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KEY FACTS

Imaging
- CT/MR done in acute seizures to rule out structural lesion
- Nuclear medicine not used in primary diagnosis but to evaluate patients with intractable epilepsy being considered for neurosurgical intervention - Interictal brain perfusion SPECT/CT: Demonstrates alteration in cerebral perfusion - Region of decreased radiotracer uptake (hypoperfusion) in epileptogenic zone - Ictal brain perfusion SPECT/CT: Demonstrates alteration in cerebral perfusion - Region of increased radiotracer uptake (hyperperfusion) in epileptogenic zone - Interictal F-18 FDG PET/CT: Reflects cerebral glucose metabolism - Region of decreased radiotracer uptake (hypometabolism) in epileptogenic zone - Signs of lateralization: Ipsilateral thalamus and contralateral cerebellum hypometabolism
Pathology
- Acute/provoked seizure: Manifestation of acute CNS injury, including metabolic, toxic, infectious, inflammatory, and structural provoking factors
- Unprovoked seizures: Related to progressive or remote CNS injury, including stroke, traumatic brain injury, and brain tumors
- Overall, most common cause of epilepsy in adults is MTS
Clinical Issues
- Lifetime prevalence of experiencing seizure: ~ 10%
- Treatment based on seizure location, etiology, age, and comorbidities
- Antiseizure medication (ASM): 1st-line treatment; however, ineffective in 1/3 of patients
- Epilepsy surgery: Reserved for medically intractable epilepsy and selected cases - Nuclear medicine critical in evaluation of surgical candidates and prediction of surgical outcome

TERMINOLOGY

Definitions
- Seizure: Transient occurrence of signs &/or symptoms due to abnormal excessive or simultaneous neuronal activity in brain
- Epileptogenic zone/focus: Part of brain that is having abnormal electric activities
- Acute/provoked seizure: Manifestation of acute CNS insult, which may not recur after underlying cause is removed
- Unprovoked seizure: Epileptic seizure in absence of acute precipitating factors
- Epilepsy: Pathologic and enduring disposition toward recurrent unprovoked seizures: (1) ≥ 2 unprovoked seizures > 24 hours apart, (2) 1 unprovoked seizure and ≥ 60% likelihood of recurrence within 10 years (by clinical picture, EEG, or imaging), or (3) epilepsy syndrome
- Epilepsy syndrome: Characteristic cluster of clinical and EEG features with specific etiologic findings that occur in recognizable pattern
- Medically intractable epilepsy: Failure of 2 appropriately chosen and dosed antiseizure medications (ASMs)

IMAGING

General Features

Best diagnostic clue

- Brain perfusion SPECT-CT
        - Alteration of cerebral perfusion depends on electric status of brain
        - Ictal phase: Blood flow in epileptogenic region can increase up to 300%; seen as area of hyperperfusion
        - Interictal phase: Hypoperfusion or normal perfusion in epileptogenic region
- F-18 FDG PET/CT
        - Cerebral glucose metabolism is closely linked to neuronal and synaptic function
        - Ictal phase: Glucose metabolism increases during seizure; seen as area of hypermetabolism
        - Interictal phase: Hypometabolism, very sensitive for lateralization and lobar regionalization of epileptogenic focus

