Role of PET and SPECT imaging in Epilepsy Surgery

1. Children & Young Adults with Epilepsy: Clinical Challenges in
Neurophysiology - Role of Functional Imaging
in Epilepsy Surgery
LALIT BANSAL, MD
ASSOCIATE PROFESSOR
CHILDREN’S MERCY HOSPITAL
KANSAS CITY, MO

2. No Disclosures to Report

3. Objectives
• When is epilepsy surgery evaluation performed?
• Indications of PET and SPECT in patients with Epilepsy
• How PET/SPECT helps with prognosis

4. Epilepsy is a disease of the brain defined by any of the following conditions:
• At least two unprovoked (or reflex) seizures occurring more than 24 hours apart
• One unprovoked (or reflex) seizure and a probability of further seizures similar to the general
recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years
• Diagnosis of an epilepsy syndrome (Tuberous Sclerosis, Dravet Syndrome etc.)
EPILEPSY

5. Epilepsy is the most common serious primary disorder of the brain:
• 10% of people will have at least 1 seizure in a lifetime
• One third of these will develop epilepsy
• approximately 1% of the world's population has active epilepsy

6. • Drug resistant epilepsy (DRE) - defined as failure of adequate trials of two tolerated and
appropriately chosen and used AED schedules (whether as monotherapies or in combination) to
achieve sustained seizure freedom
• 20 to 40 percent of patients with epilepsy (roughly 400,000 people living in the US) are likely to
have DRE
• Treatment options for DRE:
1. Medications
2. Ketogenic Diet
3. Neuromodulation – VNS, RNS
4. Epilepsy Surgery
Drug Resistant Epilepsy

7. The way to cure an epileptic (Epilepticus sic curabitur) is the
inscription of this picture showing a person with epilepsy
undergoing trepanation and cauterization. The picture is from
the Sloane manuscript, a collection of medical manuscripts from
the end of the 12th century (British Library, London)
The French ‘encyclopedia’ depicting a trepanation
(Diderot, 1763, cited by Ruisinger, 2003)
Photograph of the Burzahom skull showing trephination
(white arrow) and attempted trephination (black arrow)
on the left parietal bone. This trephination is estimated to
have been done 4000 to 4300 years ago in the
northwestern Himalayan region. (Cited from Sankhyan
AR, Weber GHJ, Int J Osteoarcheol 20011)

8. Multilobar or non-limbic % Limbic or temporal %
Cortical dysplasia
Infarct or ischemia
Rasmussen encephalitis
Tuberous Sclerosis
Remote infection
Tumor
Sturge-Weber
Post trauma
Arachnoid cyst
Leukodystrophy
50.2%
16.9%
12.4%
2.0%
5.4%
2.0%
2.0%
1.0%
0.5%
0.5%
Hippocampal sclerosis
Lesion only
Dual pathology
Cryptogenic
44.7%
27.0%
21.2%
7.1%
Pathological Substrates of Intractable Surgically Treated Patients Age 20 Years or Less at UCLA
Most common etiologies of epilepsy surgery in children ≤20 years of age
Extra-temporal (70%) Temporal (30%)

9. Epileptogenic Zone: the area of cortex that is necessary and sufficient for initiating seizures and whose removal (or
disconnection) is necessary for complete abolition of seizures

11. Testing Modalities for Epilepsy Surgery Evaluation
• Clinical Semiology of seizure
• Scalp EEG – looking for Interictal and Ictal features
• MRI brain (including thin cut flair and DTI sequences)
• PET Scan
• SPECT – Interictal and Ictal
• fMRI
• EEG source localization (e.g.: Curry)
• MEG
• Functional Mapping
• Neuropsychological evaluation
• WADA (Intra-carotid amobarbital)
• ECoG – intraoperative and extraoperative

12. Categorization of the utility of all tests in each clinical cohort derived through consensus voting
Interictal EEG and MRI were the only tests unanimously agreed to be mandatory across many clinical cohorts
Most ancillary tests mostly achieved a majority consensus across all clinical groups, although a 50/50 split vote was recorded for a few categories
Jayakar, P., Gaillard, W.D., Tripathi, M., Libenson, M.H., Mathern, G.W., Cross, J.H. and Task Force for Paediatric Epilepsy Surgery, Commission for Paediatrics, and the Diagnostic Commission of the International League Against Epilepsy, 2014. Diagnostic test
utilization in evaluation for resective epilepsy surgery in children. Epilepsia, 55(4), pp.507-518.

