What is structural epilepsy and its management?

Structural Epilepsy: Comprehensive Overview

Definition and Classification

Structural epilepsy refers to epilepsy arising from identifiable structural brain abnormalities that serve as the underlying cause of seizures, including tumors, infection, infarction, traumatic brain injury, vascular malformations, developmental abnormalities, and seizure-associated brain pathology 1.

Epilepsy is formally diagnosed when a patient has: 1

• At least two unprovoked seizures occurring more than 24 hours apart, OR
• One unprovoked seizure with a probability of recurrence similar to the general recurrence risk after two unprovoked seizures over the next 10 years, OR
• Diagnosis of a specific epilepsy syndrome

Epidemiology and Scope

• Active epilepsy affects approximately 1.2% of the United States population (3.4 million people) and 50 million people worldwide 1
• About 10% of the population experiences at least one epileptic seizure during their lifetime 1
• Approximately 30% of epilepsy patients develop drug-resistant epilepsy 2
• In newly diagnosed focal epilepsy, 1 in 5 patients has an MRI finding that is likely causative and may alter treatment options 3

Structural Causes and Pathology

Common Structural Abnormalities

The most frequently identified structural lesions include: 1

• Malformations of cortical development (MCDs): Including focal cortical dysplasias (FCDs) types I-III, which represent a broad spectrum of developmental abnormalities 4
• Hippocampal sclerosis: One of the most common findings in temporal lobe epilepsy 5
• Brain tumors: Both primary and metastatic lesions
• Vascular malformations: Arteriovenous malformations, cavernomas
• Post-traumatic changes: From traumatic brain injury
• Infectious sequelae: Including post-encephalitic changes
• Cerebrovascular disease: Stroke and infarction
• Cerebellar structural abnormalities: Including Dandy-Walker malformation, cerebellar tumors, and posterior fossa arachnoid cysts 5

Pathophysiology

The epileptogenic zone may involve exclusively the region adjacent to the structural lesion (23% of cases), extend beyond the lesion (38% of cases), or include remote noncontiguous zones (38% of cases) 6. This finding is critical because it demonstrates that structural lesions create epileptogenic networks beyond their visible boundaries.

Seizure Classification in Structural Epilepsy

Seizures are classified as: 1, 7

• Focal onset: Arising within networks of a single cerebral hemisphere, which may remain localized or become widely distributed
• Generalized onset: Rapidly affecting both hemispheres, even when caused by a focal lesion
• Unknown onset: When the origin cannot be determined

Focal seizures can be further characterized by: 1

• Motor versus nonmotor onset symptoms
• Awareness level (aware versus impaired awareness)

Diagnostic Approach

Initial Imaging Strategy

For new-onset seizures unrelated to trauma, MRI of the brain without IV contrast is the preferred initial imaging modality in non-emergent settings, while noncontrast CT of the head is appropriate in emergent situations 1, 7.

MRI Protocol Specifications

A dedicated seizure protocol should include: 7

• Coronal T1-weighted imaging
• High-resolution 3D T1-weighted gradient echo
• Coronal T2-weighted sequences
• Coronal and axial fluid-attenuated inversion recovery (FLAIR) sequences

MRI demonstrates superior sensitivity compared to CT, with better visualization of hippocampal abnormalities, cortical dysplasias, and subtle structural lesions 7. Acquisition on 3T magnets improves lesion detection 1.

CT Imaging Role

CT has a central role in emergent situations because it can accurately and rapidly identify: 1

• Intracranial hemorrhage
• Acute stroke
• Vascular malformations
• Hydrocephalus
• Large tumors requiring immediate neurosurgical intervention

A critical pitfall is assuming a normal CT excludes structural abnormality, as MRI may still reveal significant pathology 7.

Electroencephalography (EEG)

EEG is recommended as part of the neurodiagnostic evaluation for all patients with apparent first unprovoked seizure to identify epileptiform abnormalities that increase risk of seizure recurrence 7.

EEG findings in structural epilepsy: 1

• Abnormalities are common (60-70%) in patients with seizure disorders
• Typical epileptiform patterns are present in only 24-50%
• Epileptiform patterns are predictive of seizure recurrence (positive predictive value 73%, negative predictive value 79%)

Advanced Imaging Modalities

Video EEG Monitoring

Inpatient video EEG monitoring is indicated to establish the specific type of epilepsy in poorly characterized seizure types where characterization is medically necessary to select the most appropriate therapeutic regimen 2. This is particularly important in drug-resistant epilepsy, where prolonged monitoring helps determine candidacy for surgical intervention 2.

Functional Imaging

FDG-PET, ictal SPECT, and fMRI may assist in surgical planning, especially in patients with MRI-negative epilepsy 1. These modalities are particularly valuable because patients with MRI-negative epilepsy have worse prognosis for seizure-free outcomes after surgery compared to those with visible lesions 1.

SPECT imaging characteristics: 1

• Seizure focus appears as hypoperfusion on interictal examinations
• Seizure focus appears as hyperperfusion on ictal examinations
• Statistical ictal SPECT co-registered to MRI identifies hyperperfusion focus in 84% of patients

fMRI applications: 1

• Demonstrates 89% concordance with intracarotid amobarbital procedure for language lateralization in right temporal lobe epilepsy
• Shows 85% concordance for left temporal lobe epilepsy
• Can replace invasive procedures for language lateralization

High-Risk Indicators Requiring Prioritized Imaging

Prioritize imaging for patients with focal neurological deficits on examination, persistent headache, recent history of head trauma, abnormal EEG findings, or focal seizure features 7.

