Chu Fort de France !!!

Manjit S Matharu

Headache Group, Institute of Neurology & The National Hospital for Neurology and Neurosurgery

London UK

St Jude Medical

Intractable Chronic Migraine Course 22nd February 2012

ICHD-‐II Diagnostic Criteria Episodic attacks of headache lasting 4-‐72 hours with the following features:

Headache has at least two of the following characteristics:

Unilateral location

Pulsating quality

Moderate or severe pain intensity

Aggravation by routine physical activity

During headache at least one of the following:

Nausea and/or vomiting

Photophobia and phonophobia

Further sub-‐classified on basis of frequency of headaches Episodic migraine <15 days/month Chronic migraine >15 days/month

Time

Phases of Migraine

Premonitory Aura Headache & Associated Features Resolution

Complex array of symptoms reflecting focal cortical or brainstem dysfunction

Gradual evolution 5-‐30minutes (<60minutes)

Usually before headache; can be during or even

after headache

Aura symptoms occur with headache: – Always 18% – Sometimes 13% – Never 69% Types of aura: – Visual 99% – Sensory 31% – Language 18% – Motor 6%

MIGRAINE IS A FEATUREFUL HEADACHE

Pain: • Unilateral or bilateral • Throbbing, worsened by movement or activity

• Cutaneous allodynia • Neck stiffness/pain (80%)

Associated Symptoms:

Sensory hyperexcitability • Photophobia, phonophobia, osmophobia • Motion sensitivity/vertigo

Gastrointestinal disturbance • Nausea/Vomiting/Diarrhoea

ICHD-‐IIR DIAGNOSTIC CRITERIA

1. ICHD 2006 Headache Classification Committee of the International Headache Society. Olesen J et al. Cephalalgia 2006;26:742

Migraine headache occurring on of medication overuse, not attributed to another disorder.

On has at least two of the following characteristics:

Unilateral location

Pulsating quality

Moderate or severe pain intensity

Aggravation by routine physical activity

During headache at least one of the following:

Nausea and/or vomiting

Photophobia and phonophobia

and/or treated and relieved by triptan(s) or ergot before developing into a migraine

Presenter

Notes In 2006, the classification was revised (ICHD-IIR), because the criteria for chronic migraine were fulfilled by very few patients in clinical practice and in clinical trials.1 The criteria were developed further to accurately reflect the large majority of this population seen in clinical practice. The new criteria included the following, in addition to the previous classification:1 ≥5 previous attacks of migraine On ≥8 days per month for ≥3 months, the headache fulfils the following criteria: And/or treated and relieved by triptan(s) or ergot before developing into a migraine Reference ICHD 2006 Headache Classification Committee of the International Headache Society. Olesen J et al. Cephalalgia 2006;26:742−746.

1. Stovner LJ et al. Cephalalgia 2007;27:193–210. 2. World Health Organization. The Global Burden of Disease: 2004 update, Part 3, 28–37. 3. World Health Organization. Headache disorders, 2004. 4. Natoli JL, et al. Cephalagia 2010;30:599-‐609.

One-‐year prevalence of migraine is approximately 10%1

Migraine is more prevalent than common disorders such as diabetes and asthma.2

In Europe and America, WHO estimates the prevalence of migraine to be 6–8% in men and 15–18% in women.3

Chronic migraine affects 1.4-‐2.2% of people wordwide4

Migraine 50M Chronic Migraine

7.3M

Medically Refractory Chronic Migraine

1M?

European Union

Presenter

Notes Globally, headache affects approximately 50% of adults each year. Approximately 11% of cases meet the criteria for migraine.1 In Europe and America, WHO estimates the prevalence of migraine to be 6–8% in men and 15–18% in women.2 According to data from WHO, migraine is more prevalent than common disorders such as diabetes and asthma.3 The prevalence of migraine is highest in developed countries.1,3 Migraine has also been shown to be most prevalent in women during the most productive years of adult life, which results in a high pharmacoeconomic impact of this condition.4,5 References Stovner LJ et al. Cephalalgia 2007;27:193–210. World Health Organization. Headache disorders, 2004. http://www.who.int/mediacentre/factsheets/fs277/en. Accessed May 2010. World Health Organization. The Global Burden of Disease: 2004 update, Part 3, 28–37. http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/index.html. Accessed May 2010. Stovner LJ et al. Eur J Neurol 2006;13:333−345. Blumenfeld A et al. Lancet 2010. In press.

1. Menken M,Munsat T, Toole J. Archives of Neurology 2000; 57:418-420. 2. Lipton RB et al. Headache. 2001.

Migraine is one of the 20 most common causes of years of life lived with disability1

WHO global burden of disease survey rates severe migraine, along with quadriplegia, psychosis and dementia, in a group as the most disabling chronic disorders1 80% of migraine patients report severe or very severe pain2 91% of migraine patients report disability2

91% of migraine patients report disability

Lipton RB et al. Headache. 2001.

59%

67%

76%

51%

0% 20% 40% 60% 80% 100%

Missed Family/Social Leisure Activity

Household Work Productivity Reduced by 50%

Unable to Do Chores/ Household Work

Work/School Productivity Reduced by 50%

1. Natoli JL, et al. Cephalagia 2010;30:599-‐609. 2. Blumenthal AM et al Lancet 2010

71.7

56.5

67.2 61.4

44.4 48.3

0

10

20

30

40

50

60

70

80

Unable to perform normal activities

Difficult to perform normal activities

Emotional effects

Mean MSQ

score

Chronic migraine

Episodic migraine

* *

* P<0.0001

*

Affects 1.4-‐2.2% of people wordwide1

Significantly more burdensome than episodic migraine:2

Direct costs Indirect costs

Medication Absence from work (absenteeism)

Consultation Reduced productivity at work (presenteeism)

Hospital admission Lost career opportunities

Diagnostic investigations Unemployment

Migraine is an important public health problem that is associated with substantial costs1–3

In Europe, 41 million patients with migraine cost the economy €27 billion overall in 20044

1. Steiner TJ et al. Cephalalgia 2003;23:519–527. 2. Hawkins K et al. Headache 2008;48:553 563. 3. Stewart WF et al. JAMA 2003;290:2443 2454. 4. Andlin-‐Sobocki P et al. Eur J Neurol 2005;12(Suppl 1):1

Aura: Pathophysiological Hypotheses

Aura

Cortical spreading depression of Leao

Wave of excitation followed by inhibition that traverses the cortex at 3-‐6 mm/min

Wolff’s vascular hypothesis

Migraine aura secondary to cerebral hypoxia

Normal CBF

Hypo-‐ perfusion

Hyperperfusion

Hours after angiography

Headache 2 4 6 8 10 12

Wolff. Headache and other head pain. 1963 Leao. J. Neurophysiol. 1944; Leao and Morison. J. Neurophysiol. 1945 Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002

Xenon-‐133 Studies

Normal CBF

Hypo-‐ perfusion

Hyperperfusion

Relative timing of CBF, Aura and Headache

Hours after angiography

Headache Aura

2 4 6 8 10 12

Olesen et al, Ann Neurol 1990; Olesen, Migraine and other headaches: the vascular mechanisms. 1991; Olesen, The headaches. 1993

BOLD fMRI

(i) Initial cortical gray hyperemia, with

(ii) Characteristic duration, and (iii) Characteristic velocity, which is (iv) Followed by hypoperfusion, and

shows (v) Attenuated response to visual

activation, and (vi) Recovery to baseline mean level,

and (vii) Concurrent recovery of the

stimulus driven activation (viii) Spreading phenomenon did not

cross prominent sulci

Cortical spreading depression rather than vasoconstriction is the basis of aura Hadjikhani et al, PNAS 2001

Spontaneous Episodic Migraine

Weiller et al, Nature 1995

Spontaneous Episodic Migraine

Afridi et al, Arch Neurol 2005

Chronic Migraine

Matharu et al, Brain 2004

Specific dorsal rostral pontine activation in migraine

Sphenopalatine ganglion Trigeminal

ganglion

Trigeminal nucleus

Superior salivatory nucleus

Trigeminal nerve

Meninges

Pain

Adapted from Iadecola C. Nat Med 2002; Bolay H et al. Nat Med. 2002.

Visually-‐triggered Migraine

BOLD-‐fMRI Study

BOLD signal changes in brainstem before occipital cortex signal changes (consistent with CSD) or onset of visual symptoms

Cao et al, Arch Neurol 1999; Cao et al, Neurology 2002

CSD-‐triggered Trigeminovascular Activation?

TGVS=trigemino-‐vascular system. Adapted from Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386-‐398.

Vasodilation Neurogenic Inflammation

Headache Pain

Abnormal cortical activity

Hyperexcitable brain ( Ca++, Glu, Mg++)

Cortical Spreading Depression

Activation/Sensitization of TGVS

Abnormal brain stem function

Excitation of brain stem, PAG, etc.