Radiographic Findings
- CT/MR usually performed in work-up of acute provoked and unprovoked seizures to rule out structural lesion
- Nuclear medicine plays critical role in work-up of intractable epilepsy as part of multimodality process
MR Findings
- MR epilepsy-specific protocol is indicated in 1st seizure without evidence of provoking factors in initial work-up - Periictal seizure-induced signal changes: DWI and FLAIR abnormalities in cerebral cortex, hippocampi, and thalami, not restricted to vascular territories
- Focal cortical dysplasia (FCD): Blurring of gray-white junction with focal cortical thickening and T2 hyperintensity extending toward ventricle
- MST: Asymmetric decreased volume of mesial temporal lobe with associated T2-hyperintense signal
Nuclear Medicine Findings
- Not used in primary diagnosis or evaluation of recent-onset epilepsy but to evaluate patients with intractable epilepsy being considered for neurosurgical intervention
- Most beneficial in patients without visible lesion on MR, MR findings discordant with semiology/EEG, and multiple/bilateral structural lesions
- Brain perfusion SPECT/CT - Alteration of cerebral perfusion depends on electrical status of brain - Most commonly used radiotracers: Tc-99m hexamethylpropyleneamine oxime (HMPAO) and Tc-99m ethyl cysteinate dimer (ECD): Cross blood-brain barrier and reflect cerebral blood flow - Ictal: Region of increased radiotracer uptake (hyperperfusion) in epileptogenic zone - Interictal: Region of decreased radiotracer uptake (hypoperfusion) in epileptogenic zone - Sensitivity in temporal lobe epilepsy (TLE): 44% (interictal), 97% (ictal); sensitivity in extra-TLE: 40% (interictal), 66% (ictal) - Ictal SPECT is more sensitive than interictal SPECT; however, it is difficult to perform
- F-18 FDG PET/CT - Radiolabeled glucose analogue, reflecting cerebral glucose metabolism, which is closely linked to neuronal and synaptic function - Interictal: Region of decreased radiotracer uptake (hypometabolism) in epileptogenic zone - Sensitivity in TLE: 87-90% (interictal); sensitivity in extra-TLE: 38-55% (interictal) - Sensitivity and specificity in pediatric frontal lobe epilepsy: 92% and 62%, respectively - Better imaging quality and more sensitive than interictal SPECT for epileptogenic focus - Ictal PET/CT is not feasible due to uptake time of FDG (30 min); if seizure occurs during uptake, may demonstrate region of hypermetabolism in epileptogenic zone

Imaging Recommendations

Best imaging tool

- Nuclear medicine plays critical role in evaluation of intractable focal seizures
        - Helps with prediction of surgical outcome by defining "functional deficit zone"
        - Hypometabolism confined to epileptogenic zone is associated with better postoperative seizure control
        - Discordant findings, severe extratemporal &/or bilateral hypometabolism is associated with higher incidence of postoperative seizures
        - Provides important information on functional status of rest of brain

Protocol advice

- No clinical or EEG seizure evidence for 24 hours
- Fasting at least 4-6 hours
- "Resting state": Awake in quiet, dark environment for at least 30 minutes prior to and after injection
- Sedation: At least 20 minutes after radiotracer injection
        - Will cause global and regional (occipitocerebellar) reduction in metabolism and perfusion
- Blood glucose before FDG injection (150-200 mg/dL)
        - Hyperglycemia: Competitive inhibition of F-18 FDG uptake appearing as globally reduced metabolism
- Begin imaging 30-60 minutes after injection
- Continuous EEG recording during image acquisition

DIFFERENTIAL DIAGNOSIS

Psychogenic Nonepileptic Seizures
- Typically normal study, as seizures are psychogenic in etiology, though patients with epilepsy can also experience psychogenic nonepileptic seizures in addition to true electrographic seizures

PATHOLOGY

General Features

Etiology

- Imbalance between neuronal electrical excitation and inhibition in different regions of CNS
- Not hierarchical categories according to ILAE task force: (1) Structural, (2) genetic, (3) infectious, (4) metabolic, (5) immune, (6) unknown
- Acute/provoked seizure: Metabolic, toxic, infectious, inflammatory, and structural provoking factors
        - Stroke and CNS infection are most common causes
- Unprovoked seizures: CNS insult not at same time frame of seizures
        - Related to progressive or remote CNS injury
                  - Stroke: ~ 6% of stroke patients will eventually develop epilepsy
                  - Traumatic brain injury (TBI): 2x increased risk of epilepsy after TBI
                  - Brain tumor: Highest seizure prevalence in low-grade gliomas (60-85%)
        - No known etiology

Staging, Grading, & Classification
- 3-level stepwise approach for classification - Seizure type - Origin of seizure: Focal, generalized, unknown - Degree of awareness: Intact or impaired - Level of body movement: Motor or nonmotor - Epilepsy type: Focal, generalized, and combined - Epilepsy syndrome - (1) Neonatal and infantile, (2) childhood, (3) variable age, (4) idiopathic generalized epilepsies - Further subdivided within each age group into generalized, focal, or generalized and focal