14. • Interictal FDG-PET is used to identify the functional deficit zone (FDZ)
• FDZ has relatively low glucose metabolism between seizures compared to the neural tissue
contralateral to the seizure focus
• During seizures, the region of abnormal epileptic activity has relatively increased metabolism
• It is important to document acquisition time relative to the most recent seizure
• Concurrent EEG-recording is performed during acquisition to determine accurately if the scan is
interictal or ictal or w/ high spike count
PET Scan in Epilepsy

15. Receptors PET tracer Receptor subtypes
GABA
11
C flumazenil (FMZ)
*
GABAA-cBZR
Opioid
11
C-carfentanil (CFN)
**
mu
11
C-MeNTI
*
delta
11
C-diprenorphine (DPN)
*
mu, delta, kappa
18
F-cyclofoxy
*
mu, kappa
Serotonin
18
F-MPPF
*
5-HT1A
11
C-WAY-100635
*
5-HT1A
18
F-FCWAY
*
5-HT1A
Dopamine
18
F-fallypride
*
D2/D3
Acetylcholine
18
F-FA-85380 (2FA)
**
nicotinic-α4β2
76
Br-BDEX
*
muscarinic
GABAA-cBZR: γ Aminobutyric acid A-central benzodiazepine receptor; MeNTI: N1’-methylnaltrindole MeNTI; MPPF: 2’-methoxyphenyl-(N-2’-pyridinyl)-p-fluoro-benzamidoethyipiperazine; 5-HT1A: 5-
hydroxytryptamine 1A receptor WAY-100635: (3) H-(N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl) ethyl)-N-(2-pyridyl) cyclohexane-carboxamide; FCWAY: N-{2-[4-(2-methoxyphenyl) piperazino]}-N-(2-
pyridinyl) trans-4-fluorocyclohexanecarboxamide; FA-85380: fluoro-A-85380; BDEX: 4-bromodexetimide.
*Receptor antagonist;
**Receptor agonist;
PET Tracers for Receptor Imaging in Epilepsy

16. PET study Findings
Interictal
18
F-FDG Usually reduced metabolism
Ictal
18
F-FDG (or High spike count; >10/min) Increased and decreased metabolism (complex pattern)
*
Post-ictal
18
F-FDG metabolism
**
Complex pattern, increased or decreased
GABAA-cBZR receptor (
11
C-flumazenil)
(> accurate than FDG)
Reduced binding
Opioid receptor (
11
C-Cerfentanil) Increased mu and delta receptor bindings
Serotonin receptor Reduced binding
Dopamine receptor Reduced binding
11
C-alpha-methyl-L-tryptophan (Tuberous Sclerosis) Increased uptake
Interictal
15
O-H2O Usually reduced perfusion
Ictal
15
O-H2O Increased perfusion
*due to long brain uptake period of FDG
**depending on the time of injection after seizure
PET Findings in the Area of Seizure Focus
Sarikaya, I., 2015. PET studies in epilepsy. American journal of nuclear medicine and molecular imaging, 5(5), p.416.
TS FDG AMT

17. 18F-FDG Positron Emission Tomography (PET) Brain
• Glucose metabolism is tightly connected to neuronal activity
• 18F-FDG is transported from blood into cells by GLUT-1 (predominantly)
• Inside cell FDG is metabolized to FDG-6-phosphate which is trapped in the cell
• Pre-requisite: fasting 4-6 hours, glucose <150mg/dl, c-EEG to look at spike count (Interictal/Ictal)
• Indication in Epilepsy Patients
- MRI/EEG data divergent
- MRI negative cases
- Lesion extent is unknown (focal cortical dysplasia)
• Not Indicated:
- Tuberous Sclerosis (difficult to differentiate between epileptic and non-epileptic hypometabolic tubers)
- Prior resection (peri-resection zone will be hypometabolic)
- Large lesion (peri-lesional area will be hypometabolic due to pressure effect)

18. Focal right temporal hypometabolism with subtle
right hemispheric hypometabolism
Focal left frontal hypometabolism (in area of
cortical dysplasia)
Focal hypermetabolism in right occipital
region in area of cortical malformation

