Trigeminal Autonomic Cephalalgias Manjit S Matharu Headache Group, Institute of Neurology & The National Hospital for Neurology and Neurosurgery London UK Third Biennial Hull-BASH Headache Meeting 23rd January 2009

Trigeminal Autonomic Cephalgias Cluster Headache Paroxysmal Hemicrania SUNCT (Short-lasting Unilateral Neuralgiform headache with Conjunctival injection and Tearing) Unilateral head pain, predominantly V1 Very severe / excruciating Cranial autonomic symptoms Parasympathetic h Sympathetic i Attack frequency and duration differs Treatment responses differ

Paroxysmal Hemicrania IHS CLASSIFICATION CRITERIA 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 indomethacin

Trigeminal Autonomic Cephalgias Cluster Headache Paroxysmal Hemicrania SUNCT Attack frequency (daily) 1-8 1-40 3-200 Duration of attack 15-180mins 2-30mins 5-240secs Pain quality Sharp, throbbing Stabbing, burning Autonomic features +++ +++* Restless or agitated 90% 80% 65%

Trigeminal Autonomic Cephalgias Cluster Headache Paroxysmal Hemicrania SUNCT Migrainous features ++ + Triggers Alcohol NTG Cutaneous +++ - Circadian periodicity 70% 45% Absent Episodic : Chronic 90:10 35:65 10:90

Trigeminal Autonomic Cephalgias Cluster Headache Paroxysmal Hemicrania SUNCT Lifetime prevalence 1/1000 1/50,000* F:M ratio 1:2.5-7.2 1:1 1:1.5 Age Mean Range 30 6-67 37 5-68 48 19-75

Paroxysmal Hemicrania DIFFERENTIAL DIAGNOSIS Symptomatic Paroxysmal Hemicrania Cluster headache SUNCT syndrome Hemicrania continua

Symptomatic Paroxysmal Hemicrania Vascular ICA aneurysm Subclavian artery dilatation Parietal AVM MCA Stroke Occipital infarction Inflammatory or Infection Collagen vascular disease Ophthalmic herpes zoster Iatrogenic Surgical sympathectomy Tumours Pituitary tumours Frontal tumour Tuber cinereum hamartoma Sella turcica gangliocytoma Cavernous sinus meningioma Multiple parotid ca. Metastasis Non-Hodgkin’s lymphoma Pancoast syndrome Miscellaneous Essential thrombocythaemia Intracranial hypertension Maxillary cyst

Trigeminal Autonomic Cephalgias Pituitary 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 Cause CH N=24 PH N=3 SUNCT N=10 Vascular lesions 8 Tumours Pituitary tumour 12 7 3 10 Miscellaneous Idiopathic 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

Trigeminal Autonomic Cephalgias Pituitary and TACs 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.

Paroxysmal Hemicrania DIFFERENTIAL DIAGNOSIS Symptomatic Paroxysmal Hemicrania Cluster headache SUNCT syndrome Hemicrania continua

Cluster Headache Vs Paroxysmal Hemicrania Trial of Indomethacin if: Attack frequency > 5 daily Attack duration < 30 minutes Chronic subtypes Feature CH PH Gender (M:F) 2.5-7:1 1:1 Duration (min) 15 - 180 2 – 30 Frequency (attacks/day) 1- 8 1 - 40 Indomethacin - +

Paroxysmal Hemicrania DIFFERENTIAL DIAGNOSIS Symptomatic Paroxysmal Hemicrania Cluster headache Hemicrania continua SUNCT syndrome

Hemicrania Continua Unilateral headache Forehead, temple, orbit and occiput Continuous, moderate pain Exacerbations: lasting from 20 min to several days accompanied by autonomic and migrainous features occur in 75% Lack of precipitating factors Complete response to indomethacin

Paroxysmal Hemicrania TREATMENTS Indomethacin: Oral Indomethacin trial 25mgs tds 50mgs tds If high index of suspicion: 75mgs tds Lower doses for 3 days; maximum dose for 7 days Indotest (Intramuscular indomethacin) N=77

Paroxysmal Hemicrania INDOTEST 8.2+4.2 hr Time Indomethacin 50mgs intramuscularly 11.1+3.5 hr Time Indomethacin 100mgs intramuscularly N=77 Adapted from Antonaci et al. Headache 1998;38:122-8

Paroxysmal Hemicrania TREATMENTS Indometacin Persistence of efficacy 23% develop GI side effects with chronic treatment Other NSAIDS: Aspirin, naproxen, piroxicam COX-II Inhibitors: Celecoxib, Rofecoxib Topiramate Verapamil Greater occipital nerve injection N=77

