Trigeminal Autonomic. Trigeminal Autonomic Cephalalgias (TACs) María-Carmen Wilson,MD

Transcription

1 Trigeminal Autonomic Cephalalgias (TACs) María-Carmen Wilson,MD Director, Headache and Facial Pain Program Ochsner, North Shore Region Trigeminal Autonomic Cephalgias gwith autonomic features gcluster gthe paroxysmal hemicranias gsunct and SUNA gcluster-tic gcph-tic ghemicrania continua 1

2 CLUSTER AND OTHER TACs Objectives To review the clinical features of cluster headache To differentiate cluster headache from other TACs To review the pathophysiology of cluster headache To review the pharmacologic and nonpharmacologic treatment of cluster headache IHS CLASSIFICATION Cluster headache n Episodic (90%) n Chronic (10%) n Cluster period lasts for more than one year without remission or remission lasts less than 14 days n Related syndromes ICHD-3. Episodic Chronic 2

3 EPIDEMIOLOGY Prevalence (0.1% 0.4%) Predominantly male (4.3-1 male to female ratio) Mean age of onset (27 31 years) Rare before the age of 10 years Fischera M. Cephalalgia ATTACK PROFILE Unilateral orbital/supraorbital/ temporal severe pain intensity Rapid onset (5 15 min) / short duration (45 90 min) range ) Agitated patient (pacing / restless) Migrainous symptoms (nausea, photophobia, phonophobia, aura) Restlessness (in contrast to migraineurs) May A. Lancet

4 AUTONOMIC FEATURES: Parasympathetic Activity/Sympathetic Impairment Conjunctival injection lacrimation Nasal congestion / rhinorrhea Partial Horner s syndrome Facial flushing / sweating edema Drummond PD. Cephalalgia 2006 CIRCANNUAL PERIODICITY 6 4

5 CIRCADIAN PERIODICITY 1-3 attacks daily (up to 8 attacks/day) Peak time periods AM PM PM REM sleep May A. Cephalalgia ASSOCIATED FEATURES High alcohol / tobacco usage Leonine facies (heavy facial features)? Peau d orange skin? Hazel-colored eyes? Duodenal ulceration? Type A personality? 5

6 Diagnostic Criteria for Episodic Cluster gattacks fulfilling criteria for cluster headache and occurring in bouts (cluster periods) gat least 2 cluster periods lasting from 7 days to 1 year (when untreated) gseparated by pain-free remission periods of one month or more Diagnostic Criteria for Chronic Cluster gattacks fulfilling criteria for cluster headache gattacks occurring without a remission period, or with remissions lasting less than one month, for at least one year 6

7 PAIN / AUTONOMIC SIGNS Trigeminovascular activation (CGRP) Cranial parasympathetic activation (VIP) Internal carotid artery dilation (cavernous) May A. Lancet 2005 PERIODICITY DYSFUNCTIONAL HYPOTHALAMIC PACEMAKER Altered secretory circadian rhythms of hypophyseal hormone systems (melatonin, testosterone, beta-endorphin, beta-lipotropin, cortisol, prolactin) Circannual and circadian rhythmicity Seasonal predilection of cluster peroids May A. Lancet

8 HYPOTHALAMUS SUPRACHIASMATIC NUCLEUS 8

9 SYMPTOMATIC CLUSTER HEADACHE Secondary Cluster Headache gintracranial large artery aneurysms gmeninigiomas gavms gpituitary macroadenomas grecurrent nasopharyngeal carcinoma gaspergilloma in sphenoid sinus gbenign posterior fossa tumor glymphomas 9

10 CLUSTER HEADACHE DIFFERENTIAL DIAGNOSIS Feature Cluster CPH EPH SUNCT Stabbing headache Trigeminal neuralgia Gender (M:F) 4:1 1:3 1:1 2.3:1 F>M F>M Attack Duration min 2-45 min 1-30 min s <1s <1s Attack Frequency 1-8/day 1-40/day 3-30/day 1/day- 30/hr Few-many Few-many Autonomic Features Alcohol PPT Indomethacin Effect +/ Goadsby PJ, Lipton RB. Brain Evidence-Based Acute Cluster Treatments Treatment Neurology 1 EFNS 2 FDA Approved 3 Sumatriptan 6 mg subcutaneously A A Yes Dihydroergotamine mesylate injection* Yes 100% O 2 15 L/min A A No Sumatriptan 20 mg nasal B A No Zolmitriptan 10 mg nasal A A-B No Zolmitriptan 10 mg oral B B No Lidocaine nasal C B No Octreotide C B No *Not readily available. A = effective; B = probably effective; C = possibly effective; EFNS = European Federation of Neurological Societies. 1. Francis GJ, et al. Neurology. 2010;75: May A, et al. Eur J Neurol. 2006;13: Tepper DE. Headache. 2015;55(5):

