Trigeminal Autonomic Cephalalgias Manjit S Matharu Headache Group, Institute of Neurology & The National Hospital for Neurology and Neurosurgery LondonUK

Trigeminal Autonomic CephalalgiasTrigeminal Autonomic Cephalalgias

Manjit S MatharuManjit S Matharu

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

London London UKUK

Third Biennial Hull-BASH Headache Meeting 23rd January 2009

Trigeminal Autonomic CephalgiasTrigeminal Autonomic CephalgiasTrigeminal Autonomic CephalgiasTrigeminal Autonomic Cephalgias

• Unilateral head pain, Unilateral head pain, predominantly Vpredominantly V11

• Very severe / excruciatingVery severe / excruciating

• Cranial autonomic symptomsCranial autonomic symptoms– Parasympathetic Parasympathetic – Sympathetic Sympathetic

• Attack frequency and duration Attack frequency and duration differsdiffers

• Treatment responses differTreatment responses differ

• Unilateral head pain, Unilateral head pain, predominantly Vpredominantly V11

• Very severe / excruciatingVery severe / excruciating

• Cranial autonomic symptomsCranial autonomic symptoms– Parasympathetic Parasympathetic – Sympathetic Sympathetic

• Attack frequency and duration Attack frequency and duration differsdiffers

• Treatment responses differTreatment responses differ

• Cluster HeadacheCluster Headache

• Paroxysmal HemicraniaParoxysmal Hemicrania

• SUNCT (Short-lasting SUNCT (Short-lasting Unilateral Neuralgiform Unilateral Neuralgiform headache with Conjunctival headache with Conjunctival injection and Tearing)injection and Tearing)

• Cluster HeadacheCluster Headache

• Paroxysmal HemicraniaParoxysmal Hemicrania

• SUNCT (Short-lasting SUNCT (Short-lasting Unilateral Neuralgiform Unilateral Neuralgiform headache with Conjunctival headache with Conjunctival injection and Tearing)injection and Tearing)

Paroxysmal HemicraniaParoxysmal Hemicrania IHS CLASSIFICATION CRITERIAIHS CLASSIFICATION CRITERIA

Paroxysmal HemicraniaParoxysmal Hemicrania IHS CLASSIFICATION CRITERIAIHS CLASSIFICATION CRITERIA

• Severe Severe

• Unilateral Unilateral

• Orbital, supraorbital or temporal Orbital, supraorbital or temporal painpain

• 2-30 minutes duration2-30 minutes duration

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

• Associated symptoms:Associated symptoms:-Conjunctival injection-Conjunctival injection-Lacrimation-Lacrimation-Ptosis-Ptosis-Miosis-Miosis-Eyelid oedema-Eyelid oedema-Nasal congestion-Nasal congestion-Rhinorrhea-Rhinorrhea-Forehead and facial -Forehead and facial

sweatingsweating

• Stopped completely by Stopped completely by indomethacinindomethacin


Cluster

HeadacheParoxysmal Hemicrania

SUNCT

Attack frequency (daily) 1-8 1-40 3-200

Duration of attack 15-180mins 2-30mins 5-240secs

Pain qualitySharp,

throbbingSharp,

throbbingStabbing, burning

Autonomic features +++ +++ +++*

Restless or agitated 90% 80% 65%


Cluster Cluster

HeadacheHeadacheParoxysmal Paroxysmal HemicraniaHemicrania

SUNCTSUNCT

Migrainous features ++ ++ +

Triggers• Alcohol• NTG• Cutaneous

++++++

-

++-

--

+++

Circadian periodicity 70% 45% Absent

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


Cluster


SUNCT

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

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

Age• Mean• Range

306-67

375-68

4819-75

Paroxysmal HemicraniaParoxysmal HemicraniaDIFFERENTIAL DIAGNOSISDIFFERENTIAL DIAGNOSIS


• Symptomatic Paroxysmal HemicraniaSymptomatic Paroxysmal Hemicrania

• Cluster headacheCluster headache

• SUNCT syndrome SUNCT syndrome

• Hemicrania continuaHemicrania continua





Symptomatic Paroxysmal HemicraniaSymptomatic Paroxysmal HemicraniaSymptomatic Paroxysmal HemicraniaSymptomatic Paroxysmal Hemicrania

