Current Literature In Clinical Science
Imaging Brain Inflammation: If We Can See It, Maybe We Can Treat It
Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein. Gershen LD, Zanotti-Fregonara P, Dustin IH, Liow JS, Hirvonen J, Kreisl WC, Jenko KJ, Inati SK, Fujita M, Morse CL, Brouwer C, Hong JS, Pike VW, Zaqqhbi SS, Innis RB, Theodore WH. JAMA Neurol 2015;72:882–888.
IMPORTANCE: Neuroinflammation may play a role in epilepsy. Translocator protein 18 kDa (TSPO), a biomarker of neuroinflammation, is overexpressed on activated microglia and reactive astrocytes. A preliminary positron emission tomographic (PET) imaging study using carbon 11 ([11C])-labeled PBR28 in patients with temporal lobe epilepsy (TLE) found increased TSPO ipsilateral to seizure foci. Full quantitation of TSPO in vivo is needed to detect widespread inflammation in the epileptic brain. OBJECTIVES: To determine whether patients with TLE have widespread TSPO overexpression using [11C]PBR28 PET imaging, and to replicate relative ipsilateral TSPO increases in patients with TLE using [11C]PBR28 and another TSPO radioligand, [11C]DPA-713. DESIGN, SETTING, AND PARTICIPANTS: In a cohort study from March 2009 through September 2013 at the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, participants underwent brain PET and a subset had concurrent arterial sampling. Twenty-three patients with TLE and 11 age-matched controls were scanned with [11C]PBR28, and 8 patients and 7 controls were scanned with [11C]DPA-713. Patients with TLE had unilateral temporal seizure foci based on ictal electroencephalography and structural magnetic resonance imaging. Participants with homozygous low-affinity TSPO binding were excluded. MAIN OUTCOMES AND MEASURES: The [11C]PBR28 distribution volume (VT) corrected for free fraction (ƒP) was measured in patients with TLE and controls using FreeSurfer software and T1-weighted magnetic resonance imaging for anatomical localization of bilateral temporal and extratemporal regions. Side-to-side asymmetry in patients with TLE was calculated as the ratio of ipsilateral to contralateral [11C]PBR28 and [11C]DPA-713 standardized uptake values from temporal regions. RESULTS: The [11C]PBR28 VT to ƒP ratio was higher in patients with TLE than in controls for all ipsilateral temporal regions (27%–42%; P 2 standard deviations above the control mean, with greater inflammation ipsilateral to the seizure focus. This suggests that the tracer might be useful to localize side (and perhaps region) of epileptigenicity in preparation for epilepsy surgery. However, sensitivity and specificity still need to be evaluated, and it is not as yet known whether this technique would provide additive information over and above the current standard.
One limitation of the study is that it only evaluated patients with temporal lobe epilepsy, most of whom had mesial temporal sclerosis. If this is truly a localizing technique, it would be far more useful if it could identify a focus in patients with nonlesional/extratemporal epilepsy, where localization is much more difficult. Recent studies suggest that in the future, these patients will represent our surgical challenge, far more than TLE (8). One case study suggested that PK11195 (a less specific TPSO tracer) uptake was localizing in a patient with extratemporal epilepsy resulting from a cortical dysplasia (9). Another issue that will need to be explored is whether changes in uptake of these novel TPSO tracers is static or dynamic. The ideal tracer would not only identify inflammation but also show a return to normal levels as inflammation resolves, providing evidence of therapeutic success. To date, there is no evidence of how or whether tracer uptake would change as inflammation is targeted. There was no difference in uptake in patients based on seizure frequency, despite the fact that previous preclinical and human tissue research has suggested that inflammation is rapidly induced by epileptic seizures (1). This might suggest a lack of sensitivity to change. In summary, the availability of a human in vivo measure of epilepsy associated neuroinflammation may be the necessary advance that leads to effective therapeutic targeting of this potentially critically important cause of brain hyperexcitability, which in turn could potentially improve outcomes in patients who are currently treatment resistant. More research is needed, including imaging of nonlesional and extratemporal epilepsy, and correlation between PET studies using TPSO tracers and subsequent examination of tissue resected during epilepsy surgery. by Jacqueline A. French, MD References 1. Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation. Exp Neurol 2013;244:11–21. 2. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson, T. Progress report on new antiepileptic drugs: A summary of the Seventh Eilat Conference (EILAT VII). Epilepsy Res 2013;103:2–30. 3. Crespel A, Coubes P, Rousset MC, Brana C, Rougier A, Rondouin G, Bockaert J, Baldy-Moulinier M, Lerner-Natoli M. Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res 2002;952:159–169. 4. Boer K, Jansen F, Nellist M, Redeker S, van den Ouweland AM, Spliet WG, van Nieuwenhuizen O, Troost D, Crino PB, Aronica E. Inflammatory processes in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex. Epilepsy Res 2008;78:7–21. 5. Iyer A, Zurolo E, Spliet WG, van Rijen PC, Baayen JC, Gorter JA, Aronica E. Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias. Epilepsia 2010;51:1763–1773. 6. Vezzani A, Conti M, De Luigi A, Ravizza T, Moneta D, Marchesi F, De Simoni MG. Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: Functional evidence for enhancement of electrographic seizures. J Neurosci 1999;19:5054–5065.
