Fits! Jason Richards, MD Resident, UNC Dept. of Neurology

One year ago... 2

London, UK Chapel Hill, NC 3

London, UK Chapel Hill, NC 4

London, UK Chapel Hill, NC 5

London, UK Chapel Hill, NC 6

Intern House officer 7

Resident Registrar 8

Attending Consultant 9

Seizures Fits 10

http://shibleyrahman.com/dr-shibley-rahman-viewpoint/i-am-finally-discharged-from-queen-square/ 11

Stephen McKay Statue of Queen Charlotte in the Square's gardens https://en.wikipedia.org/wiki/queen_square,_london#/media/file:queen_charlotte,_queen_square.jpg 13

http://www.uclh.nhs.uk/ourservices/ourhospitals/nhnn/pages/home.aspx 15

http://www.julesthorntrust.org.uk/about_history.html 16

http://www.epilepsysociety.org.uk/epilepsy-society-research-centre#.vjw_itkrtuq 17

https://en.wikipedia.org/wiki/william_gowers_(neurologist)#/media/file:william_richard_gowers.jpg 18

https://en.wikipedia.org/wiki/gowers%27_sign#/media/file:gower%27s_sign.png 19

While away I noticed many differences: 20

While away I noticed many differences: Cultural 21

While away I noticed many differences: Health systems Cultural 22

While away I noticed many differences: Wada fmri 23

Overview Epilepsy is one of the most common neurologic diseases» affects 0.5-1% of the population» 60% are focal epilepsies 20% of patients with focal epilepsy are drug resistant» Defined as continued seizures despite two appropriate AEDs with good compliance Gelžinienė, Giedrė, et al. "Presurgical Evaluation of Epilepsy Patients." Medicina (Kaunas) 44.8 (2008): 585-92. Web. 24

Overview Chance of success decreases with successive drug trials» second AED response rate 14%» Third AED response rate 5% Gelžinienė, Giedrė, et al. "Presurgical Evaluation of Epilepsy Patients." Medicina (Kaunas) 44.8 (2008): 585-92. Web. 25

Epilepsy Surgery One of first cases performed at Queen Square by Mr. Victor Horsley» Patient was a 22 year old with epilepsy from a car accident» Suffering prolonged episodes of Jacksonian status epilepticus» In 1866, operation removed the cortical scar» Once the wound healed, the seizures resolved Taylor, D. C. "One Hundred Years of Epilepsy Surgery: Sir Victor Horsley's Contribution." Journal of Neurology, Neurosurgery & Psychiatry 49.5 (1986): 485-88. Web. 26

Epilepsy Surgery https://en.wikipedia.org/wiki/victor_horsley 27

Presurgical evaluation Careful patient selection is key for good outcomes»»»» Focal seizure onset should be established Progressive lesions should be excluded Resistance to medical therapy Seizures interfering with daily life Gelžinienė, Giedrė, et al. "Presurgical Evaluation of Epilepsy Patients." Medicina (Kaunas) 44.8 (2008): 585-92. Web. 28

Presurgical Evaluation Optimal surgery lesions just enough tissue to eliminate seizures Targeted area must not support essential functions, such as memory, motor or language» Testing is therefore need to precisely show the location of essential cortex Engel, Jerome, Jr,M.D., PhD. (1996). Surgery for seizures. The New England Journal of Medicine, 334(10), 647-653. 29

Wada fmri 30

Wada testing Test in which sodium amytal (barbiturate) is injected into the carotid arteries» Named for Juhn Wada, a Japanese»»»» psychiatrist 30 patients hospitalized with psychiatric problems underwent the procedure Each carotid artery was injected with sodium amytal, with the right being injected first Patients became hemiparetic on the side contralateral to the injection. Only one patient had a speech impediment with right sided injection. All had aphasia with left sided injection Wada, Juhn A. "Clinical Experimental Observations of Carotid Artery Injections of Sodium Amytal." Brain and Cognition: 11-13. Web. 7 Nov. 2015. 31

