1. Symposium for Patients & Caregivers

2. Andrew G. Shetter M.D. Barrow Neurological Institute Phoenix, AZ GAMMA KNIFE RADIOSURGERY FOR HYPOTHALAMIC HAMARTOMA

3. “ The delivery of a single, high dose of irradiation to a small and critically located intracranial volume through the intact skull ”. L L. LEKSELL 1949 :Lars Leksell Definition of Radiosurgery

4. A single dose of ionizing radiation given with millimeter accuracy to a small volume of tissue GK RADIOSURGERY

5. Devices for Radiosurgery - Gamma Knife - CyberKnife - Infini - Varian Trilogy system - X Knife - Novalis Brain Lab system

6. GK Procedure Stereotactic frame applied using pin fixation Anesthesia: Age 12yrs - local + sedation Age 6-12yrs - either, depending on child

7. GK Procedure - Hi Res MR scan obtained with frame in place - Images transferred to treatment planning computer for planning process that may take several hours - HH is outline and viewed in different projections or 3D

8. GK Procedure - Oval spheres or “shots” of radiation are placed within the HH to conform the radiation dose to the size and shape of the lesion - Deliver a minimum dose of 18-20Gy to margins of the HH, while keeping dose to the nearby optic chiasm and optic tracts below 8-10Gy

9. GK Procedure  After planning completed, pt brought to treatment area, placed on mobile couch, and stereotactic frame attached to GK - HH automatically positioned in center of 192 convergent radiation beams using varying predetermined target points and treatment times

10. GK Procedure  Total treatment time 30-90min - Frame removed post treatment, pt discharged same day - No convalescent interval

14. GK Results Regis et al, 2006 - 54 pts treated from 1999-2005, 27 pts followed >3 yrs and available for analysis - Median maximal diameter 9.5mm (range 5-26mm) - Median marginal radiation dose 17Gy

15. GK Results Regis et al, 2006 - 37% seizure free, 22% >90% reduction - No instances of memory loss, paralysis, endocrine dysfunction, wt gain, visual impairment - Most pts experienced improvements in behavior, school performance, and quality of life based on subjective observations by family and physicians

16. GK Results BNI Experience, Abla et al, 2010 - From 2003-2008, 19 pts treated with GK and prospectively followed - 111 pts treated with open surgery over same interval - 10 pts with >18mo follow up available for analysis - 30 pts treated with GK to date, repeat analysis in progress

17. Mean / MedianRange Age at treatment15.1 (mean) 16.2 ( median) 5.7 – 29.3 Age at onset6 in 1 st year of life 3 between ages 6 to 8 1 month – 14 years Male Sex8 of 10 Size695 mm 3 (mean) 265 mm 3 (median) 169 – 3000 Average Daily seizures3.6 (mean) 2.5 (median) 0.1 – 6.5 Max Daily Seizures15.9 (mean) 5 (median) 1 – 100 Prior treatments3 with prior resection 2 others: cyst resection / lobectomy Anesthesia type – local with iv sedation7 of 10 Followup43 months (mean) 30.5 months (median) 18 – 81 months Isocenters / shots needed7.4 (mean) 5.5 (median) 3 – 16 Marginal dose (Gy)18 (mean & median)16 – 20 Gy Maximum point dose to optic apparatus7.5 (mean) 8.3 (median) 5 – 10 Gy

18. All 3 patients with baseline STM loss experienced resolution Improved quality of life : 9 of 10 Cognitive/STM Deficits Behavioral Abnormalities

19. p = 0.5 Prior Surgeries and Outcome

20. Complications All Transient Poikilothermia (n=1) Weight Gain / Appetite Increase (n=2) Fear of the Dark (n=1) Increased Depression, now improving (n=1) No instances of: DI visual field deficits cranial nerve deficits vascular injuries new short term memory loss

21. GK for HH Advantages - 60% seizure free or nearly seizure free, comparable or sl. inferior to endoscopic resection - Minimal or no risk of memory dysfunction, stroke, endocrine abnormalities, or wt gain compared to open surgery - Radiation dose can be shaped very precisely to maximize dose to HH and minimize dose to surrounding normal structures

22. GK for HH Advantages - No risk of hemorrhage - Outpatient procedure, local anesthesia with sedation in most instances - Open surgery or laser thermoablation not precluded at a later date if GK unsuccessful

23. GK for HH Disadvantages - Limited to relatively small lesions - Latency interval of 1-3 yrs until full effect is seen, so not a good option for pts with very frequent seizures or those who are experiencing cognitive or behavioral decline - Theoretic risk of radiation producing secondary tumors many years after treatment

24. Best Candidates for GK - Small HH ( 2mm clearance between lesion and optic apparatus - Pts with intact cognitive and memory function, particularly older pts who are high functioning - Pts with relatively stable seizure frequency who are not experiencing cognitive or behavioral decline and can afford to wait 1-3 yrs to see full effect of radiosurgery - Pts with residual HH after open surgical resection who are not seizure free

25. vs Endoscopic resection vs Laser thermoablation Efficacy GK - 37% seizure free, 21% with >90% reduction, ≥ 3 yr follow up (Regis et al) Endo - 49% seizure free, 21% with >90% reduction, ≥ 1 yr follow up (Ng et al) - 36% seizure free, ≥ 1 yr follow up (Drees et al) Laser - Good initial success rate in small number of pts, no long term results available GK

26. vs Endoscopic resection vs Laser thermoablation Risks GK - No permanent neurologic deficits, rare transient poikilothermia (Regis et al, BNI) Endo - Permanent short term memory loss 8%, transient hemiparesis 11% (Ng et al) - Persistent deficits = stroke 5%, hormonal disturbance 24%, wt gain 59%, 1 death (Drees et al) Laser - No permanent neurologic deficits reported, but number of pts treated is small. Similar stereotactic procedures have 2-3% incidence of intracranial hemorrhage GK

27. vs Endoscopic Resection vs Laser Thermoablation Latency GK - Requires 1-3 yrs to see full effect. Some pts may experience temporary increase in seizures 6-12mo. post GK Endo - Immediate effect if successful, but some pts may experience recurrent seizures after being seizure free for 6-24mo. post op Laser - Immediate effect if successful. No data regarding long- term recurrence rate GK

28. GK - How Does it Work? Kerrigan et al, 2012 - HH tissue obtained at the time of surgical resection was examined in 10 pts who had undergone prior GK treatment, and compared to 19 pts who had received no prior irradiation - Total cell density was significantly decreased in the GK treated group, with a tendency to be more pronounced in pts who received a higher radiation dose  Cell loss resulting from GK may contribute to decreased excitation in the neural networks responsible for generating seizures in HH tissue

29.  GK is the least invasive and lowest risk surgical procedure for treating medically intractable epilepsy due to a small-medium size HH - Approx. 60% of pts will become seizure free or nearly seizure free post treatment - Full effect of GK treatment is not seen for 1-3 yrs - Our knowledge regarding the best surgical option for any given HH is still incomplete. Treatment decisions must be individualized and tailored to the expectations and comfort level of each patient and their family. GK for HH - CONCLUSIONS

30. 30 Thank You

31. A Special Thanks to our Sponsors Aesculap Barrow Neurological Institute @ St. Joseph’s Hospital Barrow Neurological Institute @ Phoenix Children’s Hospital Great Council for the Improved Hope for Hypothalamic Hamartoma Foundation KARL STORZ Endoskope