11 OXYGEN 100% O liters / min for 15 minutes Efficacy 70% at 15 minutes O 2 Most effective when headache at maximum intensity May delay rather than completely abort attack Main limitation is accessibility Fogan L. Arch Neurol Ekbom K,Cephalalgia 1995 Petersen AS,Cephalalgia SUMATRIPTAN SUBCUTANEOUS Effective in 90% of patients for 90% of their attacks for both acute and chronic cluster Efficacy within 15 minutes in 50% - 75% No tachyphylaxis Attack frequency not increased with prolonged use Not effective for cluster prophylaxis Gobel H et al. Neurology Ekbom K et al. Cephalalgia Cochrane,

12 Control/Supression Therapy Transitional n Prednisone (60 mg daily for 3 days, then 10 mg decrements every 3 days) n Ergotamine tartrate (1 2 mg po / suppository daily) n DHE 45 ( mg sc / im q 8 12 hrs) n Occipital nerve block Maintenance n Verapamil ( mg / day) n Methysergide (unavailable) (2 mg tid; up to 12 mg daily) n Lithium carbonate ( mg tid) n Divalproex sodium ( mg / day) Evidence-Based Preventive Cluster Treatments Treatment Neurology 1 EFNS 2 FDA Approved 3 Verapamil C A No Suboccipitalcorticosteroid injections B A No Lithium carbonate C B No Civamide B -- No Topiramate -- B No Ergotamine tartrate -- B No Valproic acid CNE C No Melatonin C C No Methysergide -- B No A = effective; B = probably effective; C = possibly effective; CNE = possibly not effective; U = uncertain. 1. Francis GJ, et al. Neurology. 2010;75: May A, et al. Eur J Neurol. 2006;13: Tepper DE. Headache. 2015;55(5):

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16 nvns Clinical Trials Study Format Key Findings Publication Royal Free Hospital (N=25) OL, case series, prevention and acute use Significant acute and prophylactic benefit Nesbitt AD, et al. Neurology PREVA (N=97) SoC comparator RCT; prevention Significant reduction in weekly cluster attacks Gaul C, et al. Cephalalgia ACT1 (N=150) Double-blind, sham controlled, RCT; acute use Significant pain reduction at 15 minutes for ech Silberstein SD, et al. Headache ACT2 (N=102) Double-blind, sham controlled, RCT; acute use Significant pain reduction at 15 minutes for ech Goadsby, PJ, et al. Cephalalgia ech = episodic cluster headache; OL = open-label; RCT = randomized controlled trial; SoC = standard of care. 31 ACT1 Study 16

17 ACT1 Study Design 1 nvns Randomization nvns Sham 1 Month 3 Months Treatment Protocol Stimulation Stimulation Stimulation 120 s 60 s 120 s 60 s 120 s Gel Gel Application Application Assessment of Response Stimulation Stimulation Stimulation 8 min 7 min 15 min 1. Silberstein SD, et al. Headache. 2016;56(8): ACT1 gone of largest randomized controlled trials of a therapeutic intervention for cluster headache gsignificant and meaningful benefit in ech, not cch patients gsafe and well tolerated ;56(8):

18 ACT2 Study Design and Stimulation Protocol 1 nvns nvns Run-in Sham nvns 1-Week Run-in Period 2-Week Double-blind Period 2-Week Open-label Period Treatment: 3 Consecutive Stimulations 120 s 120 s 120 s Treatment Protocol Optional: 3 Additional Consecutive Stimulations 120 s 120 s 120 s Initial Assessment of Pain Intensity Stimulation Stimulation Stimulation Stimulation Stimulation Stimulation 6 min 3 min 6 min 1. Goadsby PJ, et al. Cephalagia, min 35 ACT2 gin ACT2, nvns was: gsuperior to sham in ech patients, not in those with cch gsafe and well-tolerated gresults consistent with ACT1 ncan be safely and easily incorporated into existing therapeutic regimens ncan be used to treat multiple attacks per day 36 18