Central Sensitization

Presenter

Key Point: Central neuronal hyperexcitability predisposes individuals to migraine. The exact pathogenesis of migraine remains to be determined. There is increasing evidence for the neural basis of migraine. There is now an increasing body of evidence for the concept of central neuronal hyperexcitability as a pivotal physiological disturbance predisposing to migraine. The reasons for increased neuronal excitability may be multifactorial. Most recently, abnormality of calcium channels has been introduced as a potential mechanism of interictal neuronal excitability. Mutant voltage-gated P/Q type calcium channel genes likely influence presynaptic neurotransmitter release, possibly of excitatory amino-acid systems or inhibitory. It could therefore be hypothesized that genetic abnormalities result in a lowered threshold of response to trigger factors. There is also evidence from spectroscopic studies that magnesium is low in migraine We currently conceive of a migraine attack as originating in the brain. Triggers of an attack initiate a depolarizing neuroelectric and metabolic event likened to the spreading depression of Leao. This event activates the headache and associated features of the attack by mechanisms that remain to be determined, but appear to involve either peripheral trigeminovascular or brain stem pathways, or both. Excitability of cell membranes, perhaps in part genetically determined, is the brain’s route of susceptibility to attacks. Factors that increase or decrease neuronal excitability constitute the threshold for triggering attacks

Headache Management

Education and Support

Lifestyle modification and trigger management

Pharmacological Treatments

Psychological and behavioural

treatments

Surgical treatments

1. Kelman L. Cephalalgia 2007;27:394–402.

0

10

20

30

40

50

60

70

80

90

Stress Hormones Missed meals

Weather Sleep disturbance

Perfume /odours

Neck pain

Lights Alcohol Smoke Sleeping late

Heat Food

Percentage of p

atients

Triggers

• A high percentage of migraine patients report triggers • 76% to 95% of patients report triggers1 • The mean number of triggers per patient is 6.71

Presenter

Notes In a headache referral patient sample, 76% of patients affirmed that at least some of their headaches were triggered by some sort of trigger factor that they had identified. However, when the same patient sample was provided with a list of potential migraine triggers, 95% confirmed that some of the listed triggers at least occasionally triggered their headaches.1 The mean number of triggers identified by individual patients was 6.7. The 5 most common triggers identified by patients were stress; missing meals or fasting; weather change; under-sleeping; and, in women, hormonal changes.1 The frequency of individual triggers occurring at least occasionally varied enormously, from stress (79.7%) and hormones (in women; 65.1%) to, least frequently, sexual activity (5.2%). In diminishing order of frequency following stress and hormones, these were not eating (57.3%); weather (53.2%); sleep disturbance (49.8%); perfume or odour (43.7%); neck pain (specifically reported as not part of the headache but neck pain worsening and causing headache; 38.4%); lights (38.1%); alcohol (37.8%); smoke (35.7%); sleeping late (32.3%); heat (30.3%); food, not specified what (26.9%); and exercise (22.1%). 1 Patients with episodic migraine had fewer triggers associated with stress, not eating, perfume/odour, neck pain, smoke, sleeping late, and exercise than patients with chronic migraine.1 Reference Kelman L. Cephalalgia 2007;27:394–402.

Headache Management





treatments

Surgical treatments

Acute medications are used to provide relief of pain and associated symptoms1

Overuse of acute medication is common in individuals with chronic migraine1–3

20-‐30% in population; 50%–80% in headache clinics Avoid opioids and ergots if possible in patients with frequent attacks4,6 Limit the use of acute medication to <3 days/week4,5

Non-‐specific Treatments Specific Treatments

• Paracetamol 1g • NSAIDs (high-‐dose & soluble):

Aspirin 600-‐900mgs Ibuprofen 600-‐800mgs Naproxen 500-‐1000mgs Tolfenamic acid 200mgs Diclofenac 50-‐75mgs

• Opioids • Use concurrently with Prokinetics:

Domperidone 10-‐20mgs Metoclopramide 10mgs

• Triptans: Sumatriptan Rizatriptan Zolmitriptan Almotriptan Eletriptan Naratriptan Frovatriptan

• Ergot derivatives: Ergotamine 1-‐2mg tablet or suppository

1. Silberstein SD et al. eds. Headache in Clinical Practice. 2nd ed. London: Martin Dunitz; 2002:69–146. 2. Lipton RB et al. Neurology 2003;61;154–155. 3. Wang SJ et al. Pain 2001;89:285–292. 4. Diener HC et al. Lancet Neurol 2004;3:475–483. 5. Silberstein SD et al. eds. Headache in Clinical Practice. 2nd ed. London: Martin Dunitz; 2002:69–111. 6. Bigal ME et al. Headache 2008;48:1157–1168

Develops through chronic overuse of acute medication taken to treat headache or other pain1

Defined in the 2006 ICHD-‐IIR guideline as:2 – Headache on – Regular overuse for >3 months of acute symptomatic treatment drugs, during which time headaches have developed or worsened markedly

Overuse of all headache medication taken on an ad hoc basis to relieve pain may result in medication overuse headache3

Most commonly associated with regular use of: – Simple analgesics or NSAIDs on – Opioids, ergots, combination analgesics or triptans on 3

Preventives less effective with concurrent medication (analgesic) overuse

1. Manack A et al. Headache 2009;49:1206 2. ICHD 2006 Headache Classification Committee of the International Headache Society. Olesen J et al. Cephalalgia 2006;26:742 3. World Health Organization (WHO) in collaboration with the European Headache Federation (EHF). J Headache Pain 2007;8:S1 .

Presenter

Notes The history of patients with medication overuse headache shows daily or near-daily headaches that are often worse on waking in the morning and are initially aggravated by attempts to withdraw the medication.1 A diagnosis of medication overuse headache is confirmed if symptoms improve within 2 months after withdrawal of the medication.1 Reference World Health Organization (WHO) in collaboration with the European Headache Federation (EHF). J Headache Pain 2007;8:S1−47.

Very common Worldwide prevalence estimated to be 2%

60–85% patients seen in tertiary referral centres with chronic daily headache have medication overuse headache Greater impact on daily functioning than episodic migraine In one study significant impairment or reduction in function in 71% of days

1. Diener HC, Limmroth V. Lancet Neurol 2004;3:475–483. 2. Katsarava Z et al. Curr Neurol Neurosci Rep 2009;9:115–119.

* 15 days/month: simple analgesics, combinations of drugs; or 10 days/month: combination analgesics, ergotamines, triptans, opioids, barbiturates.

Preventative therapy

FAIL

Medication overuse1,2*

Detoxification

Presenter

Notes The goals for treating and managing medication overuse should be to reduce the frequency and/or severity of headache, reduce acute medication consumption, improve responsiveness to treatments, alleviate disability, improve quality of life, and prevent relapse into overuse. Standard strategies for medication overuse management include withdrawal of the overused medication, and initiation of migraine preventive.1 Either detoxification or preventive therapy can be used in patients with medication overuse but if patients fail with either approach the alternative should be tried.2 References 1. Katsarava Z et al. Curr Neurol Neurosci Rep 2009;9:115–119. 2. Diener HC, Limmroth V. Lancet Neurol 2004;3:475–483.�

Out-‐patient Setting Day Case or In-‐patient Setting

• Beta-‐blockers – Propranolol

• Antidepressants – Amitriptylline

• Serotonergic antagonist Pizotifen Methysergide

• Antiepileptic drugs (AEDs) Topiramate Valproate Gabapentin

• Calcium channel antagonists – Flunarizine

• Botox • ACE inhibitors and ARBs

– Lisinopril – Telmisartan

• Herbs, Vitamins and Minerals

• Botox • Greater occipital nerve blocks • Intravenous dihydroergotamine infusions

Headache Management





treatments

Surgical treatments

Chronic Migraine is a relatively common primary headache disorder Migraine is a neurovascular disorder Chronic Migraine is a very painful and highly disabling disorder

While there are numerous medical treatment options, a subset of these patients is intractable to conventional medical treatments. There is a clear need for novel approaches for the management of this highly disabled patient group

• Headache on > 15 days/month for at least 3 months • Affects 3-‐4% of the population • Descriptive term • Not diagnosis • Encompasses heterogeneous group of primary and secondary headache syndromes

DEFINITION

1. Silberstein SD et al. Neurology 1996;47:871

After secondary causes are ruled out

Primary headache disorders

Chronic daily headache Frequency

Chronic migraine Chronic tension-‐ type headache

New daily persistent headache

Hemicrania continua

Episodic headache Frequency <15 days/month

Short-‐duration chronic daily headache

Duration <4 hours or multiple discrete episodes

With or without medication overuse

Long-‐duration chronic daily headache

Daily or near-‐daily headache lasting

CAUSES

Migraine is typically most prevalent during the most productive years of adulthood – between the ages of 20 and 50 years1 One study suggests that 75–90% of the total economic cost of migraine is associated with absenteeism or reduced/lost workplace productivity2

People with chronic migraine are less likely to be actively working full-‐time, with an employment rate that is 81% of that for patients with low-‐frequency headache3

For those patients with chronic migraine who can work, their disorder results in a >50% reduction in productivity at work or school4

1. Stovner LJ et al. Eur J Neurol 2006;13:333–345. 2. Brown JS et al. Headache 2005;45:1012 3. Stewart WF et al. Poster presented at the 14th International Headache Congress, September 10–13 2009, Philadelphia, PA, USA. 4. Munakata J et al. Headache 2009;49:498–508.