Wada testing Anesthesia typically lasts 4-8 minutes» Once hemiplegia is confirmed, language testing and memory tests are performed Allows for localization of essential cortex Sharan, Ashwini, Yinn Cher Ooi, John Langfitt, and Michael R. Sperling. "Intracarotid Amobarbital Procedure for Epilepsy Surgery." Epilepsy & Behavior 20.2 (2011): 209-13. Web. 32

Wada testing Anesthetization is not always consistent due to variations in anatomy» Amount of flow to contralateral hemisphere can differ» Amount of posterior temporal lobe supplied by the anterior circulation is variable» Some patients have atresic anterior or posterior circulations Sharan, Ashwini, Yinn Cher Ooi, John Langfitt, and Michael R. Sperling. "Intracarotid Amobarbital Procedure for Epilepsy Surgery." Epilepsy & Behavior 20.2 (2011): 209-13. Web. 33

Wada fmri 34

MRI Atomic nuclei have magnetic orientation and spin Berger, Abi. BMJ 324 (2002): 35. 35

MRI Atoms Berger, Abi. BMJ 324 (2002): 35. Atoms in magnetic field 36

MRI Atoms in magnetic field Berger, Abi. BMJ 324 (2002): 35. 37

MRI Additional energy (in form of a radiowave) can deflect the magnetic vector and cause resonance When radiowave is stopped, the magnetic vector relaxes Time needed for magnetic vector to return to resting state is T1, Time for spin relaxation is T2 Kim, Seong-Gi, and Seiji Ogawa. "Biophysical and Physiological Origins of Blood Oxygenation Level-dependent FMRI Signals." Journal of Cerebral Blood Flow & Metabolism J Cereb Blood Flow Metab 32.7 (2012): 1188-206. Web. 38

fmri Uses blood oxygenation level dependent (BOLD) contrast» Deoxyhemoglobin is an endogenous paramagnetic contrast agent» Changes in local deoxyhemoglobin concentration lead to alterations in MRI signal intensity Coupling between neural activity and vascular dilation Kim, Seong-Gi, and Seiji Ogawa. "Biophysical and Physiological Origins of Blood Oxygenation Level-dependent FMRI Signals." Journal of Cerebral Blood Flow & Metabolism J Cereb Blood Flow Metab 32.7 (2012): 1188-206. Web. 39

fmri Glucose metabolism and cerebral blood flow are closely coupled When upstream arterioles dilate, there is a decrease in the deoxyhemoglobin This decrease is the basis of the fmri image Kim, Seong-Gi, and Seiji Ogawa. "Biophysical and Physiological Origins of Blood Oxygenation Level-dependent FMRI Signals." Journal of Cerebral Blood Flow & Metabolism J Cereb Blood Flow Metab 32.7 (2012): 1188-206. Web. 40

fmri Due to different amounts of blood and brain in different areas, one cannot accurately compare signal between different voxels Possible to compare a voxel to itself across tasks Kim, Seong-Gi, and Seiji Ogawa. "Biophysical and Physiological Origins of Blood Oxygenation Level-dependent FMRI Signals." Journal of Cerebral Blood Flow & Metabolism J Cereb Blood Flow Metab 32.7 (2012): 1188-206. Web. 41

fmri orange = language task, green = right hand motor task Duncan, John S. "Imaging in the Surgical Treatment of Epilepsy." Nature Reviews Neurology Nat Rev Neurol 6.10 (2010): 537-50. Web. 42

Language lateralization Right handed people are generally left hemisphere language dominant A 1999 study by Springer at al examined this issue using fmri» Recruited 100 normal subjects and 50 subjects with epilepsy» All were right handed» Performed a tone decision and a semantic decision task Springer, J. A. "Language Dominance in Neurologically Normal and Epilepsy Subjects: A Functional MRI Study." Brain 122.11 (1999): 2033-046. Web. 43