25
Imaging Brain Inflammation
7. Hirvonen J, Kreisl WC, Fujita M, Dustin I, Khan O, Appel S, Zhang Y, Morse C, Pike VW, Innis RB, Theodore WH. Increased in vivo expression of an inflammatory marker in temporal lobe epilepsy. J Nucl Med 2012;53:234–240. 8. Jehi L, Friedman D, Carlson C, Cascino G, Dewar S, Elger C, Engel J Jr, Knowlton R, Kuzniecky R, McIntosh A, O’Brien TJ, Spencer D, Sperling MR, Worrell G, Bingaman B, Gonzalez-Martinez J, Doyle W, French J. The evolution of epilepsy surgery between 1991 and 2011 in nine
26
major epilepsy centers across the United States, Germany, and Australia. Epilepsia 2015;56:1526–1533. 9. Butler T, Ichise M, Teich AF, Gerard E, Osborne J, French J, Devinsky O, Kuzniecky R, Gilliam F, Pervez F, Provenzano F, Goldsmith S, Vallabhajosula S, Stern E, Silbersweig D. Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia. J Neuroimaging 2013;23:129–131.
Imaging Brain Inflammation: If We Can See It, Maybe We Can Treat It
Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein. Gershen LD, Zanotti-Fregonara P, Dustin IH, Liow JS, Hirvonen J, Kreisl WC, Jenko KJ, Inati SK, Fujita M, Morse CL, Brouwer C, Hong JS, Pike VW, Zaqqhbi SS, Innis RB, Theodore WH. JAMA Neurol 2015;72:882–888.
IMPORTANCE: Neuroinflammation may play a role in epilepsy. Translocator protein 18 kDa (TSPO), a biomarker of neuroinflammation, is overexpressed on activated microglia and reactive astrocytes. A preliminary positron emission tomographic (PET) imaging study using carbon 11 ([11C])-labeled PBR28 in patients with temporal lobe epilepsy (TLE) found increased TSPO ipsilateral to seizure foci. Full quantitation of TSPO in vivo is needed to detect widespread inflammation in the epileptic brain. OBJECTIVES: To determine whether patients with TLE have widespread TSPO overexpression using [11C]PBR28 PET imaging, and to replicate relative ipsilateral TSPO increases in patients with TLE using [11C]PBR28 and another TSPO radioligand, [11C]DPA-713. DESIGN, SETTING, AND PARTICIPANTS: In a cohort study from March 2009 through September 2013 at the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, participants underwent brain PET and a subset had concurrent arterial sampling. Twenty-three patients with TLE and 11 age-matched controls were scanned with [11C]PBR28, and 8 patients and 7 controls were scanned with [11C]DPA-713. Patients with TLE had unilateral temporal seizure foci based on ictal electroencephalography and structural magnetic resonance imaging. Participants with homozygous low-affinity TSPO binding were excluded. MAIN OUTCOMES AND MEASURES: The [11C]PBR28 distribution volume (VT) corrected for free fraction (ƒP) was measured in patients with TLE and controls using FreeSurfer software and T1-weighted magnetic resonance imaging for anatomical localization of bilateral temporal and extratemporal regions. Side-to-side asymmetry in patients with TLE was calculated as the ratio of ipsilateral to contralateral [11C]PBR28 and [11C]DPA-713 standardized uptake values from temporal regions. RESULTS: The [11C]PBR28 VT to ƒP ratio was higher in patients with TLE than in controls for all ipsilateral temporal regions (27%–42%; P 2 standard deviations above the control mean, with greater inflammation ipsilateral to the seizure focus. This suggests that the tracer might be useful to localize side (and perhaps region) of epileptigenicity in preparation for epilepsy surgery. However, sensitivity and specificity still need to be evaluated, and it is not as yet known whether this technique would provide additive information over and above the current standard.