VascularVascularICA aneurysmICA aneurysm

Subclavian artery dilatationSubclavian artery dilatation

Parietal AVMParietal AVM

MCA StrokeMCA Stroke

Occipital infarctionOccipital infarction

Inflammatory or InfectionInflammatory or InfectionCollagen vascular diseaseCollagen vascular disease

Ophthalmic herpes zosterOphthalmic herpes zoster

IatrogenicIatrogenicSurgical sympathectomySurgical sympathectomy

TumoursTumoursPituitary tumoursPituitary tumours

Frontal tumourFrontal tumour

Tuber cinereum hamartomaTuber cinereum hamartoma

Sella turcica gangliocytomaSella turcica gangliocytoma

Cavernous sinus meningiomaCavernous sinus meningioma

Multiple parotid ca. MetastasisMultiple parotid ca. Metastasis

Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma

Pancoast syndromePancoast syndrome

MiscellaneousMiscellaneousEssential thrombocythaemiaEssential thrombocythaemia

Intracranial hypertensionIntracranial hypertension

Maxillary cystMaxillary cyst

Trigeminal Autonomic CephalgiasPituitary and TACs

Trigeminal Autonomic CephalgiasPituitary and TACs

Cittadini and Matharu, Neurologist 2009

Literature review of symptomatic TACs published between 1975-2007

Identified 37 symptomatic cases of CH

50% had typical presentation

33% poor response to treatments

Cittadini and Matharu, Neurologist 2009

Literature review of symptomatic TACs published between 1975-2007

Identified 37 symptomatic cases of CH

50% had typical presentation

33% poor response to treatments

Cause CH

N=24

PH

N=3

SUNCT

N=10

Vascular lesions 8

TumoursPituitary tumour

12

7 3

10

7

MiscellaneousIdiopathic granulomatous hypophysitis

4

1

Trigeminal Autonomic Cephalgias Pituitary and TACs


Levy et al, Brain 2005• 84 pituitary tumour patients with headaches studied• 9% had TACs• Functioning adenomas more likely to cause TACs• Investigate all TAC patients for pituitary tumours?

• Prevalence of pituitary tumours in TACs is unknown• 1 in 10 of the population have an incidental pituitary micro-

adenoma (< 1cm diameter) on routine MRI • 1 in 500 have a macro-adenoma

Levy et al, Brain 2005• 84 pituitary tumour patients with headaches studied• 9% had TACs• Functioning adenomas more likely to cause TACs• Investigate all TAC patients for pituitary tumours?

• Prevalence of pituitary tumours in TACs is unknown• 1 in 10 of the population have an incidental pituitary micro-

adenoma (< 1cm diameter) on routine MRI • 1 in 500 have a macro-adenoma



• Difficult to draw up definitive guidelines from retrospective reviews

• Pituitary imaging should be performed in:– Atypical phenotype/abnormal examination

– Treatment resistant cases

• Do typical cases require neuroimaging? – Increases likelihood of identifying incidental lesion

• Implication of data on pituitary lesions?– Need prospective community based study in CH patients

– Carefully elicit symptoms related to pituitary disease in all TAC patients but only perform MRI scans of the pituitary and a basal pituitary hormone profile in:

• patients with atypical features (including pituitary related symptoms)

• abnormal examination

• poor response to appropriate treatments.

• Difficult to draw up definitive guidelines from retrospective reviews

• Pituitary imaging should be performed in:– Atypical phenotype/abnormal examination

– Treatment resistant cases

• Do typical cases require neuroimaging? – Increases likelihood of identifying incidental lesion

• Implication of data on pituitary lesions?– Need prospective community based study in CH patients

– Carefully elicit symptoms related to pituitary disease in all TAC patients but only perform MRI scans of the pituitary and a basal pituitary hormone profile in:

• patients with atypical features (including pituitary related symptoms)

• abnormal examination

• poor response to appropriate treatments.