Language lateralization Springer, J. A. "Language Dominance in Neurologically Normal and Epilepsy Subjects: A Functional MRI Study." Brain 122.11 (1999): 2033-046. Web. 44

Language lateralization Study then generated a laterality index» Processed a mean of 7,899 voxels per subject» Threshold above which each voxel was considered activated» Volume of activated voxels on the left and rights sides was computed» Laterality index was generated (LV-RV)/TV» Numbers ranged from 100 (left dominant) to -100 (right dominant) Springer, J. A. "Language Dominance in Neurologically Normal and Epilepsy Subjects: A Functional MRI Study." Brain 122.11 (1999): 2033-046. Web. 45

Language lateralization Right dominant Mixed Left dominant Springer, J. A. "Language Dominance in Neurologically Normal and Epilepsy Subjects: A Functional MRI Study." Brain 122.11 (1999): 2033-046. Web. 46

Wada versus fmri The two techniques are fundamentally different Wada testing:» replicates a lesion» outcome is traditionally left dominance, right dominance or codominance Bauer, P. R., J. B. Reitsma, B. M. Houweling, C. H. Ferrier, and N. F. Ramsey. "Can FMRI Safely Replace the Wada Test for Preoperative Assessment of Language Lateralisation? A Meta-analysis and Systematic Review." Journal of Neurology, Neurosurgery & Psychiatry 85.5 (2013): 581-88. Web. 47

Wada versus fmri Two techniques are fundamentally different fmri:» the outcome is on a continuous scale» compares an activation task to a control task, highly important that the two tasks only differ with the use of language» Arbitrary voxel activation threshold To compare techniques, one must arbitrarily define dominance data for fmri Bauer, P. R., J. B. Reitsma, B. M. Houweling, C. H. Ferrier, and N. F. Ramsey. "Can FMRI Safely Replace the Wada Test for Preoperative Assessment of Language Lateralisation? A Meta-analysis and Systematic Review." Journal of Neurology, Neurosurgery & Psychiatry 85.5 (2013): 581-88. Web. 48

Wada versus fmri Bauer et al conducted a meta-analysis comparing the two techniques» Included 22 studies comparing Wada data to fmri data with a total of 504 patients» Studies provided categorical data for Wada (left, right, both) and lateralization index for fmri.» Commonly used cut-off points (-20, 0, 20) were used to convert LI to categorical Wada data Bauer, P. R., J. B. Reitsma, B. M. Houweling, C. H. Ferrier, and N. F. Ramsey. "Can FMRI Safely Replace the Wada Test for Preoperative Assessment of Language Lateralisation? A Meta-analysis and Systematic Review." Journal of Neurology, Neurosurgery & Psychiatry 85.5 (2013): 581-88. Web. 49

Wada versus fmri Bauer, P. R., J. B. Reitsma, B. M. Houweling, C. H. Ferrier, and N. F. Ramsey. "Can FMRI Safely Replace the Wada Test for Preoperative Assessment of Language Lateralisation? A Meta-analysis and Systematic Review." Journal of Neurology, Neurosurgery & Psychiatry 85.5 (2013): 581-88. Web. 50

Wada versus fmri Wada and fmri agreed 80.55% of time fmri agreed with Wada in left language representation 94.2% time (PPV) fmri agreed with Wada in right language representation 51.1% (NPV) Bauer, P. R., J. B. Reitsma, B. M. Houweling, C. H. Ferrier, and N. F. Ramsey. "Can FMRI Safely Replace the Wada Test for Preoperative Assessment of Language Lateralisation? A Meta-analysis and Systematic Review." Journal of Neurology, Neurosurgery & Psychiatry 85.5 (2013): 581-88. Web. 51

Handedness, fmri and Bayes Thomas Bayes (English) Statistician https://en.wikipedia.org/wiki/thomas_bayes 52

Handedness, fmri and Bayes Pre-test Probability Test Post-test Probability Medina, L. Santiago, Byron Bernal, and Jeniffer Ruiz. "Role of Functional MR in Determining Language Dominance in Epilepsy and Nonepilepsy Populations: A Bayesian Analysis 1." Radiology 242.1 (2007): 94-100. Web. 53