19 ACT1/ACT2 Highlights ACT1 ACT2 Size (safety) n=150 (ech 101; cch 49) n=102 (ech 30; cch 72) Geography 20 US centers 9 UK and EU centers Primary end point Response; first attack Pain free; all attacks Cervical treatment Right side Ipsilateral to attack Double-blind period One month (5 attacks) Two weeks (all attacks) Treatment regimen Maximum number of attacks treated per day 3 stimulations/attack 6 (3+3) stimulations/attack de Coo I, et al. Oral presentation: AHS 2017 Annual Meeting; IOR3 June 10, 2017; Boston, MA. Preva Study 19

20 PREVA Study Design 1 Baseline Randomized Ph Extension Phase SoC SoC+nVNS SoC (control) SoC+nVNS 2 weeks 4 weeks 4 weeks Treatment Protocol 3 Stimulations, 5-min Apart 3 Stimulations, 5-min Apart 16 min 7-10 hrs 16 min 1. Gaul C, et al. Cephalalgia. 2016;36(6): PREVA Patient Demographics and Baseline Characteristics SoC+nVNS 1 Characteristic (n=48) Control (n=49) Age (yrs), mean (SD) 45.4 (11.0) 42.3 (11.0) Sex (male); no. (%) 34 (71) 33 (67) Years since onset of chronic CH disorder; mean (SD) 4.7 (3.9) 5.0 (3.7) CH attack duration (min); mean (SD) With acute pharmacologic medications/oxygen 27.4 (19.8) 29.3 (29.9) Without acute pharmacologic medications/oxygen 95.2 (57.7) (66.8) Number of CH attacks in the 4 weeks before enrollment; mean (SD) 67.3 (43.6) 73.9 (115.8) CH = cluster headache; SD = standard deviation. 1. Gaul C, et al. Cephalalgia. 2016;36(6):

21 PREVA g Prophylactic nvns significantly reduced CH attack frequency within 2 weeks 1 - Mean therapeutic gain: 3.9 fewer attacks/week (39.5%) g SoC+nVNS continued to significantly reduce mean attacks/week compared with SoC alone in extension phase 2 g nvns can be easily incorporated into current chronic CH regimens 1 1. Gaul C, et al. Cephalalgia.2016;36(6): Gaul C, et al. J Headache Pain. 2017;18: nvns: a Promising Treatment for a Difficult Disorder g Cluster headache is a debilitating condition with suboptimal treatment options 1,2 g PREVA demonstrated the efficacy of nvns for prophylactic treatment of cch 3 g ACT1 and ACT2 demonstrated that nvns provides significant rapid and sustained relief of attacks in episodic cluster headache 4,5 1. Robbins MS, et al. Headache. 2016;56(7): Levin M. Headache. 2016;56(8): Gaul C, et al. Cephalalgia. 2016;36(6): Silberstein SD, et al. Headache. 2016;56(8): Goadsby PJ, et al. Poster presented at: AAN 2017 Annual Meeting; April 22-28, 2017; Boston, MA

22 INDICATIONS FOR SURGERY/PROCEDURALINTERVENTION Medically intractable Strictly unilateral cases Contraindications or intolerable side effects to medications Stable psychological and personality profiles including low addiction proneness SURGICAL PROCEDURES FOR CLUSTER HEADACHES Sensory trigeminal pathway procedures n Radiofrequency or glycerol rhizotomy n Gamma knife radiosurgery n Trigeminal root section n Other Autonomic (parasympathetic) pathway procedures. Nesbitt, Neurology 2015 Schoenen, Cephalalgia 2013 Bendersky, Pain Prac

23 ONS for Cluster Headache gfdg-pet study of 10 drug resistant chronic cluster pts gons reduced attack frequency >50% in 60% gons normalized the metabolism of several centers in the pain neuromatrix after 6-30 months Sphenopalatine Ganglion Block gsmall concentrated bundle of neurons in pterygopalatine fossa, at posterior attachment of middle turbinate gsensory (V2), parasympathetic, sympathetic Europe.tianmedical.com fibers 23

24 Sphenopalatine Ganglion Block grationale for blockage npns: Innervates meningeal vessels, nasal sinuses, eyes inhibition of parasympathetic outflow to these targets ncns: Polysynaptic connections between TNC + SSN SPG Stimulation Acute tx of Cluster 24

25 SPG stimulation induced remissions in Chronic Cluster 25

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