Primary diagnosis ICHD-‐II migraine or chronic migraine

Refractory Headaches cause signi quality of life despite modi factors, and adequate trials of acute and preventive medicines with established ef 1. Failed adequate trials of preventive medicines, alone or in combination, from at least 2 of 4 drug classes:

a. Beta-‐blockers b. Anticonvulsants c. Tricyclics d. Calcium channel blockers

2. Failed adequate trials of abortive medicines from the following classes, unless contraindicated:

a. Both a triptan and DHE intranasal or injectable formulation b. Either NSAID or combination analgesics

Disabling With signi disability

Schulman et al, Headache 2008;48:778-78

Manjit S Matharu Headache Group, Institute of Neurology &

The National Hospital for Neurology and Neurosurgery London

UK

St Jude Medical Intractable Chronic Migraine Course

22nd February 2012

Weiner 1995 Started performing ONS in patients who responded to repeated greater occipital nerve blocks

Weiner & Reed, 1999 Peripheral neurostimulation for control of intractable occipital neuralgia Most of these patients were reported to had chronic migraine in subsequent functional imaging study Subsequently, numerous groups reported positive experiences in several primary and secondary headache syndromes

Weiner R, Reed KL. Neuromodulation. 1999;2(3):217-21.

PRIMARY HEADACHES

Chronic migraine Chronic cluster headache Hemicrania continua

SUNCT

SECONDARY HEADACHES

Occipital neuralgia Cervicogenic headache Post-‐traumatic headache

• Open Label series • ONSTIM Study • PRISM Study • St Jude Medical Study

OPEN LABEL CASE SERIES

Author Number Mean duration of disorder

(yrs)

Number improved (>50%)

Follow up (yrs)

Popeney 25 10 22 1.5

Oh 10 12 10 0.5

Matharu 8 5.8 8 1.5

Schwedt 8 Not stated 3 1.5

TOTAL 51 43 (84%)

Popeney& Alo Headache 2003; Oh et al. Neuromodulation 2004; Schwedt et al Cephalalgia 2007; Matharu et al Brain 2004

Medication overuse probably negatively affects outcome

Occipital Nerve Stimulation for the Treatment of Intractable Chronic Migraine Headache

Saper JR, et al Cephalalgia. 2011;31(3):271-285.

Multicentre, prospective, single blind, controlled feasibility study 66 medically intractable chronic migraine Failed at least 2 classes of preventives Bilateral ONS Randomised 2:1:1 to

– Adjustable stimulation (AS) – Preset stimulation (PS) – Medical Management (MM)

• Responder defined as: – 50% reduction in headaches days/month – 3-‐point drop (VRS 0-‐10) in pain intensity

Patients enrolled

who responded to an occipital nerve block Preset Stimulation (PS)

Medical Management (MM)

2:1:1 ratio

Adjustable Stimulation (AS)

12 Weeks

(Active, N=29 completed)

(Control, N=16 completed)

(Comparator, N=17 completed)

This prospective, randomized, double-blind, controlled study examined the efficacy and safety of occipital nerve stimulation in adult chronic migraine patients.

Presenter

Investigators recruited participants and had them fill out an electronic diary for 30 days to confirm eligibility. After qualification, baseline measures were taken and all participating chronic migraineurs were implanted with a stimulator. At a 2:1 ratio, participants were assigned to either an active group or a control group. The active group received stimulation immediately while the control group’s IPGs were not activated. (They were given patient programmers that appeared to be working but did not communicate with the IPG for the first 12 weeks .) Neither the patient nor the study investigator knew whether the patient was active or control (“double-blind”). At the 12-week visit, all participants were evaluated and study results for all measures were recorded. (This ended the controlled phase of the study.) Then, all of the participants’ IPGs were activated. (This began the open-label phase of the study.) And the entire study population was followed through the 52-week endpoint, with formal evaluation at both 24 weeks and 52 weeks (one year post-implant).

6.7

1.5 1

0

1

2

3

4

5

6

7

8


Preset Stimulation (PS)

Medical Management

(MM)

27.0%

8.8%

4.4%

0%

5%

10%

15%

20%

25%

30%



Medical Management

(MM)

Mean percent reduction (SD) in headache days per month

Mean (SD) reductions in actual headache days per month

(44.8)

(28.6)

(19.1)

(10.0)

(4.6)

(4.2)

Baseline 22.4+6.3 23.4+5.1 23.7+4.3

Reduction (SD) in overall pain intensity

Responder rates

39%

6% 0%

0%

10%

20%

30%

40%

50%



Medical Management

(MM)

0

0.5

1

1.5

2



Medical Management

(MM)

1.6

0.6 0.5

Adverse Events %

Lead migration/dislodgement 24%

Therapeutic product ineffective 16%

Implant site (lead/extension tract) infection 14%

Incision site complications 8%

Implant site (IPG) infection 4%

Implant site (IPG) pain 4%

Neck pain 4%

Burning sensation 2%

Discomfort 2%

Extension migration/dislodgement 2%

High impedance 2%

Hypotension 2%

Adverse Events %

Implant site (IPG) hematoma 2%

Implant site (IPG) irritation 2%

Implant site (lead/extension tract) inflammation 2%

Lead fracture 2%

Migraine 2%

Post-procedural nausea 2%

Post-procedural pain 2%

Rash 2%

Sensation of pressure 2%

Stitch abscess 2%

Suture-related complications 2%

Tenderness 2%

Fifty-six device-related adverse events occurred in 36 out of 51 patients.

Multicentre, prospective, double blind, controlled study 132 migraine patients ( 6 days/month, 4 hrs each) Failed at least 2 acute and 2 preventive treatments Bilateral ONS Trial stimulation for 5-‐10 days Randomised in 1:1 ratio for 12 weeks

– Active stimulation (<12.7mA, 60 Hz, 250 sec) – Sham stimulation (>1mA, 2Hz, 10 sec for 1sec/90 mins)

• All subjects has active stimulation from 12 weeks onwards • Primary end-‐point: change in headache days/month at 12 weeks

Lipton RB, et al. PRISM study: Occipital nerve stimulation for treatment-refractory migraine. Presented at: 14th Congress of the International Headache Society; September 10-13, 2009; Philadelphia, PA.

Patients enrolled

1:1 ratio

Active Stimulation

12 Weeks

This prospective, randomized, double-blind, controlled study examined the safety and efficacy of occipital nerve stimulation for the preventive treatment of refractory migraine in 132 patients in 13 centres.

5–10 days

Sham Stimulation (Control)

Trial stimulation to assess its predictive

value

Two-year follow-up conducted to assess

safety.

Presenter


Mean reduction (SD) in migraine days per month

Mean percent reduction in migraine days per month

Primary efficacy measure: reduction in migraine days per month

5.5

3.9

0

1

2

3

4

5

6

Active Stimulation Sham Stimulation

(8.7)

(8.2)

27% 20%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Active Stimulation Sham Stimulation

Adverse Events Number of Cases

Non-‐targeted area sensory symptoms 18.0%

Implant site pain/discomfort 17.3%

Infection 15.0%

Incision site pain/discomfort 7.9%

Lead migration 6.8%

A two-year follow-up was conducted to assess safety. Complications included the following:

In this study, occipital nerve stimulation did not produce a statistically significant benefit in the active vs. control group. However, subgroup analysis identified several predictors of a favourable response to stimulation, including the following:

Not overusing headache medications Not using opiates A positive response to a trial stimulation

Silberstein et al. The Safety and Efficacy of Occipital Nerve Stimulation for the Management of Chronic Migraine. Presented at: 15th Congress of the International Headache Society; June 23-‐26, 2011; Berlin.

Multicentre, prospective, double blind, controlled study 157 chronic migraine patients, with VAS score > 6/10 Headache pain is posterior head pain or pain originating in the cervical region Failed at least 2 acute and 2 preventive treatments Bilateral ONS Randomised in 2:1 ratio for 12 weeks

• All subjects has active stimulation from 12 weeks onwards • Primary end-‐point: 50% VAS with no increase in average headache frequency or duration.

• Secondary end-‐points: MIDAS-‐disability days, Headache Index, Zung Pain and Distress Scale, Patient Satisfaction, Safety

Patient Enrolled

PNS Implanted

Randomize and Device Activation

Group A: Active

Group B: Control (Blind)

2:1 Ratio

52-‐week visit 24-‐week visit 12-‐week visit 4-‐week visit 80-‐ to 90-‐day roll in

Control pts were blinded using pt programmers that did not communicate with the IPG, plus pts were also told that a range of settings were being tested. Neither the patient nor the study investigator knew whether the patient was active or

control (“double-blind”) during the first 12 weeks.