Additional high-risk features in children: 7

• Postictal focal deficit that does not quickly resolve requires emergent neuroimaging
• Suspected meningitis or encephalitis warrants lumbar puncture

Laboratory Evaluation

Laboratory tests should be ordered based on individual clinical circumstances, with consideration for metabolic disturbances when clinically suggested, and toxicology screening across all age groups if drug exposure or substance abuse is suspected 7.

Management Strategies

Medical Management

Anti-Epileptic Drug (AED) Therapy

AED therapy is not necessary in patients with single or infrequent seizures unless high-risk features for recurrence are present 1. High-risk features include:

• Two or more unprovoked seizures occurring at least 24 hours apart
• Serious brain injury
• Brain MRI structural abnormalities causally linked to seizures
• Focal neurological signs
• Partial seizures
• Epileptiform EEG patterns

Approximately 25% of patients with structural epilepsy require a second AED to control seizure activity 1.

Acute Inflammatory Management

If seizures reflect an acute inflammatory event or concurrent disease flare, glucocorticoids alone or in combination with immunosuppressive therapy may be administered 1. The combination of pulse intravenous methylprednisolone and intravenous cyclophosphamide has shown effectiveness in refractory seizures with generalized disease activity 1.

Surgical Management

Maximum resection of the structural lesion offers the best chance at controlling intractable epilepsy, with postoperative seizure control achieved in 94% of patients with complete lesion excision regardless of extent of seizure focus excision 6.

Surgical outcomes by extent of resection: 6

• Complete lesion excision: 94% seizure control (17 of 18 patients)
• Incomplete lesion excision with complete seizure focus excision: 83% seizure control (5 of 6 patients)
• Incomplete lesion excision with incomplete focus excision: 52% seizure control (12 of 23 patients)

Surgical intervention could lead to seizure freedom in approximately 65% of patients with drug-resistant focal epilepsy 2.

Presurgical Evaluation

Comprehensive presurgical mapping includes: 6

• Prolonged noninvasive interictal and ictal EEG recording
• Chronically implanted subdural electrode plates for focused mapping
• Functional imaging to identify eloquent cortex and determine safe resection margins 1

Patients are more likely to be seizure-free when focal circumscribed lesions are identified on presurgical MRI compared to those without visible lesions 1.

Special Considerations

MRI-Negative Epilepsy

20-30% of temporal epilepsy and 20-40% of patients with extra-temporal lobe epilepsy have no clear lesion seen on MRI 1. These patients require:

• Advanced functional neuroimaging (FDG-PET, ictal SPECT, fMRI) 1
• More extensive presurgical evaluation
• Realistic counseling about surgical outcomes

Cerebellar Structural Abnormalities

Epilepsy associated with cerebellar malformations is usually focal, most often with a temporal lobe focus, and cerebellar lesions do not adversely affect surgical success 5. In these cases, a cerebral structural abnormality responsible for epilepsy is typically identified, most commonly hippocampal sclerosis 5.

Alternative and Complementary Therapies

The American Academy of Neurology does not recommend the use of herbal products for epilepsy treatment due to potential risks and side effects, and they should not replace standard antiepileptic medications 8.

Cannabidiol (CBD)

Cannabidiol is FDA-approved for use in childhood epilepsy, but it carries a risk of hepatotoxicity 8. Key considerations:

• Monitoring of liver enzymes is crucial
• Risk of elevated liver enzymes increases with doses above 300 mg per day 8
• Limited data available on use of cannabinoids in epilepsy treatment 8

mTOR Inhibitors

Everolimus, an mTOR-antagonist, has been introduced as a treatment for epilepsies in the context of tuberous sclerosis-associated brain lesions 4. This represents a successful translational approach targeting specific molecular pathomechanisms in structural epilepsy.

Prognosis and Long-Term Outcomes

Structural Damage Progression

Patients with newly diagnosed seizures are not generally at increased risk of seizure-induced structural cerebral damage as detected with MRI over 3.5 years 9. This finding is reassuring, as it suggests that cerebral damage may occur before the onset of seizures or develop insidiously over a more prolonged period rather than being caused by the seizures themselves 9.

Drug-Resistant Epilepsy

In cases of drug-resistant epilepsy, surgical treatment or other modern treatment approaches should be considered 8. Drug resistance affects approximately 30% of epilepsy patients and significantly impacts morbidity and mortality 2.

Critical Pitfalls to Avoid

• Never assume normal CT excludes structural pathology: MRI may reveal significant abnormalities missed on CT 7
• Do not delay appropriate EEG: Early EEG helps predict recurrence risk and guide treatment decisions 7
• Distinguish between provoked and unprovoked seizures: This distinction is critical for diagnosis and treatment planning 7
• Consider non-convulsive status epilepticus: This should be considered in patients with drug-resistant epilepsy and requires EEG for definitive diagnosis 2
• Recognize remote epileptogenic zones: The epileptogenic zone may extend beyond or be remote from the visible structural lesion 6
• Monitor for medication-related hepatotoxicity: Particularly with CBD and other newer agents 8
• Ensure specialized interpretation: Video EEG and advanced imaging require specialized expertise and neurological consultation 2