President and CEO, The Carolina Headache Foundation, Chapel Hill , NCDirector, Carolina Headache Institute , Chapel Hill, NC

Professor, University of North CarolinaContractor for Defense and Veteran Brain Injury Centers

SHS Asheville 2014

The case against adoption of occipital nerve decompression

Disclosures

• With regards to this talk, the speaker has no disclosures

• The use of off label and outside of the box treatments will be discussed.

Diener and Bungel• Placebo

– Expectation and learning• Rizatriptan

– Label accounted for 50% of the drug effect

– Sensory sensations• Acupuncture• Injections

– Placebo in Preempt

– “These aspects should receive more consideration in the conception and interpretation of clinical studies involving invasive headache treatments”

Diener HC, Bingel U. Surgical treatment for migraine: Time to fight against the knife. Cephalalgia. 2015 May;35(6):465-8

Pooled Analysis

Aurora SK et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled analyses of the 56-week PREEMPT clinical program. Headache. 2011 Oct;51(9):1358-73

58 y.o. female awoke 9/5/2013 “someone had pierced my head with a nail gun…. “

• She received steroids repeatedly with complete resolution at higher doses– No change with ergots or triptans

• Continuous “phantom of the opera” mask – No ocular symptoms ptosis or tearing– Allodynia– Nausea – Restlessness– Monocular photophobia

Additional history

• History– Diabetes– ACDF

• MRI – Brain – normal– Cervical

• Surgical changes• Prominent left paracentral C2-3

The known knowns

• Placebo– Oral triptans– PFO closure– Botox®/PREEMPT®

• The unknown knowns– ONS– TMS– SPG

• The known unknowns– CGRP antagonists– CGRP antibodies

https://www.google.com/search?q=trephining+pictures&espv=2&biw=1920&bih=922&tbm=isch&tbo=u&source=univ&sa=X&ei=QpEaVfT4FoeWNrXugqgN&ved=0CDkQ7Ak#imgdii=_&imgrc=EmubTJR5J3Q7KM%253A%3BWOiZamDnCOaogM%3Bhttp%253A%252F%252Fimage.slidesharecdn.com%252Fprehistoricmedicinelesson2-090505091552-phpapp01%252F95%252Fprehistoric-medicine-lesson-2-4-728.jpg%253Fcb%253D1241533021%3Bhttp%253A%252F%252Fwww.slideshare.net%252Fhistory.brayton%252Fprehistoric-medicine-lesson-2%3B728%3B546

Trepanation

• 5 – 10 % (Single or multiple openings) – n = >1500– Adult > child– Male > female

• ?Socially prominent• Famous or infamous

• “impossible to determine if the patients were already (or recently) dead”

• Techniques– Scraping, cutting– Straight and curved

Faria MA. Neolithic trepanation decoded- A unifying hypothesis: Has the mystery as to why primitive surgeons performed cranial surgery been solved? Surg Neurol Int. 2015 May 7;6:72

Why trephinations• Dependent variable

– Alive = ?naturalistic surgical treatment– Dead = magical ritual or “fragments as amulets”

• Outcome– “’something in the head had to do with undying’”– Why “Incompletes”

• Patient woke up

• Diagnosis– Infection?– Concussion?

• Conclusion: not just a ritual for letting out spirits or psychosurgery (epilepsy, migraine with aura, etc.)

Faria MA. Neolithic trepanation decoded- A unifying hypothesis: Has the mystery as to why primitive surgeons performed cranial surgery been solved? Surg Neurol Int. 2015 May 7;6:72

©2004American Society of Plastic Surgeons. Published by Lippincott Williams & Wilkins, Inc. 2

The Anatomy of the Greater Occipital Nerve: Implications for the Etiology of Migraine Headaches.Mosser, Scott; Guyuron, Bahman; Janis, Jeffrey; Rohrich, Rod

Plastic & Reconstructive Surgery. 113(2):693-697, February 2004.DOI: 10.1097/01.PRS.0000101502.22727.5D

Fig. 1 . Marking of cadaver head. Auditory canals and occipital protuberance were marked externally and then trans- cutaneously with methylene blue.