Presenter


Primary Outcome 50% VAS reduction with no increase in average headache frequency or duration

0 2 4 6 8

10 12 14 16 18

Active Sham

P=0.21

1 Two-sided test of no difference 2 One-sided lower 95% confidence bound

Continuous Proportion Responder Analysis Based on Mean Daily Average Pain Intensity VAS Measurements With No Increase in Average Headache Frequency or Duration

Significance demonstrated at 30% reduction in pain (p-value=0.011)

% reduction from baseline

Control Group % responders

(n=52)

Active Group % responders

(n=105) p-‐value1

met protocol objective (>10% dif.)2

0,0% 38,5% 69,5% <0,001 Yes

10,0% 30,8% 58,1% 0,001 Yes

20,0% 19,2% 41,9% 0,005 Yes

30,0% 17,3% 37,1% 0,011 Yes

40,0% 15,4% 25,7% 0,143 No

50,0% 13,5% 17,1% 0,553 No

60,0% 9,6% 11,4% 0,731 No

70,0% 1,9% 4,8% 0,664 No

80,0% 1,9% 3,8% 1 No

90,0% 0,0% 1,0% 1 No

100,0%

0%

20%

40%

60%

80%

100%

0% 20% 40% 60% 80% 100%

Percen

tage of P

atients

Percentage of Pain Reduction

Patients Achieving Various Levels of Pain Relief

Control (n=52) Active (n=105)

Presenter

This graph shows the average daily pain intensity for the control group on the green line and the active stimulation group on the purple line. It shows that 58,1% of the active group and 30,8% of the control group had at least 10% relief. 41,9% of the active group and 19,2% of the control group had at least 20% relief and so on. The study’s primary endpoint was determined to be the difference between the groups at 50% pain relief. And even though the active group did better at this measure 17,1% achieved 50% or greater pain relief, compared to 13,5% in the control group – the difference was not significant between the groups at that level. It is important to note, however, that significance was observed between the groups at the 30% pain reduction level. The additional objective of >10% differential at the 95% confidence interval is another statistical calculation to show how different the groups are. It is a higher standard than the more standard ‘difference between the groups’, discussed above. It was met at 30% pain relief but not at measurements taken at 40% or greater pain relief. Given the disability of chronic migraine patients, published reports suggest that 30% pain relief may be clinically relevant. So, while the 50% pain relief clinical study endpoint was not met; the significant difference between the groups at 30% pain relief may be meaningful - especially when considered along with all of the other study measures.

Visit Control Group (n=52) Active Group (n=105) P-Value

Baseline

Mean (± std) 17,1 (± 8.2) 20,5 (± 7,6) 0,011

Week 12

Mean Change1 -4,3 (25,1%) -7,3 (35,6%) 0,02

Difference (95% CI) -3,0 (-5,5, -0,5)

Mean Baseline and Change From Baseline in Headache Days per month—Last Value Carried Forward

Patient diaries recorded whether or not patients had a headache each day, the daily average headache intensity, and the daily headache duration, in hours. Data was used to identify Headache Days, defined as a day with a headache

lasting four or more hours with at least moderate intensity.

1 Adjusted for study center, prior use of alternative therapy, and baseline

Significant reduction -3.0 days in Headache Days (per month) between Active & Control groups (p=0.02)

Presenter

NOTE: Even though this was not an end-point variable in the original study, it is a measurement that many neurologists will be very interested in seeing. It has become one of the most common ways of measuring chronic migraine. Presenting this slide might lead to questions about why this statistic differs from MIDAS Headache Days which was reported previously (at the IHC) and is presented on slide 13. This more common measure differs from the MIDAS Headache Days in the following ways: Headache Days on this slide is measured using daily patient diary entries during a single month vs. The MIDAS Assessment which is a one-time question asking about headaches over the previous 90 days. A Headache Day, on this slide, is defined specifically as a day with a headache lasting 4 hours or more and at least moderate intensity vs. The MIDAS Assessment which does include criteria to define a headache day.


Baseline

Mean (± std) 56,0 (± 17,2) 59,5 (± 16,2) 0,221

Week 12

Mean Change1 -6,1 -13,6 0,006

Difference (95% CI) -7,5 (-12,8, -2,2)

Mean Baseline and Change From Baseline in Daily Average Pain Intensity VAS Measurements By Visit —Last Value Carried Forward

The patient-recorded average pain intensity in their electronic diary using a VAS with a 100 mm line to indicate severity progression.

Patients were asked to record these measurements on each day that they experienced headache.


The active group had significant reduction in relief in average pain intensity on days with pain vs. the control group (P=0.006).

Presenter

If study participants experienced any pain on a given day, they were asked to record the average pain intensity they experienced that day. The results of the baseline one-month diary record (pre-implant) were averaged to give the baseline measure; and the one-month diary taken at the end of the 12-weeks blinded study were averaged to give the 12 week measure. At baseline there was no significant difference between the groups (P=0,221). But at 12-weeks, the difference was highly significant (P=0,006). The active group had significantly greater relief in average pain intensity on days with pain than the control group.


Baseline

Mean (± std) 152,7 (± 77,1) 158,4 (± 76,8) 0,664

Week 12

Mean Change1 -20,4 -64,6 <0,001

Difference (95% CI) -44,1 (-65,4, -22,9)

Mean Baseline and Change From Baseline in the MIDAS Headache Questionnaire Sum of Items 1 – 5—Last Value Carried Forward

The Migraine Disability Assessment (MIDAS) is a questionnaire which measures headache-related disability during the previous 90 days based on five disability questions.


The MIDAS questionnaire was completed at baseline and 12 weeks after the system was implanted. The reduction in disability of 44.1 days between the groups is statistically significant (p<0.001).

Presenter

The Migraine Disability Assessment (MIDAS) questionnaire is probably the most widely used migraine measurement tool. It measures how many life-days patients miss, due to migraine. It considers days lost in terms of work/school days, household work days and social activity days. It also considers days where significant productivity (50+%) was lost at work/school or household work over the 90 day period. The worst possible score is 270 (90 days lost in work/school + 90 days lost in household work + 90 days lost in social activities). These results show that over the course of the controlled study, the active group improved significantly more than the control group, with the average active MIDAS score declining 64,6 compared to a 20,4 reduction in the control group.

The differences reported between the Active and Control Groups for both measures were statistically significant (p<0,001).

17,2%

42,1%

0%

20%

40%

60%

80%

100%

Percentage of Pain Relief Since Surgery

Control Group (n=52) Active Group (n=105)

19,2%

51,4%

0%

20%

40%

60%

80%

100%

Percentage of Patients Satisfied With Headache Relief

Control Group (n=52) Active Group (n=105)

Active group participants reported (on average) 42,1% pain relief and 51,4% of them were satisfied with their level of pain relief.

Presenter

Finally, patients were asked what percentage of pain relief they had experienced over the course of the 12-week study, and whether or not they were satisfied with that level of pain relief. Active group participants achieved (on average) 42,1% pain relief and 51,4% of them were satisfied with their level of pain relief. This was significantly better than the control group which reported 17,2% pain relief on average; only 19,2% of the control group was satisfied with the pain relief they experienced.

Adverse Event + Total

(N=153) n (%)

Lack of efficacy/return of symptoms 15 (9,8%)

Persistent pain and/or numbness at IPG/lead site 15 (9,8%)

Normal battery depletion 12 (7,8%)

Unintended stimulation effects 10 (6,5%)

Lead migration 9 (5,9%)

Battery failure 8 (5,2%)

Lead breakage/fracture 5 (3,3%)

Infection 4 (2,6%)

Battery passivation 3 (2,0%)

Device malfunction–programmer 3 (2,0%)

A total of 76 patients experienced one or more anticipated adverse events during the first open label study phase (50 in the Active group and 26 in the Control group).

A total of 114 adverse events occurred in these 78 patients. All events were reviewed and classified into the appropriate category. According to this classification, 42 events were classified as hardware-related, 28 events were classified as biological-related, 28 events were classified as stimulation-related, and 16 events were classified as non-device/procedure-related.

Adverse Event + Total

(N=153) n (%)

Nausea/vomiting 3 (2,0%)

Expected post-‐op pain/numbness at IPG/lead site 2 (1,3%)

Skin erosion 2 (1,3%)

Hematoma 1 (0,7%)

Seroma 1 (0,7%)

Wound site complications 1 (0,7%)

Pain or swelling at IPG site–trauma-‐related 1 (0,7%)

Allergic reaction to surgical materials 1 (0,7%)

Device malfunction–IPG 1 (0,7%)

IPG migration 1 (0,7%)

Presenter

The most common biological adverse event was persistent pain and/or numbness at the IPG/lead site (9,8%)

Anatomical Convergence of Trigeminal and Cervical input

MECHANISM OF ACTION

Functional Convergence of Trigeminal and Cervical input

Bartsch et al, Brain 2002

MECHANISM OF ACTION

1. Effect at Segmental level

Gate-Control Theory of Pain Activation of somatosensory afferent A- nerve fibres blocks nociceptive transmission at a segmental level

2. Involvement of Supraspinal

Structures

Gate control at supraspinal level Activation of descending antinociceptive pathways

3. Neuroplasticity

MECHANISM OF ACTION

Paraesthesia-related rCBF changes

Significant activation in the dorsal rostral pons, anterior cingulate cortex and left pulvinar

Matharu et al, Brain 2004

MECHANISM OF ACTION

Patients with chronic migraine are often left without effective treatment, leading lives that are painful and compromised.1

Occipital nerve stimulation involves a minimally invasive surgical procedure.

While the body of evidence is still emerging, ONS appears to be promising in managing the pain and disability of intractable chronic migraine.

Frequent causes of adverse events are related to lead migration.

Predictors of response and long-‐term outcome are largely unknown

Reserved for medically-‐intractable and highly disabled patients

Performed in experienced headache centres

1. Saper JR, Dodick DW, Silberstein SD, McCarville S, Sun M, Goadsby PJ; ONSTIM Investigators. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia. 2011;31(3):271-285.