Neuralgiform attacks with Conjunctival injection and Tearing SUNCT Short-lasting Unilateral Neuralgiform attacks with Conjunctival injection and Tearing

SUNCT IHS CLASSIFICATION CRITERIA Unilateral orbital, supraorbital or temporal pain Stabbing or pulsating pain 10-240 seconds duration Attack frequency from 3-200/day Pain is accompanied by conjunctival injection and lacrimation

Trigeminal Autonomic Cephalgias Cluster Headache Paroxysmal Hemicrania SUNCT Attack frequency (daily) 1-8 1-40 3-200 Duration of attack 15-180mins 2-30mins 5-240secs Pain quality Sharp, throbbing Stabbing, burning Autonomic features +++ +++* Restless or agitated 90% 80% 65%

Trigeminal Autonomic Cephalgias Cluster Headache Paroxysmal Hemicrania SUNCT Migrainous features ++ + Triggers Alcohol NTG Cutaneous +++ - Circadian periodicity 70% 45% Absent Episodic : Chronic 90:10 35:65 10:90

Trigeminal Autonomic Cephalgias Cluster Headache Paroxysmal Hemicrania SUNCT Lifetime prevalence 1/1000 1/50,000* F:M ratio 1:2.5-7.2 1:1 1:1.5 Age Mean Range 30 6-67 37 5-68 48 19-75

SUNCT DIFFERENTIAL DIAGNOSIS Secondary causes Posterior fossa pathology Pituitary tumours Trigeminal neuralgia Primary stabbing headache Paroxysmal hemicrania

SUNCT Vs Trigeminal Neuralgia Feature SUNCT TN Gender (M:F) 1.5:1 1:2 Site of pain V1 V2/3 Duration (secs) 5-240 <5 Autonomic features Prominent Sparse Refractory period Absent Present Trigeminal Vascular loop 7% 47-90%

SUNCT DIFFERENTIAL DIAGNOSIS Primary Stabbing Headache Stabbing or jabbing pain Ophthalmic trigeminal distribution Last a few seconds (rarely up to 1 minute) Occurs at irregular intervals Site of pain varies from attack to attack Spontaneous attacks only Autonomic features absent Attacks subside with indomethacin

MRI (including pituitary views) Pituitary hormone profile SUNCT INVESTIGATIONS MRI (including pituitary views) Pituitary hormone profile Trial of indomethacin

Greater occipital nerve injection 8 63% SUNCT TREATMENTS Doses Number Efficacy Lamotrigine 100-400mg/d 25 68% Topiramate 50-400mg/d 21 52% Gabapentin 600-3600mg/d 22 45% IV lidocaine 1.3-3.3 mg/kg/hr 11 100% Greater occipital nerve injection 8 63% Cohen et al. Migraine Trust Symposium, September 2006

SUNCT TREATMENTS 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 Cohen, Matharu, Goadsby. IHS, 2007

Hypothalamic Stimulator SUNCT TREATMENTS Hypothalamic Stimulator Leone M, Ann Neurol 2005.

Trigeminal Autonomic Cephalgias PATHOPHYSIOLOGY Cluster Headache PET Study May et al, Lancet 1998 Ipsilateral hypothalamic activation in CH

Paroxysmal Hemicrania Trigeminal Autonomic Cephalgias PATHOPHYSIOLOGY Paroxysmal Hemicrania PET Study Matharu et al, Ann Neurol 2006 Contralateral hypothalamic activation in PH

Trigeminal Autonomic Cephalgias PATHOPHYSIOLOGY SUNCT fMRI Studies May et al, Ann Neurol 1999 Sprenger et al, Pain 2005 Cohen et al, Cephalalgia 2004 Hypothalamic activation in SUNCT

Functional Neuroimaging of Primary Headaches Headache Phase Episodic and Chronic Migraine Spontaneous Episodic Migraine Spontaneous Episodic Migraine Chronic Migraine Weiller et al, Nature 1995 Afridi et al, Arch Neurol 2005 Matharu et al, Brain 2004 Specific dorsal rostral pontine activation in migraine

Trigeminal Autonomic Cephalgias PATHOPHYSIOLOGY Hemicrania Continua PET Study Posterior Hypothalamus Dorsal Rostral Pons Matharu et al, Headache 2004

Functional Neuroimaging of Primary Headaches Activation pattern in primary headaches Migraine CH SUNCT PH HC Posterior hypothalamus ü Dorsal rostral pons Primary headaches can be pathophysiologically differentiated on the basis of distinct patterns of brain activation Dorsal pontine and hypothalamic activation are markers of migrainous symptoms and cranial autonomic features, respectively These structures that likely play a pivotal role in the pathophysiology of primary headache syndromes

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