Cluster Headache Vs Paroxysmal HemicraniaCluster Headache Vs Paroxysmal HemicraniaCluster Headache Vs Paroxysmal HemicraniaCluster Headache Vs Paroxysmal Hemicrania

Trial of Indomethacin if:Trial of Indomethacin if:

1.1. Attack frequency Attack frequency >> 5 daily 5 daily

2.2. Attack duration Attack duration << 30 minutes 30 minutes

3.3. Chronic subtypesChronic subtypes

FeatureFeature CHCH PHPH

Gender (M:F)Gender (M:F) 2.5-7:12.5-7:1 1:11:1

Duration (min)Duration (min) 15 - 18015 - 180 2 – 302 – 30

Frequency (attacks/day)Frequency (attacks/day) 1- 81- 8 1 - 401 - 40

IndomethacinIndomethacin -- ++






• SUNCT syndromeSUNCT syndrome




• SUNCT syndromeSUNCT syndrome

Hemicrania ContinuaHemicrania ContinuaHemicrania ContinuaHemicrania Continua

• Unilateral headacheUnilateral headache

• Forehead, temple, orbit and occiputForehead, temple, orbit and occiput

• Continuous, moderate painContinuous, moderate pain

• Exacerbations:Exacerbations:

– lasting from 20 min to several days lasting from 20 min to several days

– accompanied by autonomic and migrainous featuresaccompanied by autonomic and migrainous features

– occur in 75%occur in 75%

• Lack of precipitating factorsLack of precipitating factors

• Complete response to indomethacinComplete response to indomethacin

• Unilateral headacheUnilateral headache

• Forehead, temple, orbit and occiputForehead, temple, orbit and occiput

• Continuous, moderate painContinuous, moderate pain

• Exacerbations:Exacerbations:

– lasting from 20 min to several days lasting from 20 min to several days

– accompanied by autonomic and migrainous featuresaccompanied by autonomic and migrainous features

– occur in 75%occur in 75%

• Lack of precipitating factorsLack of precipitating factors

• Complete response to indomethacinComplete response to indomethacin

Paroxysmal Hemicrania Paroxysmal Hemicrania TREATMENTSTREATMENTS


N=77

Indomethacin:Indomethacin:

• Oral Indomethacin trialOral Indomethacin trial

– 25mgs tds25mgs tds


– If high index of suspicion: 75mgs tds If high index of suspicion: 75mgs tds

– Lower doses for 3 days; maximum dose Lower doses for 3 days; maximum dose for for 7 days7 days

• Indotest (Intramuscular indomethacin)Indotest (Intramuscular indomethacin)

Indomethacin:Indomethacin:

• Oral Indomethacin trialOral Indomethacin trial



– If high index of suspicion: 75mgs tds If high index of suspicion: 75mgs tds

– Lower doses for 3 days; maximum dose Lower doses for 3 days; maximum dose for for 7 days7 days

• Indotest (Intramuscular indomethacin)Indotest (Intramuscular indomethacin)

Paroxysmal Hemicrania Paroxysmal Hemicrania INDOTESTINDOTEST

Paroxysmal Hemicrania Paroxysmal Hemicrania INDOTESTINDOTEST

N=77

Time

Indomethacin 50mgs intramuscularly

8.2+4.2 hr

Indomethacin 100mgs intramuscularly

11.1+3.5 hr

Time

Adapted from Antonaci et al. Headache 1998;38:122-8



N=77

• IndometacinIndometacin

Persistence of efficacyPersistence of efficacy

23% develop GI side effects with chronic treatment23% develop GI side effects with chronic treatment

• Other NSAIDSOther NSAIDS: : Aspirin, naproxen, piroxicamAspirin, naproxen, piroxicam

• COX-II InhibitorsCOX-II Inhibitors: : Celecoxib, RofecoxibCelecoxib, Rofecoxib

• TopiramateTopiramate

• VerapamilVerapamil

• Greater occipital nerve injectionGreater occipital nerve injection

• IndometacinIndometacin

Persistence of efficacyPersistence of efficacy

23% develop GI side effects with chronic treatment23% develop GI side effects with chronic treatment

• Other NSAIDSOther NSAIDS: : Aspirin, naproxen, piroxicamAspirin, naproxen, piroxicam