©2004American Society of Plastic Surgeons. Published by Lippincott Williams & Wilkins, Inc. 2

Fig. 2 The Anatomy of the Greater Occipital Nerve: Implications for the Etiology of Migraine Headaches.Mosser, Scott; Guyuron, Bahman; Janis, Jeffrey; Rohrich, Rod

Plastic & Reconstructive Surgery. 113(2):693-697, February 2004.DOI: 10.1097/01.PRS.0000101502.22727.5D

Fig. 2 . (Above, left) Elevated scalp and subcutaneous tissue. The trapezius has been elevated on the specimen's right side to reveal the semispinalis and splenius muscles. (Above, center) Greater occipital nerve seen running through the semispinalis muscle. (Above, right) Superficial marking of the greater occipital nerve. (Below, left) Deep marking of the greater occipital nerve. Dashed line marks the midline. (Below, right) Division of overlying muscle to measure intramuscular distance. GON, greater occipital nerve.

Surgical versus non surgical treatment for carpal tunnel ‐syndrome

Cochrane Database of Systematic Reviews8 OCT 2008 DOI: 10.1002/14651858.CD001552.pub2http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001552.pub2/full#CD001552-fig-00101

1: Verdugo RJ, Salinas RA, Castillo JL, Cea JG. Surgical versus non-surgical treatment for carpal tunnel syndrome. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD001552. doi: 10.1002/14651858.CD001552.pub2. Review. PubMed PMID: 18843618

Surgical versus non surgical treatment for carpal tunnel ‐syndrome

Cochrane Database of Systematic Reviews8 OCT 2008 DOI: 10.1002/14651858.CD001552.pub2http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001552.pub2/full#CD001552-fig-00102

Surgical versus non surgical treatment for carpal tunnel ‐syndrome

Cochrane Database of Systematic Reviews8 OCT 2008 DOI: 10.1002/14651858.CD001552.pub2http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001552.pub2/full#CD001552-fig-00102

Surgical versus non surgical treatment for carpal tunnel ‐syndrome

Cochrane Database of Systematic Reviews8 OCT 2008 DOI: 10.1002/14651858.CD001552.pub2http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001552.pub2/full#CD001552-fig-00102

It's the Effect Size, StupidWhat effect size is and why it is important

Robert CoeSchool of Education, University of Durham, email r.j.coe@dur.ac.uk

Paper presented at the Annual Conference of the British Educational Research Association, University of Exeter, England, 12-14 September 2002

Effect Size Percentage of control group

who would be below average person in experimental group

Rank of person in a control group of 25 who would be equivalent to the average

person in experimental group

Probability that you could guess which group a person was in from knowledge of

their 'score'.

Equivalent correlation, r(=Difference in percentage 'successful' in each of the

two groups, BESD)

Probability that person from experimental group will be

higher than person from control, if both chosen at

random (=CLES)

0.0 50% 13th 0.50 0.00 0.50

0.1 54% 12th 0.52 0.05 0.53

0.2 58% 11th 0.54 0.10 0.56

0.3 62% 10th 0.56 0.15 0.58

0.4 66% 9th 0.58 0.20 0.61

0.5 69% 8th 0.60 0.24 0.64

0.6 73% 7th 0.62 0.29 0.66

0.7 76% 6th 0.64 0.33 0.69

0.8 79% 6th 0.66 0.37 0.71

0.9 82% 5th 0.67 0.41 0.74

1.0 84% 4th 0.69 0.45 0.76

1.2 88% 3rd 0.73 0.51 0.80

1.4 92% 2nd 0.76 0.57 0.84

1.6 95% 1st 0.79 0.62 0.87

1.8 96% 1st 0.82 0.67 0.90

2.0 98% 1st (or 1st out of 44) 0.84 0.71 0.92

2.5 99% 1st (or 1st out of 160) 0.89 0.78 0.96

3.0 99.9% 1st (or 1st out of 740) 0.93 0.83 0.98

Table I: Interpretations of effect sizes

It's the Effect Size, Stupid: What effect size is and why it is important Robert Coe

0.6 73% 7th 0.62 0.29 0.66 0.7 76% 6th 0.64 0.33 0.69 0.8 79% 6th 0.66 0.37 0.71 0.9 82% 5th 0.67 0.41 0.74 1.0 84% 4th 0.69 0.45 0.76 1.2 88% 3rd 0.73 0.51 0.80 1.4 92% 2nd 0.76 0.57 0.84

Table I: Interpretations of effect sizes

In other words:

“If there were no overlap at all and every single person in the afternoon group had done better on the test than everyone in the morning group, then this would seem like a very substantial difference. On the other hand, if the spread of scores were large and the overlap much bigger than the difference between the groups, then the effect might seem less significant.”