CLINICAL ISSUES

Presentation

Most common signs/symptoms

- Ictal semiology: Clinical characteristics of seizure, including both subjective symptoms and objective signs
        - Can be broadly divided into (1) auras, (2) alteration of consciousness, (3) motor, (4) autonomic, and (5) cognitive manifestations

Other signs/symptoms

- Postictal state: Changes in behavior, motor function, and neuropsychologic performance from end of seizure until return to normal neurologic function
- Cognitive and neuropsychologic disorders
        - TLE: Memory impairment, anxiety, depression
        - Frontal lobe epilepsy: Impairment in motor function, emotional control, inhibition

Demographics
- Lifetime prevalence of experiencing seizure: ~ 10%
- Acute/provoked seizure incidence: 29-39/100,000/year - Age predominance: < 1 year and older adult population - Most common causes: Fever, TBI, cerebrovascular disease, drug withdrawal, infection, and metabolic insults
- Epilepsy lifetime prevalence: 7.6/1,000 - Most common cause of epilepsy in adults is mesial temporal sclerosis (MTS)
Treatment
- Choosing treatment is based on seizure location, etiology, age, and comorbidities
- ASM: 1st-line treatment; reduces chance of recurrence by > 50%
- Medically intractable epilepsy: Occurs in 1/3 of epilepsy patients (> 30%) - Increased risk: Structural etiology (MTS, glioneuronal tumors, and FCD)
- Epilepsy surgery - Offered to patients with medically intractable epilepsy - "Early" surgery considered in patients with non-drug-resistant focal epilepsy with well-established clinical, imaging, and EEG correlations - Favorable prognostic factor for epilepsy surgery: Presence of structural lesion - Unfavorable prognostic factor for epilepsy surgery: Long disease duration - Seizure remission rate > 80% in TLE and 55% in extra-TLE
- Neurostimulation - Vagal nerve stimulation: 30% achieve seizure reduction and < 10% seizure freedom at long-term follow-up - Deep brain stimulation: Significant and sustained reduction in seizures in patients with refractory focal epilepsies not eligible for surgery - Responsive neurostimulation: > 60% reduction in seizure frequency, retained over long-term follow-up

DIAGNOSTIC CHECKLIST

Consider
- Interictal F-18 FDG PET more sensitive than interictal SPECT - Highly sensitive for lateralization of focal seizures (95% of MR positive-, 69% of MR equivocal-, and 84% of MR-negative patients) - Highly sensitive for localization of TLE, however, less sensitive for extra-TLE foci - Overestimates size of epileptogenic focus - If there are multiple potential candidates, does not clarify which one(s) may be offending lesion
Image Interpretation Pearls
- Before imaging review, do not review specific clinical data, as it may increase reader bias and overcall
- Ensure absence of major imaging artifact and ensure axis is level and symmetric
- Fuse with high-resolution MR if available
- Window image according to deep gray nuclei and choose color scale with most step-offs
- Review images side-by-side and lobe-by-lobe, ideally starting with temporal lobes
- Start review in axial and confirm asymmetry in coronal
- Do not stop looking, even after finding candidate; there may be multiple
- Look for signs of lateralization: Ipsilateral thalamus, contralateral cerebellum
- After initial review, check areas of concern previously identified clinically on EEG &/or MR and reexamine
- Consider subtraction imaging when comparing ictal to interictal SPECT
- Compare to normal database (PET) when available - Statistic parametric mapping can help identify focal areas of abnormality that are difficult to identify by visual analysis alone