Category Adverse Event + Total

(N=153) n (%)

Patients with one or more anticipated AE 76

Hardware-‐Related

Normal battery depletion 12 (7,8%)

Lead migration 9 (5,9%)

Battery failure 8 (5,2%)

Lead breakage/fracture 5 (3,3%)

Battery passivation 3 (2,0%)

Device malfunction–programmer 3 (2,0%)

Device malfunction–IPG 1 (0,7%)

IPG migration 1 (0,7%)

Stimulation-‐Related

Lack of efficacy/return of symptoms 15 (9,8%)

Unintended stimulation effects 10 (6,5%)

Nausea/vomiting 3 (2,0%)



Presenter

The most common hardware related adverse event was normal battery depletion (7,8%) The most common stimulation related adverse event was lack of efficacy or return of symptoms (9,8%)

Category Adverse Event + Total

(N=153) n (%)

Patients with one or more anticipated AE 76

Biological

Persistent pain and/or numbness at IPG/lead site 15 (9,8%)

Infection 4 (2,6%)

Expected post-‐op pain/numbness at IPG/lead site 2 (1,3%)

Skin erosion 2 (1,3%)

Hematoma 1 (0,7%)

Seroma 1 (0,7%)

Wound site complications 1 (0,7%)

Pain or swelling at IPG site–trauma-‐related 1 (0,7%)

Allergic reaction to surgical materials (sutures, antibiotic, anesthesia) 1 (0,7%)

Non-‐Device-‐Related Other 16 (10,5%)



Presenter

The most common biological adverse event was persistent pain and/or numbness at the IPG/lead site (9,8%)

65

Patient selection for successful therapy Zaza Katsarava

Headaches

Headache = 80% Migraine = 15-18% TTH = 30-70% Chronic headache 3-4%

Chronic Headache

Chronic Headache = HA

The reasons to define chronic vs. episodic HA Individual burden Burden of social environment Co-morbidities Costs

Chronic Headache

The prevalence of chronic headache is about 3-4% For systemic review see Stovner et al, 2006

69

After Secondary Causes Are Ruled

Out

Episodic Headache Frequency <15

days/month

Short-Duration Chronic Daily

Headache Duration <4 hours or

multiple discrete episodes

Chronic Daily Headache (Long

Duration) Daily or near-‐daily

headache lasting

Chronic Tension-

Type Headache

New Daily Persistent Headache

Hemicrania Continua

Silberstein SD et al. Neurology. 1996;47:871-‐875. Dodick D. N Engl J Med. 2006;354:158-‐165.

With or Without Medication

Overuse

Chronic Headache Frequency

days/month

Primary Headache Disorders

Chronic Migraine

Presenter

Primary chronic daily headache (CDH) of long duration is a syndrome characterized by headaches not attributable to a secondary disorder that last more than 4 hours a day and occur 15 or more days per month.1-3 This syndrome affects 4% of the general population and 30% to 84% of patients seen in headache clinics.3 The criteria most frequently used to classify primary chronic daily headache of long duration are those proposed by Silberstein and Lipton.1 According to these criteria, the chronic daily headache syndrome encompasses 4 main diagnoses: Chronic migraine Chronic tension-type headache New daily persistent headache Hemicrania continua These subgroups are further divided into those with and without medication overuse. References: 1. Silberstein SD, Lipton RB, Sliwinski M. Classification of daily and near-daily headaches: field trial of revised IHS criteria. Neurology. 1996;47:871-875. 2. Dodick D. Chronic daily headache. N Engl J Med. 2006;354:158-165. 3. Bigal ME, Lipton RB, Tepper SJ, Rapoport AM, Sheftell FD. Primary chronic daily headache and its subtypes in adolescents and adults. Neurology. 2004;63:843-847.

70

CM = migraine on 15 days/month CTTH = TTH on 15 days/month

71

Visu

al a

nalo

gue

scal

e

Visu

al a

nalo

gue

scal

e

72

Visu

al a

nalo

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scal

e

Visu

al a

nalo

gue

scal

e

73 Vi

sual

ana

logu

e sc

ale

time

With migraine features

Without migraine features

With migraine features

Without migraine fetures

Triptan

Migraine

TTH? Abortive Migraine? TTH

Abortive Migraine

74

IHS 2004, CM = migraine on 15 days/month No medication overuse Diary is needed Rely on patients recall Too restrictive

75

IHS 2006, CM =

Migraine HA on 8 HA days is migraine No medication overuse

76

Allergan, PREEMPT, CM =

Migraine HA on 50% is migraine

77

American way to do it, Silberstein-‐Lipton CM =

Migraine HA on

No diary is needed

78

Mail/phone interviews

Population-based sample N = 18,000

9968 respondents Response rate = 63.4%

Annual follow-ups

Presenter

The German Headache Consortium (GHC) study is a population-based, longitudinal cohort study which aims to investigate the prevalence and incidence of chronic headaches within the general population of Germany. The study population comprised a random sample of 16,500 inhabitants of 3 regions in Germany: Essen, a large town (population 585,481) in the North Rhine-Westphalia region in western Germany; Münster, a middle-sized town (population 272,890) in western Germany ; and the rural area of Sigmaringen, a small town with a population of 16,501 and 20 surrounding villages in the south Germany. Study participants had to be aged between 18 and 65 years. All participants received a mail questionnaire . In cases of nonresponse, a reminder was sent 2 weeks later. Subjects who still did not respond were repeatedly called and asked by trained medical students for a phone interview to be performed based on the same questionnaire. Following 8 unsuccessful calls, subjects were considered nonresponders. Individuals who refused to complete the interview either by mail or by phone were also considered nonresponders. Reference Katsarava Z et al. Migraine Trust 2008 Poster.

79

1. Katsarava et al. Cephalalgia, 2011. 2. Olesen J et al. Cephalalgia.

2006;26(6):742-746. 3. Silberstein SD et al. Headache.

1994;34:1-7.

Chronic Migraine definition IHS, 2006 ( migrainous) ICHD-2 definition2

Chronic Migraine definition S-L ( migrainous) Silberstein-Lipton Criteria3

2.8%

Chronic Migraine definition PREEMPT ( migrainous)

1.9% 0.5%

0.4%

Chronic Daily Headache (

Presenter

The German Headache Consortium mailed questionnaires to a random sample of 15,705, 18- to 65-year-olds in Germany. Four definitions were compared: chronic migraine I (at least 15 headache/days a month with at least 50% of headaches being migraine or probable migraine), chronic migraine II (at least 15 headache days/month with at least 8 migraine or probable migraine days), chronic migraine III (at least 15 headache days/month with any migraine or probable migraine days), and chronic headache (at least 15 headache days/month). Results were stratified by medication overuse, defined as intake of acute headache drugs on at least 15 days/month. There were 9,968 respondents, for a response rate of 63.4%. The definition of chronic migraine I was the most restrictive (prevalence 0.4%; medication overuse=27%), followed by chronic migraine II (prevalence 0.5%; medication overuse=31%), chronic migraine III (prevalence 1.9%; medication overuse=11%), and chronic headache (prevalence 2.8%; medication overuse 12%). Epidemiologically, all groups were fairly similar: females (chronic migraine I=70%; chronic migraine II=69%; chronic migraine III=71%; chronic headache=64%), mean age: 44-46 years (±14), mean BMI 25.3-26.5, and low (non-high school) education chronic migraine I=70%; chronic migraine II=73%; chronic migraine III=78%; chronic headache=72%). Chronic migraine prevalence varies by case definition. Chronic migraine I is a subset of chronic migraine II, which is in turn a subset of chronic migraine III, and all are subsets of chronic headache. Optimal definitions of chronic migraine for use in clinical practice and epidemiologic research will require additional field testing. Reference Katsarava et al. Migraine Trust 2008 Abstract.

CM according to S-L = 185

IHS MIG criteria

TTH criteria

IHS CM = 45

The rest, 185 – 45 = 140

IHS TTH = 40

What is the rest? N = 100

81

CM is NOT just more MIG

82

Definition Females Age BMI Low

Education Medication Overuse*

CM-‐I ( 70% 44 26.4 70% 27%

CM-‐II (migrainous, including overuse) 69% 45 26.5 73% 31%

CM-‐III ( any migrainous) 71% 46 25.9 78% 11%

High-‐frequency EM (9-‐14 days/month) 70% 40 24.3 66% 13%

Low frequency EM (0-‐8 days/month) 66% 40 24.1 60% 16%

Katsarava et al. Migraine Trust 2008. Abstract. GHC = German Headache Consortium.

Presenter

The 3 different case definitions have similar demographics. This study and the previous slide show that no matter which definition we use, chronic migraine has consistent demographics but there are differences in the profiles of chronic migraine and episodic migraine. Medication overuse is highest in patients with CM with more headaches having migrainous features. Reference Katsarava et al. Migraine Trust 2008. Abstract

83

41

31 3026

1519

0

10

20

30

40

50

60

70

Allergies or Hay Fever

Sinusitis Asthma Bronchitis Depression Chronic Pain

Anxiety High Blood Pressure

High Cholesterol

Obesity Arthritis

Chronic migraineEpisodic migraine

Buse D et al. J Neurol Neurosurg Psychiatry. 2010; In press.