It's the Effect Size, Stupid: What effect size is and why it is important Robert Coe

Outcomes of surgery in CTS

• N = 4• Surgery = steroids (“unclear”) > splinting• Comments

– Lack of blinding– Duration of symptoms– “Although the better results in the surgical group are

statistically significant, the lower limit of the CI is close to the non-significant threshold”

• Adverse events require identification of subgroups most likely to benefit

• “Still a need for well designed clinical trials”

MRA in the diagnosis of neurovascular compression in patients with trigeminal neuralgia

Boecher et al, Neuroradiology 1998; 40:88-95

MRA in the diagnosis of neurovascular compression in patients with trigeminal neuralgia

Boecher et al, Neuroradiology 1998; 40:88-95

Gardellaet al,.Cephalalgia 21 (10), 996-999

TIC/SUNCT with Vascular Loop

The trigeminal nerve is being fenestrated by a branch of the superior cerebellar artery

Gardellaet al,.Cephalalgia 21 (10), 996-999

56-year-old woman with a 12-year history of multiple sclerosis and a 6-year history of left trigeminal neuralgia

Friedman et al, J Comput Assist Tomogr. 2001 Sep-Oct;25(5):727-32

©2004American Society of Plastic Surgeons. Published by Lippincott Williams & Wilkins, Inc. 2

Fig. 2 The Anatomy of the Greater Occipital Nerve: Implications for the Etiology of Migraine Headaches.Mosser, Scott; Guyuron, Bahman; Janis, Jeffrey; Rohrich, Rod

Plastic & Reconstructive Surgery. 113(2):693-697, February 2004.DOI: 10.1097/01.PRS.0000101502.22727.5D

Fig. 2 . (Above, left) Elevated scalp and subcutaneous tissue. The trapezius has been elevated on the specimen's right side to reveal the semispinalis and splenius muscles. (Above, center) Greater occipital nerve seen running through the semispinalis muscle. (Above, right) Superficial marking of the greater occipital nerve. (Below, left) Deep marking of the greater occipital nerve. Dashed line marks the midline. (Below, right) Division of overlying muscle to measure intramuscular distance. GON, greater occipital nerve.

Nerve Injury

• Neuropraxia• Axonotmesis• Neurotmesis

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAYQjB1qFQoTCNTihtjVj8YCFVGAkgod6akM-w&url=http%3A%2F%2Fdetail.chiebukuro.yahoo.co.jp%2Fqa%2Fquestion_detail%2Fq1055748370&ei=eLR9VdTGFtGAygTp07LYDw&psig=AFQjCNHFeb0aQ9qyEXab2EGiqxNptfrm-w&ust=1434387850671728: Accessed 14JUN2015

Nerve Injury

• Neuropraxia– Ephatic transmission

• TN– Secondary headache?

• MS– “Shocky pains”

• “positive phenomenology”– ?CSD and aura – CNS– Triptans

Neuropraxia

• What is the pathology– Carpal Tunnel– Trigeminal neuralgia

• Occipital Neuralgia– Is there a motor branch of the ON’s?

• Wasting?• EMG?

– Cutaneous innervation?• Is there a test?• How about a pin?

• Post Traumatic Headache

A “BOO BOO”* Headache?

*Source: Ann Scher personal communication

Nerve Injury

• Axonotmesis– Neuronal failure

• ?brown out versus black out• Reparable

– Synkinesis after bell’s palsy– Sensory changes– ?CNS including neurolimbic

– Diffuse Axonal Injury

Axonotmesis

• Negative phenomena– Motor or sensory– ?Macrosomatic illusion– Central changes

• Reversible • Persistent deficits?

• Ablations?– Cold v hot– Clinical recurrence in time

Nerve Injury

• Neurotmesis– Negative and late positive phenomena

• Spasticity • Phantom limb• Central sensory hallucinosis• Behavioral Changes

The Big Question

Is migraine a disorder of the peripheral nervous system disorder?