One limitation of the study is that it only evaluated patients with temporal lobe epilepsy, most of whom had mesial temporal sclerosis. If this is truly a localizing technique, it would be far more useful if it could identify a focus in patients with nonlesional/extratemporal epilepsy, where localization is much more difficult. Recent studies suggest that in the future, these patients will represent our surgical challenge, far more than TLE (8). One case study suggested that PK11195 (a less specific TPSO tracer) uptake was localizing in a patient with extratemporal epilepsy resulting from a cortical dysplasia (9). Another issue that will need to be explored is whether changes in uptake of these novel TPSO tracers is static or dynamic. The ideal tracer would not only identify inflammation but also show a return to normal levels as inflammation resolves, providing evidence of therapeutic success. To date, there is no evidence of how or whether tracer uptake would change as inflammation is targeted. There was no difference in uptake in patients based on seizure frequency, despite the fact that previous preclinical and human tissue research has suggested that inflammation is rapidly induced by epileptic seizures (1). This might suggest a lack of sensitivity to change. In summary, the availability of a human in vivo measure of epilepsy associated neuroinflammation may be the necessary advance that leads to effective therapeutic targeting of this potentially critically important cause of brain hyperexcitability, which in turn could potentially improve outcomes in patients who are currently treatment resistant. More research is needed, including imaging of nonlesional and extratemporal epilepsy, and correlation between PET studies using TPSO tracers and subsequent examination of tissue resected during epilepsy surgery. by Jacqueline A. French, MD References 1. Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation. Exp Neurol 2013;244:11–21. 2. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson, T. Progress report on new antiepileptic drugs: A summary of the Seventh Eilat Conference (EILAT VII). Epilepsy Res 2013;103:2–30. 3. Crespel A, Coubes P, Rousset MC, Brana C, Rougier A, Rondouin G, Bockaert J, Baldy-Moulinier M, Lerner-Natoli M. Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res 2002;952:159–169. 4. Boer K, Jansen F, Nellist M, Redeker S, van den Ouweland AM, Spliet WG, van Nieuwenhuizen O, Troost D, Crino PB, Aronica E. Inflammatory processes in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex. Epilepsy Res 2008;78:7–21. 5. Iyer A, Zurolo E, Spliet WG, van Rijen PC, Baayen JC, Gorter JA, Aronica E. Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias. Epilepsia 2010;51:1763–1773. 6. Vezzani A, Conti M, De Luigi A, Ravizza T, Moneta D, Marchesi F, De Simoni MG. Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: Functional evidence for enhancement of electrographic seizures. J Neurosci 1999;19:5054–5065.
25
Imaging Brain Inflammation
7. Hirvonen J, Kreisl WC, Fujita M, Dustin I, Khan O, Appel S, Zhang Y, Morse C, Pike VW, Innis RB, Theodore WH. Increased in vivo expression of an inflammatory marker in temporal lobe epilepsy. J Nucl Med 2012;53:234–240. 8. Jehi L, Friedman D, Carlson C, Cascino G, Dewar S, Elger C, Engel J Jr, Knowlton R, Kuzniecky R, McIntosh A, O’Brien TJ, Spencer D, Sperling MR, Worrell G, Bingaman B, Gonzalez-Martinez J, Doyle W, French J. The evolution of epilepsy surgery between 1991 and 2011 in nine
26
major epilepsy centers across the United States, Germany, and Australia. Epilepsia 2015;56:1526–1533. 9. Butler T, Ichise M, Teich AF, Gerard E, Osborne J, French J, Devinsky O, Kuzniecky R, Gilliam F, Pervez F, Provenzano F, Goldsmith S, Vallabhajosula S, Stern E, Silbersweig D. Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia. J Neuroimaging 2013;23:129–131.