%

*p<0.05.

Data from the American Migraine Prevalence and Prevention (AMPP) study.

*

*

* *

* *

*

* * *

*

• Chronic migraine was defined as reported ICHD-2 diagnosis of migraine and days/month

Presenter

Across the board there are higher rates of comorbidities with chronic migraine than with episodic migraine.1 Reference: 1. Buse D, Manack A, Serrano D, Turkel C, Lipton R. Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry. 2009; In press.

9944 responders (of 18.000 = 55%) Prevalences:

HA : cHA = 255, eHA = 5361, noHA = 4040, missing = 288 MIG : cMIG = 108, eMIG = 1601, noHA = 4030, 4205 excluded TTH : cTTH = 50, eTTH = 1203, noHA = 4030, 5283 excluded Combination of MIG and TTH and unclassifiable excluded Chronic back pain = 1290

84

Presenter

85

N cBP OR 95% CI

No HA 3259 316 (9.6%) Referent = 1

Episodic HA 4903 807 (16.5%) 2.3 2.0 – 2.7

Chronic HA 229 146 (63.7%) 14.5 10.7 – 20.0

Age (in years) 1.03 1.02 – 1.04

Males 3925 489 (12.5%) Referent = 1

Females 4466 801 (17.9%) 1.4 1.2 – 1.6

No daily drinking 7437 1125 (15.1%) Referent = 1

Daily drinking 954 143 (15.0%) 1.1 0.9 – 1.4

No smoking 5850 808 (13.8%) Referent = 1

Smoking 2541 466 (18.3%) 1.4 1.2 – 1.6

High education 2879 279 (9.7%) Referent = 1

Low education 5512 981 (17.8%) 1.6 1.3 – 1.8

BMI 4667 602 (12.9%) Referent = 1

BMI 25-‐30 2717 417 (15.3%) 1.1 1.0 – 1.3

BMI 1007 239 (23.7%) 1.8 1.5 – 2.1

Presenter

86

N cBP OR 95% CI

No Headache 3238 314 (9.7%) Referent = 1

Episodic MIG 1462 279 (19.1%) 2.6 2.1 – 3.2

Chronic MIG 100 66 (66%) 15.8 10.2 – 24.5

Age (in years) 1.03 1.02 – 1.04

Males 2410 250 (10.4%) Referent = 1

Females 2390 409 (17.1%) 1.4 1.1 – 1.7


Daily driking 608 67 (11.0%) 0.97 0.7 – 1.3


Smoking 1471 243 (16.5%) 1.5 1.2 – 1.8


Low education 3327 520 (15.6%) 1.6 1.3 – 2.0

BMI 2556 304 (11.9%) Referent = 1

BMI 25-‐30 1622 214 (13.2%) 1.1 0.9 – 1.3

BMI 622 124 (19.9%) 1.6 1.2 – 2.0

Presenter

87

N cBP OR 95% CI

No Headache 3238 314 (9.7%) Referent = 1

Episodic TTH 1104 170 (15.4%) 2.1 1.7 – 2.7

Chronic TTH 47 29 (61.7%) 13.7 7.4 – 25.3

Age (in years) 1.03 1.02 – 1.04

Males 2435 247 (10.1%) Referent = 1

Females 1954 266 (13.6%) 1.4 1.1 – 1.7


Daily driking 618 79 (12.8%) 1.2 0.9 – 1.6


Smoking 1295 176 (13.6%) 1.4 1.1 – 1.7


Low education 3013 397 (13.2%) 1.5 1.2 – 1.9

BMI 4923 207 (4.2%) Referent = 1

BMI 25-‐30 2857 188 (6.6%) 1.3 1.02 – 1.6

BMI 1067 102 (9.6%) 2.0 1.5 – 2.6

Presenter

Central sensitization Blink reflex and pain evoked potentials in MOH Transient increase, normalizing again after withdrawal (Ayzenberg et al. 2006)

101520253035404550

Controls

Ep migraine

Triptan MOH

Analgesic MOH

Triptan MOH

Analgesics MOH

3. Release of pain-enhancing neuropeptides, such as CGRP

5. Activation of cortical pain centers via thalamus

Thalamus

4. Activation of trigeminal nucleus caudalis can result in central sensitization

Spinothalamic track

Trigeminal Nerve

Trigeminal Gangli

on

TNC

2. Stimulation of meningeal sensory nerve (trigeminal)

Vessel dilation

Nerve

Peptide release

Inflammation

6. PAIN

CGRP = calcitonin gene-related peptide; TNC = trigeminal nucleus candalis.

1. Pietrobon D et al. Nat Rev Neurosci. 2003;4:386-398.

2. Pietrobon D. Neuroscientist. 2005;11:373-386.

1. Central disinhibition

Presenter

[NOTE TO SPEAKER: This slide is a build.] Current evidence indicates that cortical spreading depression (CSD) is the most probably primary event in trigeminovascular system (TGVS) activation in migraine with aura and, perhaps, also migraine without aura.1 [Build 1] CSD leads to the release of a variety of substances in the extracellular fluid in the cortex, including neuropeptides such as calcitonin gene-related peptide (CGRP) and glutamate as well as K+ ions, H+ ions, nitric oxide (NO), arachidonic acid, and prostaglandins.2 [Build 2] May directly activate and/or sensitize the meningeal trigeminovascular afferents.2 [Build 3] Central sensitization: the sustained firing of sensitized meningeal nociceptors leads to the activation and sensitization of second-order central TGV neurons (in the nucleus caudalis).2 [Build 4] Ultimately resulting in the activation of cortical pain centers and additional activation of the TGVS.2 [Build 5] Activation of neurons in structures involved in the processing and perception of pain like the thalamus, the caudal periaqueductal gray region (PAG), and the cortex.2 References: 1. Pietrobon D, Striessnig J. Neurobiology of migraine. Nat Rev Neurosci. 2003;4:386-398. 2. Pietrobon D. Migraine: new molecular mechanisms. Neuroscientist. 2005;11:373-386.

Post-traumatischer Kopfschmerz Reversible VBM changes in chronic posttraumatic headache

Presenter

We then set out to show gray matter changes related to the development of chronic headache over time. We investigated patients that developed chronic headache after whiplash injury due to minor car accident. These are mostly young, generally healthy individuals before the accident, that then develop daily or near daily headache after a motor vehicle accident. We again performed high-resolution MRI for voxel based morphometry at baseline (which was within the first 14 days after the accident), after 3 months (following IHS definition criteria for chronic headache associated with whiplash injury), and again after one year. Longitudinal analysis of chronic patients at baseline and after 3 months revealed gray matter decrease in the anterior cingulate cortex (ACC) [x=+14, y=+22, z=+40] and dorsolateral prefrontal cortex (DLPFC) [x=-43, y=+16, z=+51] after three months. These changes resolved almost completely after one year as the pain subsided in most patients.

Transformation is often gradual and can evolve over several months or years1,2

Transformation is neither inexorable nor irreversible; spontaneous or induced remissions are possible and common1,2

Transformation happens in some but not all episodic patients (~3% of episodic migraine sufferers)2

91

1. Lipton RB. Neurology. 2009;72:S3-S7. 2. Bigal ME, Lipton RB. Curr Opin Neurology

2008;21:301-308.

No migraine

Low-frequency episodic migraine

High-frequency episodic migraine

Chronic migraine

Presenter

This slide presents a conceptual framework for understanding the potential transitions in migraine. Episodic migraine may progress to chronic migraine, and chronic migraine patients may experience remission to episodic migraine.1,2 We will first focus on the progression of episodic migraine to chronic migraine. References: 1. Lipton RB. Tracing transformation: Chronic migraine classification, progression, and epidemiology. Neurology. 2009;72:S3-S7. 2. Bigal ME, Lipton RB. The prognosis of migraine. Curr Opin Neurology. 2008;21:301-308.

Right diagnosis Multimodal approach

Patient education Psychological co-morbidities Physiotherapy

Stop medication overuse (if any) Preventive medication

Topiramate, BOTOX Betablockers, Valproate etc.

Right diagnosis

Do not miss secondary headache Do not mix CM and CTTH Do not miss MOH Do consider psychiatric co-morbidities

??? Medication overuse headache

Chronic headache with medication overuse

http://www.hoentzsch.com/pics/anwendungen/tabletten.jpg

Suggestion for IHS classification

17. Chronic migraine due to ..... 17.1. divorce 17.2. hyperactive child 17.3. sick and bed fasted parent 17.4. ………….

http://docs.gimp.org/2.2/images/filters/examples/render-taj-maze.jpg

1. Diener HC, Limmroth V. Lancet Neurol. 2004;3:475-483. 2. Katsarava Z et al. Curr Neurol Neurosci Rep. 2009, 9:115-119.

Medication Overuse1,2

Preventive Therapy Detoxification

* 15 days/month: simple analgesics, combinations of drugs; or 10 days/month: combination analgesics, ergotamines, triptans, opioids, barbiturates.