Guyuron B, Yohannes E, Miller R, Chim H, Reed D, Chance MR. Electron microscopic and proteomic comparison of terminal branches of the trigeminal nerve in patients with and without migraine headaches. Plast Reconstr Surg. 2014 Nov;134(5):796e-805e

Guyuron B, Yohannes E, Miller R, Chim H, Reed D, Chance MR. Electron microscopic and proteomic comparison of terminal branches of the trigeminal nerve in patients with and without migraine headaches. Plast Reconstr Surg. 2014 Nov;134(5):796e-805e

Protein plasma extravasation

Jakubowski et al, Exploding vs. imploding headache in migraine prophylaxis with Botulinum Toxin A. Pain. 2006 Dec 5;125(3):286-95.

IMPLODING VERSUS EXPLODING

Outside - In Inside - Out

Kosaras B, Jakubowski M, Kainz V, Burstein R. Sensory innervation of the calvarial bones of the mouse. J Comp Neurol. 2009 Jul 20; 515(3):331-48

Single site injection 25 each side

N = 29 (24 female)Dose = 50 unitsImproved = 24Resolved = 16Change = 5.2 –> 0.7Incomplete = 6.4 –> 2.1

Corrugator supercilii

Behmand RA, Tucker T, Guyuron B. Single-site botulinum toxin type a injection for elimination of migraine trigger points. Headache. 2003 Nov-Dec; 43 (10) :1085-9

Supplemental figure 1: Injection scheme

The figure illustrates the five injection points in the glabellar region. In the verum group

women/men received 29U/39U of onabotulinumtoxinA in total. We injected 7U/9U to the

procerus muscle (a), 6U/8U bilaterally to the medial part of the corrugator muscles (b), and

5U/7U bilaterally to the lateral part of the corrugator muscles (c).

Fig. 1

Journal of Psychiatric Research 2012 46, 574-581DOI: (10.1016/j.jpsychires.2012.01.027) Copyright © 2012 Elsevier Ltd Terms and Conditions

Fig. 2

Journal of Psychiatric Research 2012 46, 574-581DOI: (10.1016/j.jpsychires.2012.01.027) Copyright © 2012 Elsevier Ltd Terms and Conditions

I feel pretty?• 90% of the participants guessed their group

allocation correctly with firm conviction.– They named presence or absence of cosmetic change as

the major unblinding factor. • Psychometric raters guessed 60% of group allocations

correctly. – They were less convinced about their guesses and improvement

in depressive symptoms or lack of it was the major clue.

• Treatment expectancy and rationale credibility ratings did not differ between groups at baseline and did not predict clinical outcome

• Treatment response was not associated with the appraisal of the cosmetic change

What they told me: “ “

All of medicine begins with the wound

©2010American Society of Plastic Surgeons. Published by Lippincott Williams & Wilkins, Inc. 2

I Am Pretty

Chronic Headaches/Migraines: Extending Indications for Breast Reduction.Ducic, Ivica; Iorio, Matthew; Al-Attar, Ali

Plastic & Reconstructive Surgery. 125(1):44-49, January 2010.DOI: 10.1097/PRS.0b013e3181c2a63f

And size doesn’t matter

Gonzalez MA, Glickman LT, Aladegbami B, Simpson RL. Quality of life after breast reduction surgery: a 10-year retrospective analysis using the Breast Q questionnaire: does breast size matter? Ann Plast Surg. 2012 Oct;69(4):361-3

And size doesn’t matter

• N = 178– Response rate = 29.6% (Total = 600)

• Macromastia = 85%• Asymmetry = 5.6%• Cosmesis = 2.5%

– Satisfaction• Overall = 2.8/3.0• No difference in amount of tissue removed (p = 0.57)

• What about the others?Gonzalez MA, Glickman LT, Aladegbami B, Simpson RL. Quality of life after breast reduction surgery: a 10-year retrospective analysis using the Breast Q questionnaire: does breast size matter? Ann Plast Surg. 2012 Oct;69(4):361-3

Voodoo Death: takotsubo (Japanese octopus-trapping pot) -like cardiomyopathy• Myocardial stunning

– Transient left ventricular dysfunction – Mainly in older women

• Chest pain• With or without heart failure

• Pathology– Modest cardiac enzyme leak– and the coronary arteries are normal. – Cardiac biopsy: contraction-band necrosis (catecholamine excess)

• Recovery from this so-called can be complete• “May resemble other neurologic disorders (ASAH)”

March 9, 2006 “Voodoo” Death Revisited Martin A. Samuels, MD reviewing Ako J et al. Am J Med 2006 Jan. Martin A. Samuels, MD Stress-induced cardiomyopathy is an ages-old, well-studied phenomenon.