19. Correlation of hypometabolism with EEG delta slowing
(Spearman's rho, r= 0.46; p < 0.001)
Altay, Ebru Erbayat, A. James Fessler, Martin Gallagher, Hrayr P. Attarian, Farrokh Dehdashti, Victoria J. Vahle, Jeffrey Ojemann, Joshua L. Dowling, and Frank G. Gilliam. "Correlation of severity of FDG‐PET hypometabolism and interictal
regional delta slowing in temporal lobe epilepsy." Epilepsia 46, no. 4 (2005): 573-576.
18F-FDG Decrease uptake
Mild = 20-40%
Moderate = 40-70%
Severe = >70%

20. • Calculating the asymmetry index can help identify epileptogenic zone
• For PET Hypo/hypermetabolism
>10% difference between two homologous regions is considered significant
• In epilepsy patients, PET hypometabolism
– 15% difference has sensitivity of 80%, specificity – 94%
– 10% difference has sensitivity of 100%, specificity – 75%
Kumar, Ajay, and Harry T. Chugani. "The role of radionuclide imaging in epilepsy, part 1: sporadic temporal and extratemporal lobe epilepsy." Journal of Nuclear Medicine 54, no. 10 (2013): 1775-1781
Ding YS, Chen BB, Glielmi C, et al. A pilot study in epilepsy patients using simultaneous PET/MR. Am J Nucl Med Mol Imaging2014;4:459–470
Bansal, Lalit, Ian Miller, Ann Hyslop, Sanjiv Bhatia, Michael Duchowny, and Prasanna Jayakar. "PET hypermetabolism in medically resistant childhood epilepsy: Incidence, associations, and surgical outcome." Epilepsia 2016, 57(3):436–444

21. Factors Affecting the Rate of Glucose Metabolism in the Brain
• EEG spike wave index – associated with PET hypermetabolism
- High spike wave (>10/min)
Bansal, L et al. "PET hypermetabolism in medically resistant childhood epilepsy: incidence, associations, and surgical outcome." Epilepsia 57, no. 3 (2016): 436-444
- Ictal PET
• Glucose level
- Hyperglycemia (171-200 mg/dl) – associated with ~55-60% reduced FDG uptake in healthy brain
- Hypoglycemia (61-70 mg/dl) – no significant difference
Sarikaya I, Albatineh AN, Sarikayaa A. Effect of various blood glucose levels on regional FDG uptake in the brain. Asia Ocean J Nucl Med Biol. 2020;8(1):46-53. doi:10.22038/aojnmb.2019.14418
• Longstanding uncontrolled seizures
- may show extensive areas of hypometabolism, likely involving seizure propagation pathways or indicating the
effect of the seizures on connected brain regions
• Use of antiepileptic drugs
- absolute rates of glucose metabolism can be decreased by barbiturates > valproate, phenytoin, or carbamazepine
• Ketogenic Diet
- Can decrease cerebral glucose metabolism rate (~20%)
Courchesne-Loyer et al. "Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: a dual tracer quantitative positron emission tomography study." Journal of Cerebral Blood Flow &
Metabolism 37, no. 7 (2017): 2485-2493

22. • Sensitivity of FDG-PET in identification of EZ:
- Temporal Lobe Epilepsy – 84-90%
- Extra-Temporal Lobe Epilepsy – 33-55%
• PET localized seizure focus:
- 95% MRI positive patients
- 84% MRI negative patients
• PET can help in decision making in ~53% presurgical patients with normal or discordant MRI/EEG

23. • 18F-FDG PET may shows a large area of hypometabolism and extend beyond the EZ
• FDG-PET can not always differentiate mesial from lateral TLE as glucose hypometabolism may extend to the lateral
aspect of the abnormal temporal lobe
• TLE-PET may show hypometabolism in the ipsilateral parietal/frontal cortex, thalamus, contralateral Temp Lobe
- represent the epileptic network involved in seizure propagation
- related to the behavioral and neuropsychologic changes
- cannot reliably be used to precisely determine the surgical margin
Helps:
- deciding subdural electrode placement
- evaluates the functional status of the rest of the brain
- helps predicts postsurgical neurocognitive outcome, depend on the integrity of the remaining (unresected) cortex
• Bilateral temporal hypometabolism in patients with unilateral temporal lobe epilepsy - if possible, PET should be
performed 2 days after the last seizure
Difficulties with PET Results