• COX-II InhibitorsCOX-II Inhibitors: : Celecoxib, RofecoxibCelecoxib, Rofecoxib

• TopiramateTopiramate

• VerapamilVerapamil

• Greater occipital nerve injectionGreater occipital nerve injection

SUNCT SUNCT SUNCT SUNCT

SShort-lasting hort-lasting

UUnilateral nilateral

NNeuralgiform attacks with euralgiform attacks with

CConjunctival injection and onjunctival injection and

TTearingearing

SUNCT SUNCT IHS CLASSIFICATION CRITERIAIHS CLASSIFICATION CRITERIA

SUNCT SUNCT IHS CLASSIFICATION CRITERIAIHS CLASSIFICATION CRITERIA

• Unilateral orbital, supraorbital or temporal painUnilateral orbital, supraorbital or temporal pain

• Stabbing or pulsating painStabbing or pulsating pain

• 10-240 seconds duration10-240 seconds duration

• Attack frequency from 3-200/dayAttack frequency from 3-200/day

• Pain is accompanied by conjunctival injection and lacrimationPain is accompanied by conjunctival injection and lacrimation

• Unilateral orbital, supraorbital or temporal painUnilateral orbital, supraorbital or temporal pain

• Stabbing or pulsating painStabbing or pulsating pain

• 10-240 seconds duration10-240 seconds duration

• Attack frequency from 3-200/dayAttack frequency from 3-200/day

• Pain is accompanied by conjunctival injection and lacrimationPain is accompanied by conjunctival injection and lacrimation


Cluster


SUNCT

Attack frequency (daily) 1-8 1-40 3-200

Duration of attack 15-180mins 2-30mins 5-240secs

Pain qualitySharp,

throbbingSharp,

throbbingStabbing, burning

Autonomic features +++ +++ +++*

Restless or agitated 90% 80% 65%


Cluster Cluster

HeadacheHeadacheParoxysmal Paroxysmal HemicraniaHemicrania

SUNCTSUNCT

Migrainous features ++ ++ +

Triggers• Alcohol• NTG• Cutaneous

++++++

-

++-

--

+++

Circadian periodicity 70% 45% Absent

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


Cluster


SUNCT

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

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

Age• Mean• Range

306-67

375-68

4819-75

SUNCT SUNCT DIFFERENTIAL DIAGNOSISDIFFERENTIAL DIAGNOSIS


• Secondary causesSecondary causes

– Posterior fossa pathologyPosterior fossa pathology

– Pituitary tumoursPituitary tumours

• Trigeminal neuralgiaTrigeminal neuralgia

• Primary stabbing headachePrimary stabbing headache

• Paroxysmal hemicraniaParoxysmal hemicrania

SUNCT Vs Trigeminal NeuralgiaSUNCT Vs Trigeminal NeuralgiaSUNCT Vs Trigeminal NeuralgiaSUNCT Vs Trigeminal Neuralgia

FeatureFeature SUNCTSUNCT TNTN

Gender (M:F)Gender (M:F) 1.5:11.5:1 1:21:2

Site of painSite of pain VV11 VV2/32/3

Duration (secs)Duration (secs) 5-2405-240 <5<5

Autonomic featuresAutonomic features ProminentProminent SparseSparse

Refractory periodRefractory period AbsentAbsent PresentPresent

Trigeminal Vascular loopTrigeminal Vascular loop 7%7% 47-90%47-90%



• Stabbing or jabbing painStabbing or jabbing pain• Ophthalmic trigeminal Ophthalmic trigeminal

distributiondistribution• Last a few seconds (rarely Last a few seconds (rarely

up to 1 minute)up to 1 minute)• Occurs at irregular Occurs at irregular

intervalsintervals

• Site of pain varies from Site of pain varies from

attack to attackattack to attack• Spontaneous attacks onlySpontaneous attacks only• Autonomic features Autonomic features

absentabsent• Attacks subside with Attacks subside with

indomethacinindomethacin

Primary Stabbing HeadachePrimary Stabbing Headache

SUNCT SUNCT INVESTIGATIONSINVESTIGATIONS

SUNCT SUNCT INVESTIGATIONSINVESTIGATIONS

MRI (including pituitary views)MRI (including pituitary views)

