreted as focal clonic seizures 6

Critical Diagnostic Pitfalls

A major pitfall is misdiagnosing generalized-onset seizures as focal seizures when they acquire focal features during evolution. 4

• Generalized-onset seizures can evolve to focal discharges on EEG, with focal rhythmic activity localizing to temporal or frontal regions 7
• This phenomenon occurs years after epilepsy onset and mimics focal seizures clinically 7
• Misdiagnosis leads to inappropriate narrow-spectrum antiepileptic medications that may worsen generalized seizures 7
• Four of six patients in one series were initially misdiagnosed with complex partial seizures when they actually had generalized-onset seizures with focal evolution 4

Causes of Seizures

Structural/Symptomatic Causes

Certain seizure types are likely associated with structural brain lesions including tumors, infection, infarction, traumatic brain injury, vascular malformations, developmental abnormalities, and seizure-associated brain pathology. 1

• Trauma-related seizures subdivide into immediate (from injury force itself) and late seizures 1
• Structural causes are more common with focal epilepsies 1

Genetic/Idiopathic Causes

Many generalized seizures have genetic underpinnings, particularly primary generalized epilepsy syndromes. 5

• Juvenile myoclonic epilepsy and childhood absence epilepsy are genetic generalized epilepsies 5
• The rate of structural findings on imaging is low in neurologically normal patients with generalized seizures 5

Investigation of Seizures

Clinical Assessment

Differentiation between generalized and focal seizures remains fundamentally a clinical process based on meticulous history and examination. 3

• Document seizure semiology in detail, including onset characteristics and awareness level 3
• Age at onset, underlying etiologies, and comorbidities help predict seizure type 3
• Infants and young children present unique challenges due to variable expression at different developmental stages 3

Electroencephalography (EEG)

EEG is essential but rarely achieves distinction between focal and generalized epilepsy in isolation. 3

• Focal seizures: Show ictal discharges originating from one hemisphere 1
• Generalized seizures: Display generalized spike-and-wave or polyspike-and-wave discharges, or generalized fast activity 7
• Confounding factor: Focal EEG abnormalities can occur in idiopathic generalized epilepsies, particularly juvenile myoclonic epilepsy 6
• Interictal epileptiform activity helps classification but must be interpreted with clinical context 7

Neuroimaging

For New-Onset Seizures (Acute Setting)

Non-contrast CT has a central role in emergent acute seizures to rapidly identify structural pathology requiring immediate intervention, including intracranial hemorrhage, stroke, vascular malformation, hydrocephalus, and tumors. 1

• CT is sensitive for calcified and bony lesions 1
• However, 78.8% of children with new-onset seizures show no findings on CT 1

For Focal Seizures (Non-Emergent)

MRI is superior to CT and should be the primary imaging modality for newly diagnosed seizures, as it is more sensitive for detecting brain abnormalities. 1

• MRI demonstrated focal abnormalities in 55% of children with seizures versus only 18% for CT 1
• 29% of abnormal intracranial findings were missed on initial CT but detected on subsequent MRI 1
• Use dedicated epilepsy protocols with 3T scanners when possible, including T1-weighted volumetric acquisition with 1mm isotropic voxels and high-resolution coronal slices optimized for hippocampal pathology 1

For Generalized Seizures in Neurologically Normal Patients

MRI is rarely indicated in neurologically normal patients with generalized seizures because the rate of positive findings is low given their genetic basis. 1, 5

• Only 2% of low-risk patients (no predisposing condition, no focal features) had abnormal MRI findings 1
• CT has even more limited utility, with only 6% positivity for generalized seizures versus 50% for focal epilepsy 1

For Intractable/Refractory Epilepsy

MRI with dedicated epilepsy protocols is the most sensitive and specific anatomic imaging technique for intractable seizures, with sensitivity of 84% and specificity of 70%. 1

• Functional imaging (FDG-PET, SPECT) may identify seizure foci occult on anatomic imaging and guide surgical planning 1
• Advanced techniques include evaluation of neurotransmitter alterations using specialized PET tracers (11C-flumazenil for GABA, 18F-MPPF for serotonin) 1

Additional Investigations

• Genetics testing: Particularly relevant for suspected genetic generalized epilepsies 3
• Immune markers: When autoimmune etiology is suspected 3
• Metabolic workup: Based on clinical presentation and age 3

Treatment Implications

Correct classification is essential because generalized-onset seizures with focal features respond favorably to medications effective against absence and myoclonic seizures, not to narrow-spectrum agents used for focal epilepsy. 7, 4

• Three patients became seizure-free and three improved significantly when switched to appropriate generalized epilepsy medications after correct diagnosis 4
• Narrow-spectrum agents can aggravate generalized-onset seizures 7