Trigeminal Autonomic Cephalalgias Manjit S Matharu Headache Group

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 23 rd January 2009

Trigeminal Autonomic Cephalgias • Cluster Headache • Paroxysmal Hemicrania • SUNCT (Short-lasting Unilateral Neuralgiform headache with Conjunctival injection and Tearing) • Unilateral head pain, predominantly V 1 • Very severe / excruciating • Cranial autonomic symptoms – Parasympathetic h – Sympathetic i • Attack frequency and duration differs • Treatment responses differ

Paroxysmal Hemicrania IHS CLASSIFICATION CRITERIA • 2 -30 minutes duration • Associated symptoms: -Conjunctival injection -Lacrimation -Ptosis -Miosis -Eyelid oedema -Nasal congestion -Rhinorrhea -Forehead and facial sweating • >5 attacks daily at least 50% of the time • Stopped completely by indomethacin • Severe • Unilateral • Orbital, supraorbital or temporal pain

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

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 Lifetime prevalence F: M ratio Paroxysmal Hemicrania SUNCT 1/1000 1/50, 000* 1: 2. 5 -7. 2 1: 1. 5 30 6 -67 37 5 -68 48 19 -75 Age • Mean • Range

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

Symptomatic Paroxysmal Hemicrania Vascular Tumours ICA aneurysm Subclavian artery dilatation Parietal AVM MCA Stroke Occipital infarction Pituitary tumours Frontal tumour Tuber cinereum hamartoma Sella turcica gangliocytoma Cavernous sinus meningioma Multiple parotid ca. Metastasis Non-Hodgkin’s lymphoma Pancoast syndrome Inflammatory or Infection Collagen vascular disease Ophthalmic herpes zoster Iatrogenic Surgical sympathectomy 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 Cause CH N=24 Vascular lesions 12 7 SUNCT N=10 3 10 7 8 Tumours PH N=3 Pituitary tumour Miscellaneous Idiopathic granulomatous hypophysitis 50% had typical presentation 33% poor response to treatments 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 microadenoma (< 1 cm 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 Feature CH PH Gender (M: F) 2. 5 -7: 1 1: 1 Duration (min) 15 - 180 2 – 30 1 - 8 1 - 40 - + Frequency (attacks/day) Indomethacin Trial of Indomethacin if: 1. 2. Attack frequency > 5 daily Attack duration < 30 minutes 3. Chronic subtypes

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 – 25 mgs tds – 50 mgs tds – If high index of suspicion: 75 mgs 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 50 mgs intramuscularly 11. 1+3. 5 hr Time Indomethacin 100 mgs 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

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

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 Lifetime prevalence F: M ratio Paroxysmal Hemicrania SUNCT 1/1000 1/50, 000* 1: 2. 5 -7. 2 1: 1. 5 30 6 -67 37 5 -68 48 19 -75 Age • Mean • Range

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

SUNCT Vs Trigeminal Neuralgia Feature Gender (M: F) Site of pain Duration (secs) Autonomic features Refractory period Trigeminal Vascular loop SUNCT TN 1. 5: 1 1: 2 V 1 V 2/3 5 -240 <5 Prominent Sparse Absent Present 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

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

SUNCT TREATMENTS Doses Number Efficacy Lamotrigine 100 -400 mg/d 25 68% Topiramate 50 -400 mg/d 21 52% Gabapentin 600 -3600 mg/d 22 45% IV lidocaine 1. 3 -3. 3 mg/kg/hr 11 100% 8 63% Greater occipital nerve injection 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

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

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

Trigeminal Autonomic Cephalgias PATHOPHYSIOLOGY SUNCT f. MRI 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 Weiller et al, Nature 1995 Afridi et al, Arch Neurol 2005 Chronic Migraine 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 Dorsal rostral pons ü SUNCT PH HC ü Posterior hypothalamus CH ü ü • 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