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References

Selected References

Huff JS et al: Seizure. StatPearls, 2024
Linka L et al: Effect of the revised definition of epilepsy on treatment decisions and seizure recurrence after a first epileptic seizure. Eur J Neurol. 30(6):1557-64, 2023
Audrey C et al: Prevalence of seizures in brain tumor: a meta-analysis. Epilepsy Res. 187:107033, 2022
Pelliccia V et al: Early epilepsy surgery for non drug-resistant patients. Epilepsy Behav Rep. 19:100542, 2022
Rathore C: Classical and novel signs in seizure semiology. In Sylaja PN: IAN Reviews in Neurology 2022: Epilepsy - Innovations and Advances. Jaypee Brothers Medical Publishers Pvt Ltd, 2022
Vera-González A: Pathophysiological mechanisms underlying the etiologies of seizures and epilepsy. In: Czuczwar SJ: Epilepsy. Exon Publications, 2022
Wirrell EC et al: Methodology for classification and definition of epilepsy syndromes with list of syndromes: report of the ILAE Task Force on Nosology and Definitions. Epilepsia. 63(6):1333-48, 2022
Riva A et al: New trends and most promising therapeutic strategies for epilepsy treatment. Front Neurol. 12:753753, 2021
Beghi E: The Epidemiology of epilepsy. Neuroepidemiology. 54(2):185-91, 2020
Sarmast ST et al: Current classification of seizures and epilepsies: scope, limitations and recommendations for future action. Cureus. 12(9):e10549, 2020
Falco-Walter JJ et al: The new definition and classification of seizures and epilepsy. Epilepsy Res. 139:73-9, 2018
Liu JT et al: Surgical versus medical treatment of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsy Behav. 82:179-88, 2018
Fisher RS et al: ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 55(4):475-82, 2014
Gok B et al: The evaluation of FDG-PET imaging for epileptogenic focus localization in patients with MRI positive and MRI negative temporal lobe epilepsy. Neuroradiology. 55(5):541-50, 2013

Images

Selected Images

Coronal T2 MR in a 45-year-old woman with focal seizures shows asymmetric decreased volume and increased T2 signal involving the right mesial temporal lobe, consistent with mesial temporal sclerosis.*

Coronal interictal fused F-18 FDG PET/MR demonstrates corresponding hypometabolism involving the right mesial temporal lobe, consistent with a concordant epileptogenic zone.

Coronal T2 MR in a 20-year-old woman with focal seizures shows a cortically based T2-hyperintense lesion centered in the left parahippocampal gyrus, biopsy-proven DNET.*

Coronal fused F-18 FDG PET/MR shows a region of interictal hypometabolism in the left parahippocampal gyrus , extending beyond the lesion . It is critical for F-18 FDG PET to identify the extent of seizure focus and adjacent functional deficit zone for planning of seizure-free surgical outcomes.

Axial fused F-18 FDG PET/CT in a patient with global encephalopathy with EEG reporting nonlateralizing and nonlocalizing seizures shows subtle bilateral regions of hypometabolism and asymmetric decreased FDG uptake in the left thalamus , suggesting left lateralization.

Axial fused PET/CT in the same patient shows asymmetric decreased FDG uptake in the left cerebellum suggests contralateral right lateralization (i.e., nonlateralizing).

Axial T1 MR in a 61-year-old woman with intractable epilepsy and diagnosis of tuberous sclerosis at age 19 shows a right parietal lesion with features suggesting DNET.

Sagittal FLAIR MR also shows a focal area of gray-white interface obscuration with mild signal hyperintensity in the left postcentral gyrus and a subjacent linear hyperintensity extending to the ventricular margin, consistent with small focal cortical dysplasia (FCD).

Axial F-18 FDG PET demonstrates photopenia in the region of the known right parietal mass.

Sagittal F-18 FDG PET images show focal interictal hypometabolism in the left postcentral gyrus , correlating with FCD seen on MR. EEG reported all seizure onsets were in the right lateral posterior temporal lobe, corresponding to the region of the tumor. Patient underwent total resection of right parietal brain mass with no recurrent seizure activity after surgery.

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KEY FACTS

Imaging

Pathology

Clinical Issues

TERMINOLOGY

Definitions

IMAGING

General Features

Best diagnostic clue

Radiographic Findings

MR Findings

Nuclear Medicine Findings

Imaging Recommendations

Best imaging tool

Protocol advice

DIFFERENTIAL DIAGNOSIS

Psychogenic Nonepileptic Seizures

PATHOLOGY

General Features

Etiology

Staging, Grading, & Classification

CLINICAL ISSUES

Presentation

Most common signs/symptoms

Other signs/symptoms

Demographics

Treatment

DIAGNOSTIC CHECKLIST

Consider

Image Interpretation Pearls

References

Selected References

Images

Selected Images

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Raw Permalink Blame History