Voodoo Death: Martin Samuels Comments:

• “ It is amusing to behold the naïve amazement of those who believe that everything meaningful in medicine can be found via an internet search engine…do not include a single one of the most important articles on the subject. The entire phenomenon has been well-known since antiquity.”

March 9, 2006 “Voodoo” Death Revisited Martin A. Samuels, MD reviewing Ako J et al. Am J Med 2006 Jan. Martin A. Samuels, MD Stress-induced cardiomyopathy is an ages-old, well-studied phenomenon.

Figure: ECGs and head CT/CTA Preoperative ECG shows diffuse T-wave inversions (QTc 459 msec).

Susanne Muehlschlegel et al. Neurology 2008;70:e28-e29

Teaching NeuroImage: Cerebral T-waves from an aneurysmal

cardunculus compression

Voodoo Death: takotsubo-like cardiomyopathy

• “cardunculus” = INSULA– Amygdala and hypothalamus -> vagus nerve & stellate ganglia. – Catecholamines in the endocardium migrate without synapses -

calcium channels - in myocardial cell contraction

• Catecholamine excess - causes contraction-band necrosis• Mechanism

– catecholamine excess– stress (adrenaline and certain corticosteroids)– nervous system stimulation– cardiac reperfusion

March 9, 2006 “Voodoo” Death Revisited Martin A. Samuels, MD reviewing Ako J et al. Am J Med 2006 Jan. Martin A. Samuels, MD Stress-induced cardiomyopathy is an ages-old, well-studied phenomenon.

Voodoo Death: Martin Samuels Comments:

• “All neurogenic heart disease may be understood…making neurocardiology a valuable window into the world of psychosomatic (neurovisceral) medicine”

March 9, 2006 “Voodoo” Death Revisited Martin A. Samuels, MD reviewing Ako J et al. Am J Med 2006 Jan. Martin A. Samuels, MD Stress-induced cardiomyopathy is an ages-old, well-studied phenomenon.

Statistic or Miracle?

Ytterstad E, Brenn T. Mortality after the death of a spouse in Norway. Epidemiology. 2015 May;26(3):289-94.

Statistical Miracle

Treatment of migraine attacks with sumatriptan. The Subcutaneous Sumatriptan International Study Group. N Engl J Med. 1991 Aug 1;325(5):316-21

“You don’t believe in statistics”

Treatment of migraine attacks with sumatriptan. The Subcutaneous Sumatriptan International Study Group. N Engl J Med. 1991 Aug 1;325(5):316-21

Treatment of migraine attacks with sumatriptan. The Subcutaneous Sumatriptan International Study Group. N Engl J Med. 1991 Aug 1;325(5):316-21

Statistics

• # of papers– 1847

• # of authors– Too many to count

• # of patients treated– Millions

• # of dose– > 1,000,000,000

Treatment of migraine attacks with sumatriptan. The Subcutaneous Sumatriptan International Study Group. N Engl J Med. 1991 Aug 1;325(5):316-21

Guyuron et al., A Placebo-Controlled Surgical Trial of the Treatment of Migraine Headaches. Plastic & Reconstructive Surgery. 124(2):461-468.

Guyuron et al., A Placebo-Controlled Surgical Trial of the Treatment of Migraine Headaches. Plastic & Reconstructive Surgery. 124(2):461-468.

Statistical Miracle?

2

Table 2 Overall Change from Baseline to 12 Months by Location and Type of Surgery

Guyuron et al., A Placebo-Controlled Surgical Trial of the Treatment of Migraine Headaches. Plastic & Reconstructive Surgery. 124(2):461-468.

Guyuron et al., A Placebo-Controlled Surgical Trial of the Treatment of Migraine Headaches. Plastic & Reconstructive Surgery. 124(2):461-468.

Miracles

Statistics

• # of papers– Surgery + migraine = 1461

• + Guyuron = 42• + entrapment = 10

• # of authors– See above

• # of patients treated– Unknown

• # of placebo controlled studies– None

Conclusions

• Placebo is complex• There is more to life than placebos

– Including death• Things may be knowable

– And some are not• Proving that things work

– Statistics– Attention to history

• Listen to those who know

Thank you for your attention

President and CEO, The Carolina Headache Foundation, Chapel Hill , NCDirector, Carolina Headache Institute , Chapel Hill, NC

Professor, University of North CarolinaContractor, Defense and Veteran Brain Injury Center

TNS 2015