24. 18F-FDG PET as Prognostic Indicator
• Greater severity of preoperative hypometabolism in the resected temporal lobe is associated with significantly
better postoperative seizure control
• Severe extratemporal and bilateral hypometabolism is associated with a higher incidence of postoperative
seizures
• Extratemporal hypometabolism (not uncommon in TLE) is associated with a poor seizure outcome after surgery
• In unilateral temporal lobe epilepsy:
- bitemporal glucose hypometabolism is associated with poor memory performance
- prefrontal hypometabolism is associated with impaired executive function
- ipsilateral insular cortex hypometabolism may correlate with emotional or somesthetic symptoms
- b/l lateral temporal and b/l medial prefrontal hypometabolism associated with interictal aggressive behavior
- thalamic hypometabolism contralateral to the epileptic foci related to poor surgical outcome

25. SPECT
(Single-photon Emission Computed Tomography)
In
Evaluation
of
Epilepsy Surgery

26. Team Work
Team Effort of Multiple Specialties
Nuclear Medicine
Technologist
Neurophysiology EEG
Technologist
Epileptologist Radiologist

27. Indications for SPECT
• Independent bilateral temporal lobe seizures
• In patients with 2 or more lesions in the MR (TS, dual pathology).
• MR negative cases
• In neocortical extratemporal epilepsy, uptake is usually less extensive and intense
• MRI/EEG/PET discordance, 30–40% patients may showed discordant MRI & EEG
• FCD: Precisely delimit or confine the zone of seizure onset in the dysplastic territory
• Extensive, multi-lobar or bilateral lesional epilepsy, PVH, neurocutaneous syndromes or MCD
• Patients who have previous resection/gliosis/encephalocele with non-localizable residual lesions

28. INTERICTAL SPECT
• Interictal SPECT is often normal
• It may shows an area of hypoperfusion in the functional deficit zone (seen in 50–70% focal seizures TL)
• Not specific of the epileptogenic zone as other cerebral lesions may produce hypoperfusion
• Sensitivity of interictal SPECT is low
• Ideally, should be performed with last seizure > 24 hour

29. Ictal SPECT
• May indicate the zone of seizure origin
• Area of hyper-perfusion - reflects the seizure onset zone +/- propagation area (depend on injection time and EEG)
• May show an areas of hypoperfusion around the area of hyper-perfusion (vascular steal/inhibition of the propagation)
• During post-ictal phase the hyper-perfusion progressively transforms into hypoperfusion
• Typical Injection Timing:
- Early (with in 60 -100 seconds) – shows hyper-perfusion (ictal zone +/- propagation)
- After 60-100 seconds – in MTLE, hyper-perfusion mesial and hypoperfusion lateral TL
- Post-ictal (2-3 minutes after the seizures) – Extensive or diffuse hypoperfusion
- Personal observation - <15 seconds – best results, limits propagation

30. ICTAL SPECT SENSTIVITY
• Ictal Temporal lobe seizure - ~90%
• Post-ictal Temporal lobe seizure - 60%
• Ictal Extratemporal Seizure - 66%
• Post-Ictal Extratemporal Seizure - 20-50%
• SISCOM in extratemporal epilepsy - 88%
• EEG data while reading SPECT, increases sensitivity, as one can focus in the ictal onset/propagation
region for subtle changes

31. 12-year old male presenting with seizures as teeth clenching, 2-3/week

32. Seizure onset – wide distribution right hemisphere
12-year old male presenting with seizures as teeth clenching, 2-3/week

33. Ictal injection 10 seconds
12-year old male presenting with seizures as teeth clenching, 2-3/week
• 1 stage resection w/ ECOG – lesion + SPECT area
• SPECT helped in identifying primary focus of seizure
• Patient seizure free post surgery - 2 years
PET ICTAL SPECT

34. Ictal injection 8 seconds
17-year old female presenting with seizures as right arm stiffening and h/o interhemispheric lipoma resection
• Helped localize the ictal area
• MRI lesion was identified after SPECT focus

35. 6-year old male with focal onset absence seizures (eye rolling and beh arrest) – 5-10/day

36. Ictal Injection 2 seconds
6-year old male with focal onset absence seizures (eye rolling and beh arrest) – 5-10/day, failed 3 medicines
MRI Brain Hyper PET Ictal SPECT

38. Questions?