Manjit S Matharu

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

London UK

29 March 2014Cumbria

Unilateral head pain, predominantly V1

Excruciating

Cranial autonomic symptomsParasympathetic hyperactivity

Sympathetic deficit

Attack frequency and duration differs

Treatment responses differ

Highly disabling disorders

Cluster headache

Paroxysmal hemicrania

Short-lasting unilateral neuralgiform headache attacks

SUNCT

SUNA

Hemicrania continua

IHS CLASSIFICATION CRITERIA

• Severe

• Unilateral

• Orbital, supraorbital or temporal pain

• 15-180 minutes duration

• Attack frequency ranging from 1 every other day to 8 daily

• Associated symptoms:

-Conjunctival injection

-Lacrimation

-Ptosis

-Miosis

-Eyelid oedema

-Nasal congestion

-Rhinorrhea

-Forehead and facial sweating/redness

-Aural fullness

• Sense of restlessness or agitation during headache

• Severe

• Unilateral

• Orbital, supraorbital or temporal pain

• 2-30 minutes duration

• >5 attacks daily at least 50% of the time

• Associated symptoms:

-Conjunctival injection

-Lacrimation

-Ptosis

-Miosis

-Eyelid oedema

-Nasal congestion

-Rhinorrhea

-Forehead and facial sweating

• Stopped completely by indometacin

IHS CLASSIFICATION CRITERIA

• Unilateral trigeminal distribution pain

• 1-600 seconds duration

• Isolated stabbing, repetitive stabs or saw-tooth pattern

• Attack frequency >1daily at least 50% of the time

• Pain is accompanied by cranial autonomic features

• Cutaneous triggers (similar to trigeminal neuralgia)

• Absence of refractory period

IHS CLASSIFICATION CRITERIA

IHS CLASSIFICATION CRITERIA

A. Unilateral headache

B. Present for >3 months, with exacerbations of moderate/severe intensity

C. At least one of the following

1. At least one ipsilateral cranial autonomic symptom2. Restless or agitated

D. Complete response to therapeutic doses of indomethacin

Cluster Headache

Paroxysmal Hemicrania

SUNCT/SUNA

Attack frequency (daily) 1-8 1-40 1-200

Duration of attack 15-180mins 2-30mins 1-600secs

Pain qualitySharp,

throbbingSharp,

throbbingNeuralgiform

Pain intensity Very severe Very severe Very severe

Circadian periodicity 70% 45% Absent

Cluster Headache

Paroxysmal Hemicrania

SUNCT/SUNA

Autonomic features +++ +++ +++

Migrainous features ++ ++ +

Restless or agitated 90% 80% 65%

Aura 14% Rare Rare

Triggers• Alcohol• Cutaneous

+++-

+-

-+++

Episodic : Chronic 90:10 35:65 10:90

Cluster Headache

Paroxysmal Hemicrania

SUNCT/SUNA

Lifetime prevalence 1/1000 1/50,000 1/15,000

F:M ratio 1:2.5-7.2 1:1 1:1.5

Age• Mean• Range

306-67

375-68

4819-75

HYPOTHALAMIC DYSFUNCTION?

• Clinical features

• Neuroendocrine studies

• Genetics

• Functional imaging studies

• Structural imaging studies

• Magnetic resonance spectroscopy

• Animal experimental work

• Deep brain stimulation

HYPOTHALAMIC DYSFUNCTION

Cluster HeadachePET Study

SUNCTfMRI Study

May et al, Lancet 1998

Paroxysmal HemicraniaPET Study

Matharu et al, Ann Neurol 2006

Hemicrania ContinuaPET Study

Matharu et al, Headache 2004May et al, Ann Neurol 1999

Cranial autonomic symptoms mediated via trigemino-autonomic loop Hypothalamus is involved in mediating anti-nociceptive and autonomic responses. There are direct hypothalamic-trigeminal connections. TACs occur due to a central disinhibition of the trigeminal-autonomic reflex by the hypothalamus

Trigeminal neuralgia: 47-90%

Cohen et al, Brain 2006: 7%, dedicated trigeminal scans NOT performed

Williams et al, J Clin Neurosc 2008: 88%

Lambru et al, Abstract presented at AAN, Hawaii 2011

SUNA(N=35)

SUNCT(N=52)

Total(N=87)

Ipsilateral 15 (43%) 20 (39%) 35 (40%)

Bilateral 4 (11%) 8 (15%) 12 (14%)

Contralateral 2 (6%) 1 (2%) 3 (3%)

No loop 14 (40%) 23 (44%) 37 (43%)

IPSILATERAL LOOP : 54%

CONTRALATERAL LOOP : 17%

Williams et al, JNNP 2010Trigeminal microvascular decompression in 9 patients; 6 pain free at 2 years follow up

Medical Treatment

Abortive Therapy Preventative Therapy

Transitional Therapy

2026 26

21

78 74

57

40

0102030405060708090

Oxygen Sumatriptaninjection

Sumatriptannasal spray

Zomitriptannasal spray

% p

atie

nts

wit

h h

ead

ach

e re

spo

nse

Placebo

Treatment

Time= 15min 15 min 30 min 30 min

N= 150 134 77 69

Cohen et al, JAMA 2009; van Vliet J et al, Neurology 2003; Cittadini E et al. Arch Neurol 2006; Ekbom K et al. Acta Neurol Scand. 1993

• Randomised, controlled, double blind studies in cluster headache

**

*

*

*P<0.05

Leone M et al. Neurology. 2000.