Presenter

The goals for treating and managing medication overuse should be to reduce the frequency and/or severity of headache, reduce acute medication consumption, improve responsiveness to treatments, alleviate disability, improve quality of life, and prevent relapse into overuse. Standard strategies for medication overuse management include withdrawal of the overused medication, and initiation of migraine preventive.1 Either detoxification or preventive therapy can be used in patients with medication overuse but if patients fail with either approach the alternative should be tried.2 References: 1. Katsarava, Z et al. Medication overuse headache. Curr Neurol Neurosci Rep. 2009;9:115-119. 2. Diener HC, Limmroth V. Medication-overuse headache: a worldwide problem. Lancet Neurol. 2004; 3: 475-483.�

Education Withdrawal Preventive medication Psychological treatment Follow up

4

Diener HC, Limmroth V. Lancet Neurol. 2004;3:475-483.

Single analgesic Combination analgesics

Ergotamines Triptans

Days of Withdrawal Therapy

0 1 3 4 5 6 7 8 9 10 11 12 2 13 14

100 90 80 70 60 50 40 30 20 10

Patie

nts

With

Hea

dach

e (%

) 3

2

1

0

Hea

dach

e In

tens

ity

Days of Withdrawal Therapy 1 3 5 6 7 8 9 10 11 12 2 13 14

Presenter

This slide shows the course of headache intensity (left) and percentage of patients with headache (right) during 14 days of withdrawal therapy after a diagnosis of medication overuse.1 Patients who overuse triptans are very responsive to withdrawal of medication and tend to respond well to this strategy.1 Reference: 1. Diener HC, Limmroth V. Medication-overuse headache: a worldwide problem. Lancet Neurol. 2004;3:475-483.

Hagen K et al. Cephalalgia. 2009;29:221-232.

Controls Abrupt withdrawal only Prophylaxis from the start

Months Following Withdrawal

No.

of H

eada

che

Day

s/M

onth

30

25

20

15

10

5

0 0 2 3 4 5 6 7 8 9 10 11 12 1

Prophylaxis from the start

Controls Abrupt withdrawal only

Month 3 Month 5 Month 12 0

10

60

50

40

30

20 Pa

tient

s Ex

hibi

ting

a 50

% R

educ

tion

in

Hea

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e D

ays/

Mon

th

(%)

P = 0.01

Months Following Withdrawal

Presenter

In a study to determine whether patients did better with preventive treatment initiated prior to discontinuation of medications or whether abrupt withdrawal provided the same results, it was shown that starting preventive treatment prior to withdrawal resulted in better outcomes. Fifty-six patients were analyzed in a 1-year, open-label, multicenter study. Subjects were randomly assigned to receive prophylactic treatment from the start without detoxification, undergo a standard outpatient detoxification program without prophylactic treatment from the start, or no specific treatment (5-month follow-up).1 The number of headache days at baseline per month did not differ significantly between groups. The prophylaxis group had the greatest decrease in headache days compared to baseline, and also a significantly more pronounced reduction in total headache index (headache days/month x headache intensity x headache hours) at Months 3 (P=0.003) and 12 (P=0.017) compared with the abrupt withdrawal group. At Month 12, 53% of patients in the prophylaxis group had at least 50% reduction in monthly headache days compared with 25% in the abrupt withdrawal group (P=0.081).1 The study shows that early preventive treatment without a previous detoxification program reduced total headache suffering more effectively than abrupt withdrawal.1 Medication-overuse treatment recommendations2: Fluid replacement Analgesics Tranquilizers Neuroleptics Amitriptyline Valproate Intravenous dihydroergotamine Cortisone Metoclopramide or domperidone Reference: 1. Hagen K, Albretsen C, Vilming ST, et al. Management of medication overuse headache: 1-year randomized multicentre open-label trial. Cephalalgia. 2009;29:221-232. 2. Diener HC, Limmroth V. Medication-overuse headache: a worldwide problem. Lancet Neurol. 2004;3:475-483.

1. Everything that is true for conservative treatment is also true for ONS

1. Education 2. Realistic goals 3. Take your time 4. Give time to patients

Conservative treatment

1. Betablocker (Metoprolol 100-200mg) 2. Calcium channel antagonist (Flunarizine 5-10mg) 3. Valproic acid 600-900mg 4. Topiramate 50-200mg 5. BOTOX

Topiramate Efficacy Mean Change in Headache Days 0.7

0.20.1

-0.6

0.5

-3.5*

-5.4**-4.7**

-2.9-3.0*

-6-5-4-3-2-1012

Wk 4 Wk 8 Wk 12 Wk 16 Last 4 wks

Placebo TopiramatePrimary endpoint

* p < 0.05 vs placebo ** p < 0.01 vs placebo

26 25 20 15 27 32 30 25 24 32

Patients

BOTOX Efficacy Mean Change in Headache Days

Peripheral Nerve Stimulation for the Management of Intractable Chronic Migraine Implant Techniques

Laurence Watkins Consultant Neurosurgeon National Hospital for Neurology & Neurosurgery, London

Intractable Chronic Migraine Course, Leiden February 2012

Introducing a novel procedure

Theoretical background and peer support Registered with NICE (on hold until CE mark awarded)

Likely to now “re-‐visit” guidance Business case to Trust – novel procedures protocol Support from Trust management, R&D, host PCT (Funding Body) Cadaveric workshops Developing a PCT “application pack” and a strict protocol for

Multidisciplinary assessment Rigorous consent procedure so that patients are aware of relative novelty of the procedure Documented audit of complications and outcome

First Meeting (with implanter)

Check have been fully assessed in Headache Neurology Clinic (chronic, disabling, intractable) General fitness & airway satisfactory; reflux? MRI ? (because can’t have MRI once ONS is implanted) Any major surgery planned ? (because restriction of monopolar diathermy once ONS implanted) Explaining procedure

Discussion with patient

Known risks: may not help infection requiring removal of implant electrode migration neck stiffness breakage or failure of components tethering to skin or muscle skin erosion

Clearance from Funding Body/PCT

Hospital Stay

Typically 3-‐4 days, but could be reduced if pre-‐op assessment, implant activation and patient education all done in clinic Postoperative programming of the implant Teaching patient to use the “handset control” +/-‐ recharger

Follow up clinics

Typically 4 in first year Joint assessment with Headache Neurologist and Specialist Nurse, additional post-‐operative appointments in Neurosurgery Clinic. Sometimes all combined in day care unit Gradually refine the settings to get best response (headache diary), without patient discomfort

Stages of the operation

Insertion of electrodes LA + Sedation

Test stimulation of electrodes Awake

Insertion of battery and tunnelling of leads Asleep (GA with LMA)

Alternatively GA throughout if difficult airway or reflux (or patient preference)

USA: 2 stage procedure

Occipital Nerve Anatomy PNS electrode should overlay the course of the occipital nerves Epifascial plane Direction of insertion

Medial to lateral Lateral to medial

Fluoroscopic control Anchoring

Lead Placement (Anchor Midline)

Occipital Nerve Anatomy PNS electrode should overlay the course of the occipital nerves Epifascial plane Direction of insertion

Medial to lateral Lateral to medial

Fluoroscopic control Anchoring

Main technical challenges

Placing electrodes to get paraesthesiae Anchoring/looping the electrodes Minimising infection risk Not “instant” result so can’t really do “trial electrodes”

Technique first described for Occipital Neuralgia

Then for Transformed (Chronic) Migraine

Lead Placement (Anchor at Mastoid)

Procedural Details

Procedural Details

Procedural Details

Anchoring the Electrodes

Attach to the hard underlying fascia Use non-‐absorbable sutures Choice of anchor

long (tubular) anchor, butterfly anchor others commercially available

Anchor direction—no kinks Loops at “every level” (cervical, chest and behind IPG)

Lead Tunneling and IPG Placement: Gluteal, Infraclavicular, or Abdominal

CAUTION: It is important to place strain relief loops at the site of the lead-extension connection and at the IPG connection.

Migraine Study Key Adverse Events Summary

Adverse Event Controlled Phase Open-Label Phase

Persistent pain, numbness at implant site 23 (15%) 15 (10%)

Lead migration 20 (13%) 9 (6%)

Unintended stimulation effects (migration?) 7 (4%) 10 (7%)

Infection 7 (4%) 4 (3%)

Skin erosion 6 (4%) 2 (1%)

Lead breakage, fracture 2 (1%) 5 (3%)

“Out” Migration

Migration of occipital nerve stimulation electrode leads Both left and right leads have migrated away from their original position Try reprogramming prior to revision surgery

Extreme “Out” Migration

“Extreme” migration of occipital nerve stimulation electrode lead The electrode lead has migrated all the way toward the generator pocket

“In” Migration

“In” migration of the occipital nerve stimulation electrode lead. A. Original electrode lead position, B. Electrode position 8 month after insertion

with “in” migration to the contralateral side of the neck

A. B.

Insertion Plane Too Deep Too Superficial

Skin Erosion

PRECAUTION: Skin Erosion—Because PNS leads used to aid in the management of intractable chronic migraine are placed under the skin, be careful to place the lead at the appropriate depth to avoid the risk

of skin erosion.