Handedness, fmri and Bayes P is probability T+ is positive test result D+ is hemispheric language dominance D- is no hemispheric language dominance Medina, L. Santiago, Byron Bernal, and Jeniffer Ruiz. "Role of Functional MR in Determining Language Dominance in Epilepsy and Nonepilepsy Populations: A Bayesian Analysis 1." Radiology 242.1 (2007): 94-100. Web. 54

Handedness, fmri and Bayes Pre-test Probability: Population studies Test: Likelihood ratio Post-test Probability Medina, L. Santiago, Byron Bernal, and Jeniffer Ruiz. "Role of Functional MR in Determining Language Dominance in Epilepsy and Nonepilepsy Populations: A Bayesian Analysis 1." Radiology 242.1 (2007): 94-100. Web. 55

Handedness, fmri and Bayes Pre-test Probability: Population studies Both studies used Wada to determine handedness Medina, L. Santiago, Byron Bernal, and Jeniffer Ruiz. "Role of Functional MR in Determining Language Dominance in Epilepsy and Nonepilepsy Populations: A Bayesian Analysis 1." Radiology 242.1 (2007): 94-100. Web. 56

Handedness, fmri and Bayes Test: Likelihood ratio Medina, L. Santiago, Byron Bernal, and Jeniffer Ruiz. "Role of Functional MR in Determining Language Dominance in Epilepsy and Nonepilepsy Populations: A Bayesian Analysis 1." Radiology 242.1 (2007): 94-100. Web. 57

Handedness, fmri and Bayes Test: Likelihood ratio fmri sensitivity and specificity are each 92.5% Likelihood ratio was 12.3» LR = Sensitivity/(1-specificity) Medina, L. Santiago, Byron Bernal, and Jeniffer Ruiz. "Role of Functional MR in Determining Language Dominance in Epilepsy and Nonepilepsy Populations: A Bayesian Analysis 1." Radiology 242.1 (2007): 94-100. Web. 58

Handedness, fmri and Bayes Medina, L. Santiago, Byron Bernal, and Jeniffer Ruiz. "Role of Functional MR in Determining Language Dominance in Epilepsy and Nonepilepsy Populations: A Bayesian Analysis 1." Radiology 242.1 (2007): 94-100. Web. 59

Handedness, fmri and Bayes fmri Wada Left Not left Left 333 23 Not left 49 99 Sensitivity = 0.87 Specificity = 0.81 LR+ = 4.58 Medina, L. Santiago, Byron Bernal, and Jeniffer Ruiz. "Role of Functional MR in Determining Language Dominance in Epilepsy and Nonepilepsy Populations: A Bayesian Analysis 1." Radiology 242.1 (2007): 94-100. Web. Bauer, P. R., J. B. Reitsma, B. M. Houweling, C. H. Ferrier, and N. F. Ramsey. "Can FMRI Safely Replace the Wada Test for Preoperative Assessment of Language Lateralisation? A Meta-analysis and Systematic Review." Journal of Neurology, Neurosurgery & Psychiatry 85.5 (2013): 581-88. Web. 61

Handedness, fmri and Bayes Sensitivity = 0.87 Specificity = 0.81 LR+ = 4.58 Probability of left language in RH subjects» Pre-test = 80-91%» Post-test = 95-98% Medina, L. Santiago, Byron Bernal, and Jeniffer Ruiz. "Role of Functional MR in Determining Language Dominance in Epilepsy and Nonepilepsy Populations: A Bayesian Analysis 1." Radiology 242.1 (2007): 94-100. Web. Bauer, P. R., J. B. Reitsma, B. M. Houweling, C. H. Ferrier, and N. F. Ramsey. "Can FMRI Safely Replace the Wada Test for Preoperative Assessment of Language Lateralisation? A Meta-analysis and Systematic Review." Journal of Neurology, Neurosurgery & Psychiatry 85.5 (2013): 581-88. Web. 62