0

0.5

1

1.5

2

2.5

3

Run in 5 days 1st week 2nd week

Verapamil 120 mg tid

Placebo* p < 0.001 vs

placebo

N=30

6/15 0/15

12/15 0/15

*

*15 15

PREVENTIVE TREATMENTS

Doses Comments

Verapamil 240-960mg/d ECG monitoring required

Lithium 400-2000mg/d(0.8-1.0mM)

Regular serum lithium levels, thyroid function and renal function checks

Methysergide 3-12mg/d European Medicines Agency restrictions:• Started and supervised by specialist

headache clinics• Severe intractable cluster headache• 6 monthly monitoring for visceral fibrosis

Topiramate 50-800mg/d

Gabapentin 900-3600mg/d

Melatonin 9-15mg/d

Valproate 600-2000mg/d

Oral corticosteroidsSuboccipital steroid injection

• 43 patients (15 CCH, 28 ECH), with >2 attacks per day• 3 suboccipital injections of cortivazol 3.75mg or placebo, 48-72 hours

apart• Primary outcome: reduction of daily attacks to mean of <2 in the 72 hours

period after the third injection

Leroux et al, Lancet Neurology 2011

• Open label study suggests efficacy of GONB (using methylprednisolone and lidocaine) in CCH

CH

Number 83

Complete response 42%

Partial response (>50%) 15%

Median duration (days) 21

Abu Bakar et al, Eur J Neurol. 2014 Feb;21(2):338-43

• Cutaneous atrophy and alopecia are well recognised complications of GONB

• Risk increases with low solubility agents (triamcinilone) and superficial injections

Lambru et al, Headache 2012

Doses Number Efficacy

Indometacin 75-300mg/d 47 100%

COX-2 Inhibitors 16 44%

Topiramate 50-400mg/d 15 46%

Greater Occipital Nerve Blocks

22 45%

Cittadini, Matharu, Goadsby AAN 2008

Doses Number Efficacy

Indometacin 75-225mg/d 39 100%

COX-2 Inhibitors:

Rofecoxib

Celecoxib

9

5

33%

60%

Topiramate 12 41%

Greater Occipital Nerve Blocks

23 35%

Cittadini et al, Brain 2010; Peres & Silberstein, Headache 2002

Doses Number Efficacy

Lamotrigine 100-600mg/d 94 70%

Oxcarbazepine 600-2400mg/d 35 63%

Topiramate 50-800mg/d 59 49%

Duloxetine 60-120mg/d 17 53%

Gabapentin 600-3600mg/d 62 31%

IV lidocaine 1.3-3.3 mg/kg/hr 32 91%

Greater occipital nerve injection

61 34%

Lambru et al. International Headache Society Congress, 2011

Destructive surgeryNo role in primary headache syndromes

Dissectional SurgeryMVD in SUNCT/SUNA

Neuromodulation Targets for stimulation• Occipital nerves

• Migraine• TAC• Hemicrania continua

• Sphenopalatine ganglion• Cluster headache

• Hypothalamus• TAC

Occipital Nerve Stimulation

• Subcutaneous leads inserted to cross greater and lesser occipital nerves

• Inserted via midline incision or lateral incision under local or general anaesthesia

• Cylindrical or paddle style electrodes

• Battery and pulse generator sited over chest or in abdomen

• Stimulation parameters adjusted so that patients experience comfortable paraesthesia

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.

Responder rates

39%

6%0%

0%

10%

20%

30%

40%

50%

AdjustableStimulation (AS)

PresetStimulation (PS)

MedicalManagement

(MM)

6.7

1.5

1

0

1

2

3

4

5

6

7

8

AdjustableStimulation (AS)

PresetStimulation (PS)

MedicalManagement

(MM)

Mean (SD) reductions in actual headache days per month

(10.0)

(4.6)

(4.2)

22.4+6.3 23.4+5.1 23.7+4.3

Advances and challenges in neurostimulation for headachesDelphine Magis and Jean Schoenen, Lancet Neurology 2012

9 medically intractable patients: 6 SUNCT, 3 SUNA

At least 5 preventives tried: lamotrigine, topiramate, gabapentin, pregabalin, carbamazepine, oxcarbazepine, mexiletine

Bilateral ONS

Follow up 38 months (24-55 months)

Prospective follow up

Lambru G et al, Pain Physician 2014;17(1):29-41.