Pituitary hormone profilePituitary hormone profile

Trial of indomethacinTrial of indomethacin

SUNCT SUNCT TREATMENTSTREATMENTS


DosesDoses NumberNumber EfficacyEfficacy

LamotrigineLamotrigine 100-400mg/d100-400mg/d 2525 68%68%

TopiramateTopiramate 50-400mg/d50-400mg/d 2121 52%52%

GabapentinGabapentin 600-3600mg/d600-3600mg/d 2222 45%45%

IV lidocaineIV lidocaine 1.3-3.3 mg/kg/hr1.3-3.3 mg/kg/hr 1111 100%100%

Greater occipital Greater occipital nerve injectionnerve injection

88 63%63%

Cohen et al. Migraine Trust Symposium, September 2006



Cohen, Matharu, Goadsby. IHS, 2007

Topiramate in SUNCT

• Cross-over RCT of topiramate 50 bd vs placebo• Primary endpoint was reduction in attack frequency by 50% • Secondary endpoint was reduction in ‘attack load’ • N=5

Results•Beneficial in 2 – one had complete cessation of attacks, and one had a 71% reduction in attack load. •Placebo response in one•Two had no benefit



Hypothalamic StimulatorHypothalamic Stimulator

Leone M, Leone M, Ann NeurolAnn Neurol 2005. 2005.

Trigeminal Autonomic Cephalgias Trigeminal Autonomic Cephalgias PATHOPHYSIOLOGYPATHOPHYSIOLOGY


Cluster HeadachePET Study

May et al, Lancet 1998

Ipsilateral hypothalamic activation in CH



Paroxysmal HemicraniaPET Study

Matharu et al, Ann Neurol 2006

Contralateral hypothalamic activation in PH



SUNCTfMRI Studies

May et al, Ann Neurol 1999 Cohen et al, Cephalalgia 2004Sprenger et al, Pain 2005

Hypothalamic activation in SUNCT

Functional Neuroimaging of Primary HeadachesHeadache Phase

Functional Neuroimaging of Primary HeadachesHeadache Phase

Episodic and Chronic MigraineEpisodic and Chronic MigraineEpisodic and Chronic MigraineEpisodic and Chronic Migraine

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



Hemicrania ContinuaHemicrania ContinuaHemicrania ContinuaHemicrania ContinuaPET Study

Matharu et al, Headache 2004

Posterior Hypothalamus Dorsal Rostral Pons

• Primary headaches can be pathophysiologically differentiated on the basis of Primary headaches can be pathophysiologically differentiated on the basis of distinct patterns of brain activationdistinct patterns of brain activation

• Dorsal pontine and hypothalamic activation are markers of migrainous Dorsal pontine and hypothalamic activation are markers of migrainous symptoms and cranial autonomic features, respectivelysymptoms and cranial autonomic features, respectively

•

• These structures that likely play a pivotal role in the pathophysiology of These structures that likely play a pivotal role in the pathophysiology of primary headache syndromesprimary headache syndromes

• Primary headaches can be pathophysiologically differentiated on the basis of Primary headaches can be pathophysiologically differentiated on the basis of distinct patterns of brain activationdistinct patterns of brain activation

• Dorsal pontine and hypothalamic activation are markers of migrainous Dorsal pontine and hypothalamic activation are markers of migrainous symptoms and cranial autonomic features, respectivelysymptoms and cranial autonomic features, respectively

•

• These structures that likely play a pivotal role in the pathophysiology of These structures that likely play a pivotal role in the pathophysiology of primary headache syndromesprimary headache syndromes

Activation pattern in primary headachesActivation pattern in primary headachesActivation pattern in primary headachesActivation pattern in primary headaches

Functional Neuroimaging of Primary HeadachesFunctional Neuroimaging of Primary HeadachesFunctional Neuroimaging of Primary HeadachesFunctional Neuroimaging of Primary Headaches

MigraineMigraine CHCH SUNCTSUNCT PHPH HCHC

Posterior hypothalamus

Dorsal rostral pons

““Pain is a more Pain is a more terrible lord of terrible lord of mankind than mankind than even death itself” even death itself”

Albert SchweitzerAlbert Schweitzer

““Pain is a more Pain is a more terrible lord of terrible lord of mankind than mankind than even death itself” even death itself”

Albert SchweitzerAlbert Schweitzer

Documents

Trigeminal Autonomic Cephalalgias Manjit S Matharu Headache Group, Institute of Neurology & The National Hospital for Neurology and Neurosurgery LondonUK