Cost and Complications 63

Cost of testing Medina et al, 2004 study looking at costs»»»» 39 children with planned neurosurgery Most undergoing procedure for seizure control Undergoing preoperative Wada or fmri Analyzed costs related to care Medina, L. Santiago, Elsa Aguirre, Byron Bernal, and Nolan R. Altman. "Functional MR Imaging versus Wada Test for Evaluation of Language Lateralization: Cost Analysis." Radiology 230.1 (2004): 49-54. Web. 64

Cost of testing Medina, L. Santiago, Elsa Aguirre, Byron Bernal, and Nolan R. Altman. "Functional MR Imaging versus Wada Test for Evaluation of Language Lateralization: Cost Analysis." Radiology 230.1 (2004): 49-54. Web. 65

Wada testing complications 2005 European study by Hagg et al:» Surveyed European epilepsy centers about Wada testing and complications» A total of 1,373 Wada tests were performed by 15 centers between 2000 and 2005» Ratio of Wada tests to surgeries fell 56% in 2000 and 35% in 2005» 15 complications (1.09%) were seen» 5 compliations (0.36%) with permanent morbidity Haag A, Knake S, Hamer HM, et al. The Wada test in Austrian, Dutch, German, and Swiss epilepsy centers from 2000 to 2005: a review of 1421 procedures. Epilepsy Behav 2008;13:83 89. 68

Wada testing complications Haag A, Knake S, Hamer HM, et al. The Wada test in Austrian, Dutch, German, and Swiss epilepsy centers from 2000 to 2005: a review of 1421 procedures. Epilepsy Behav 2008;13:83 89. 69

Wada testing complications Study at University of Michigan from 2015» Reviewed 431 patients who underwent Wada testing» Data collected on occurrence of any adverse clinical event and events thought to be complications to the procedure» Neurologic changes related to the patient s underlying illness were not considered procedure-related complications.» 25 patients (5.8%) had an adverse event» 9 patients (2.1%) had events classified as complications Beimer, Nicholas J., Henry A. Buchtel, and Simon M. Glynn. "One Center's Experience with Complications during the Wada Test." Epilepsia 56.8 (2015): n. pag. Web. 70

fmri complications No known biological hazards of fmri 1 MRI does not use harmful radiation 1 Deoxyhemoglobin is an endogenous molecule, no contrast injected 2 1) Berger, Abi. BMJ 324 (2002): 35. 2) Kim, Seong-Gi, and Seiji Ogawa. "Biophysical and Physiological Origins of Blood Oxygenation Level-dependent FMRI Signals." Journal of Cerebral Blood Flow & Metabolism J Cereb Blood Flow Metab 32.7 (2012): 1188-206. Web. 71

Conclusions Wada fmri 72

Conclusions fmri agreed with Wada in left language representation 94.2% time Given left language representation on fmri in a right handed patient, 95 to 99% chance Wada will show left language Wada has a 1-2% complication rate Wada costs over 3.7 times as much as fmri 73

Conclusions Use of Wada is decreasing» A 1993 study found that up to 85% of centers performed a Wada on all preoperative temporal lobe epilepsy assessments» A 2008 study found that only 12% of centers used Wada for all preoperative evaluations» 2008 study demonstrated more than a third never or rarely used Wada testing Sharan, Ashwini, Yinn Cher Ooi, John Langfitt, and Michael R. Sperling. "Intracarotid Amobarbital Procedure for Epilepsy Surgery." Epilepsy & Behavior 20.2 (2011): 209-13. Web. 74

Conclusions fmri? fmri 75

Thank you! Dr. Browner Dr. Shin Shay Slifko and everyone in the UNC OIA The numerous NHS registrars and fellows The NHNN consultants, particularly: Dr. Wehner, Dr. Diehl, Prof. Sander, Prof. Duncan, Prof. Sisodiya and Dr. Jarman 76

Resident s Question Time 77