Results

8/9 (89%) reported meaningful benefit

Benefit built up over 2 weeks – 3 months

Worsened rapidly with flat battery

1 patient developed hemicrania continua - successfully treated with indomethacin

Response to GON not predictive of response to ONS

Degree of Improvement % Number

Pain free 100% 4

Substantial 81-98 4

No benefit 0% 1

Miniaturised BION Device

Burns et al, Lancet Neurol 2008

6 medically intractable hemicrania continua patients ( one patient did not have hemicrania continua)

At least 4 groups of preventives tried:

BION

Cross-over design:

Follow up 14 months (6-21 months)

AED, Antidepressants, Calcium channel blockers, Beta-blockers, Serotonergic modulators

3 months on, 1 month off, subsequently on

Burns et al, Lancet Neurol 2008Results

5/6 (83%) reported meaningful benefit

Benefit built up over 2 days -3 months

Worsened rapidly when stimulator off

Degree of Improvement % Number

Substantial 80-95% 4

Moderate 30% 1

Worse* -20% 1

* Patient has migraine not hemicrania continua

Safety data are good but surgical revision are frequent

Low post-operative infection risk

Electrode migration – frequent, often in the first year

Electrode site pain

Myofascial incision site pain,

Muscle recruitment

Neck stiffness

Battery site pain and contact dermatitis

Despite adverse events and revisions, most undergo procedure again and recommend it to others

Definitive diagnosis of primary headache syndrome

Highly disabled

Medically intractable – failed trials (lack of efficacy or developed adverse effects) of appropriate preventives

PRIMARY HEADACHE DRUGS

Chronic migraine Beta-blocker, Tricyclics, Serotonergic antagonists , Antiepileptics (Topiramate, Sodium Valproate, Gabapentin), Calcium channel antagonists, Botox, GONB, IV DHE

Chronic cluster headache

Verapamil, Lithium, Methysergide, Topiramate, Gabapentin, Sodium Valproate, Melatonin, GONB, IV DHE

SUNCT Lamotrigine, Topiramate, Gabapentin, Pregabalin, Carbamazepine/oxcarbazepine, Duloxetine, Mexiletine, IV lidocaine, GONB

Hemicrania continua / Chronic Paroxysmal hemicrania

Indometacin, COX-II inhibitors, Topiramate, Verapamil, Gabapentin, Pregabalin, Melatonin, GONB

Anatomical and Functional Convergence of Trigeminal and Cervical input

MECHANISM OF ACTION

Bartsch et al, Brain 2002

1. Effect at Segmental level

Gate-Control Theory of Pain Activation of somatosensory afferent A-b 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

18FDG-PET study in 10 chronic cluster (CCH) patients

7 patients had ≥ 90% improvement with ONS

Magis et al, BMC Neurology 2011

Metabolic normalization in the pain neuromatrix suggests that ONS acts in CCH through slow neuromodulatory processes.

• Randomly treated attacks with full, sub-perception, or sham stimulation.

• Assessed pain relief at 15 minutes • 32 patients enrolled; 28 completed

study • Most patients (81%) experienced

transient, mild/moderate loss of sensation within distinct maxillary nerve regions; 65% of events resolved within three months.

• Repeated SPG neurostimulation may decrease the frequency of CH attacks – warrants further investigation

* P<0.0001

Schoenen J, et al. Cephalalgia. 2013.

Electrodes implanted PRECISELY into region of abnormal brain activity

Connected with wires to a battery implanted under the skin in the chest

High frequency electrical current inhibits abnormal brain activity around electrode tip

HYPOTHALAMIC DYSFUNCTION

Cluster HeadachePET Study

SUNCTfMRI Study

May et al, Lancet 1998

Paroxysmal HemicraniaPET Study

Matharu et al, Ann Neurol 2006

Hemicrania ContinuaPET Study

Matharu et al, Headache 2004May et al, Ann Neurol 1999

Advances and challenges in neurostimulation for headachesDelphine Magis and Jean Schoenen, Lancet Neurology 2012

• 64% of the patients report at least 50% improvement• Mean follow up 1.6 years• Adverse events: death (1), haemorrhage (1), TIA (1)

Patients (n) Pain free patients

At least 50% improvement in headache frequency and/or intensity

Total number improved

Total 64 27 (42%) 14 (22%) 41 (64%)

Bartsch, Cephalalgia 2008

• Median improvement in Headache load (HAL) was 79% (range 22-100%)

• Time lag to greatest response

• 5 patients showed 50% or more objective improvement in HAL at last follow up

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BASELINE 3 MONTH 6 MONTH 9 MONTH 12 MONTH 24 MONTH 36 MONTH

P1

P2

P3

P4

P5

P6

Miller et al, International Headache Society Congress, 2013

Trigeminal Autonomic Cephalalgias• Cause of significant disability thereby underlining the

importance of rapid diagnosis and treatment• Progress in unravelling the pathophysiology of these disorders• New treatments are being developed on the basis of the

anatomy and physiology of these conditions

Neuromodulation• Promising treatment for primary headache syndromes• Large randomised controlled studies are needed• Predictors of response and long-term outcome are largely

unknown• Reserved for medically-intractable and highly disabled

patients• Performed in experienced headache centres