Erosion of occipital nerve stimulation electrode lead

Minimizing the Possibility of Erosion—Electrode Insertion Plane

Minimizing the Risk of Infection Meticulous aseptic technique, closed gloving Perioperative antibiotics Avoid excessive tissue dissection Meticulous hemostasis Appropriate size of incision

not too small not too large

Avoid over-‐tightening of sutures

Wound edge antisepsis Glove change/clean before handling implant Local gentamicin, triclosan impregnated sutures

PRECAUTION: Infection—Follow proper infection control procedures. Infections related to system implantation might require that the device be explanted.

CE marking does not necessarily indicate regulatory approval status for all markets. Please refer to the instructions for use for a full listing of indications, contraindications, warnings and precautions. Genesis is a trademark of Advanced Neuromodulation Systems, Inc d/b/a St. Jude Medical Neuromodulation Division. ST. JUDE MEDICAL, the nine-squares symbol, and MORE CONTROL. LESS RISK. are trademarks and service marks of St. Jude Medical, Inc. and its related companies.

Safety and Trademark Information

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Right diagnosis Patient education Multimodal treatment Psychological evaluation if necessary Preventive medication (as mentioned above) BOTOX Neuromodulation

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Management of patients after implantation Zaza Katsarava

Before implantation

The diagnosis was right All conservative options were not successful Illness behavior / secondary benefit was excluded ONS pro/contra were discussed

Realistic goals Possible side effects

After implantation

Am I cured? No you are not Medical treatment should be continued

Our experience

Cen Eur Neurosurg 2011; 72(2): 84-89

ONS Cluster HA in Essen

10 patients with chronic intractable CH Prospective re-evaluation of treatment non response

Chronic Verapamil 450, topiramate 150, Lithium plasma therapeutic range Alone or in combination

Psychological evaluation



Daily attack frequency 6 (2-14) vs. 3 (0.4-11)

Intensity 8 (6-9) vs. 6 (2-9)

Positive effects

Frequency of cluster attacks declined first 7 patients reduced the number acute medication 7 patients became responsive to oxygen 3 patients decreased preventive medication

Exacerbations

7 patients had a temporary exacerbation bouts lasted between 3-6 weeks Increase of preventive medication Prednisone pulse therapy

Complications

7 patients had a temporary exacerbation bouts lasted between 3-6 weeks Increase of preventive medication Prednisone pulse therapy

neurologist

complications

local infection in one patient Explantation and re-implantation

Dislocation of the electrode in 1 patients

Sensations in a “wrong” place Innervation of muscles

Scare formation around the thoracic connector 1patient

Discomfort Re-operation

complications

Patients with abdominal generator experienced feeling of pressure when they carried heavy objects Patients with gluteal generator experienced feeling of a “foreign body” on an uncomfortable chair

Neurosurgeon

Conclusion

ONS Treatment is a team work

Neurologist Neurosurgeon psychologist Nurse

Pathways for Therapy Success

Dr Denys FONTAINE Hopital Pasteur, Centre Hospitalier Universitaire de Nice FRANCE

Objectives

• to increase the success rate

• to decrease the complication rate

• to manage the eventual complications

• to improve the patient access to therapy

Selection of the patients

• done by a neurologist specialized in headache disorders

• be sure of your diagnosis

• avoid medication overuse headache

• avoid patients looking for secondary benefit

• avoid psychiatric co-morbidities

Information to the patients

• explain the principles / advantages / disadvantages

• device implanted, surgery

• chronic perception of paresthesias

• potential recharge process

• reasonable / realistic expectations

• global rate of improvement : 30 %

• delayed response (several weeks or months)

• attack frequency, days without migraine

• random efficacy

• possibility of complications

• possibility of hardware explantation

• informed consent

Surgery

ELECTRODES IMPLANTATION TECHNIQUES

Principles ONS electrode should overlay the course of the occipital nerve(s) right spot Epifascial plane Anchoring Tunnelization Unilateral / bilateral IPG adapted to your electrode(s) Trained neurosurgeon

Too superficial : skin erosion, lead externalization

Too deep : muscle contraction, spasms, neck stiffness, discomfort

• Attach to the hard underlying fascia Use anchor or sutures placed directly on the

lead without an anchor (but do not use monofilament or polypropylene) • use 2 loops: one in the retromastoid incision and one in the lower cervical incision to allow lead extension during neck movements

• attach the lead above the superior one, and below the inferior one

• avoid sharp bends to avoid lead fracture

Perioperative antibiotics Avoid excessive tissue dissection Meticulous hemostasis Avoid over-‐tightening of the sutures Plan exit site of trial electrodes to avoid crossing the path of permanent device and respect sufficient delay between trial and definitive implantation

respect the patients’ choice (esthetical considerations, preexisting devices, scars, …) and your personal preference one or two step according to the patient operating position anticipate the movements of the neck and trunk / elongation of the lead anticipate the need of recharge process

After the operation

Post-surgical management

• identify early the eventual complications

• do not hesitate to re-operate early in case of migration, infection, hardware dysfunction

• follow up by the neurologist and the surgeon, in close contact

• adaptation of the medication according to the ONS outcome

Patient education

• initial parameters setting by the team : surgeon / neurologist, eventually a clinical nurse and/or company assistant

• use of the remote control use and eventually recharge process

• identify one privileged contact (Nurse +++): telephone number or email address in case of problem with the therapy itself

• especially if patients are referred from far away

Patient journey

• neurologist: identification of candidate patient with CIM • discussion about the therapy, principles, potential benefits and constraints • visit with the surgeon : repetition of the information, surgical risks, consent • surgery • parameters setting : contact and education with the clinical nurse / company

• post op surgeon visit: assessment of eventual complications, compliance with the device / therapy • post op neurologist visit: adaptation of the medication, follow-up

• registry

The surgeon personal point of view

• importance of a multidisciplinary cohesive team (we cannot manage these patients alone)

• recruitment, selection, medication, follow-up neurologist • surgery, surgical complications surgeon • parameters setting, first line safety support clinical nurse

• having a key contact with company who can support and ensure logistics go well

• identify the hardware (labeling is not so clear) and do not change it frequently once you have done your own choice

• this surgery is simple and successful if you follow few rules and avoid the pitfalls

• patients with chronic primary headache are usually less complex to manage than patients with chronic neuropathic pain, but not always

178

Developing referral networks Zaza Katsarava

Headaches

Headache = 80% Migraine = 15-18% TTH = 30-70% Chronic headache 3-4%

WHO’s Global Burden of Disease Study (GBD) 2000

inclusion of migraine, but not tension-type headache

181

Mail/phone interviews

Population-based sample N = 18,000

9968 respondents Response rate = 63.4%

Annual follow-ups

Presenter

The German Headache Consortium (GHC) study is a population-based, longitudinal cohort study which aims to investigate the prevalence and incidence of chronic headaches within the general population of Germany. The study population comprised a random sample of 16,500 inhabitants of 3 regions in Germany: Essen, a large town (population 585,481) in the North Rhine-Westphalia region in western Germany; Münster, a middle-sized town (population 272,890) in western Germany ; and the rural area of Sigmaringen, a small town with a population of 16,501 and 20 surrounding villages in the south Germany. Study participants had to be aged between 18 and 65 years. All participants received a mail questionnaire . In cases of nonresponse, a reminder was sent 2 weeks later. Subjects who still did not respond were repeatedly called and asked by trained medical students for a phone interview to be performed based on the same questionnaire. Following 8 unsuccessful calls, subjects were considered nonresponders. Individuals who refused to complete the interview either by mail or by phone were also considered nonresponders. Reference Katsarava Z et al. Migraine Trust 2008 Poster.

Preventive treatment in Migraine

7% of MIG patients had preventive medication 18% of CM patients had preventive medication

Estimates for 1.000.000 population

About 300-500.000 have occasional headaches 100.000 have migraine 3.000 have chronic daily headache Headaches belong to primary care = GP About 10% should be referred to Neurologist About 10% should be referred to headache specialist

Advocacy for headache patients

GP Neurologists Headache specialists Patients Pharmaceutical companies Governments

Who is interested in what

Patients = suffering / QoL Doctors = patients, ethical, financial ? Companies = ethical / financial Government = ?

Unless increase of productivity is demonstrated

Headache clinics in Georgia

Population 4,435,200 53% urban 47% rural 1,080,000 inhabitants in the Capital City, Tbilisi.

Three headache clinics

Each serving a population of 10.000 people

Medical service and drug supply for 6 months for free

Duration 18 months

OUTCOMES: QoL, Satisfaction and SUSTAINABILITY

Estonia

Population 1,340,000 Intervention place city Tartu

Network of a headache clinic at the Univ. of Tartu and 7 general practitioners

Headache service completely covered by insurance

Education of GPs

Duration 12 months


Bulgaria

Population 7.351.234 Intervention place: 8 regions of the country

Network of a headache clinics at central hospitals general practitioners

Headache service completely covered by insurance

Education of GPs

Duration 24 months


Turkey

Intervention place: A large company with 5000 employees

Screen employees for headache

Offer a headache service in the company office

Complicated cases send to the university of Izmit

Duration 24 months

OUTCOMES: Decrease of lost time and increasing in productivity

Conclusions

Advocacy is need to raise awareness of Patients GP

Referral network is needed Bottom down approach Country / Region dependent

Suggestion

Identify tertiary headache clinic Usually university Headache management is more than implantation

Identify referring region GP Neurologists Patients

Identify people

Technology

Chu Fort de France !!!